CN115798673B - Combined drug recommendation method and device - Google Patents
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Abstract
The invention discloses a combined drug recommendation method, which comprises the following steps: judging the combination mode of two single-component medicines in the to-be-detected combined medicine for each double-medicine combination; if the combination is non-constant proportion combination, acquiring a first characterization parameter which characterizes an actual drug effect corresponding to each concentration combination of the combined drug to be tested and an actual drug effect of each of the two single-component drugs under the independent action of the corresponding concentrations; determining a second characterization parameter S characterizing the degree of synergy of each concentration combination based on a preset evaluation model Loewe And a third characterization parameter S Bliss The method comprises the steps of carrying out a first treatment on the surface of the Determining a fourth characterization parameter which characterizes the synergy degree of each combination drug based on the first characterization parameter, the second characterization parameter and the third characterization parameter; obtaining a sixth characterization parameter for characterizing the sensitivity of the combined drug to be tested; and screening out target combined medicines from all the combined medicines to be tested based on the fourth characterization parameter and the sixth characterization parameter. Correspondingly, a recommending device is also provided.
Description
Technical Field
The invention relates to the field of biological medicine, in particular to a combined medication recommending method and a device thereof.
Background
Along with the rapid development of the life medicine industry, preclinical detection and prognosis means for malignant tumors are gradually enriched. At present, cancer can be diagnosed from the gene level, and the progress of tumor, the degree of malignancy, etc. can be detected. Common genetic diagnostics include EGFR, HER-2, K-ras assays, and the like. Disease models at various cellular, organoid and animal levels are also becoming important preclinical diagnostic models for in vitro drug susceptibility testing, achieving in vitro diagnosis and efficacy assessment of malignant tumors to some extent. At present, based on basic research of the disease models, single-drug treatment is mostly adopted to evaluate the drug effect in vitro. However, in modern medical practice, single-drug therapy is rarely used, and multi-drug combination (or called combination) is often used. The reasons for multi-drug combination application mainly comprise: 1) Since cancer is a complex disease, regulated by a variety of signals and heterogeneous. For a certain type of cancer of different individuals, no medicine with wide curative effect exists at present, and drug resistance is often generated after the medicine is treated, so that the cancer recurs and progresses, and finally the patient dies. 2) The indications and therapeutic window of any drug are limited and have different properties and different degrees of toxic side effects. Therefore, the purpose of the combined drug is to obtain the maximum therapeutic effect and reduce the toxic and side effects to the greatest extent, so the combined drug is one of the most commonly used and effective therapeutic means in the modern medical practice at present, and compared with the single drug, the combined drug can enhance the drug effect on the basis of high-efficiency anticancer, reduce the toxic and side effects and reduce the drug resistance development, thereby improving the prognosis of patients to a certain extent. However, the evaluation criteria for in vitro combination studies are different, different detection and analysis methods may draw different conclusions, and how to scientifically evaluate the effect of the combination becomes a challenge. There is no simple and general method for evaluating the effect of combined administration. When administered in combination, interactions between the drugs, e.g., interactions between drug effects, e.g., When drugs with different or similar action mechanisms are combined, the enhancement or weakening of the drug effect is also called as synergistic effect; whereas the sensitivity of the combination, i.e. the level of therapeutic response, is generally measured in terms of the percentage of cellular activity or growth inhibition. The ideal case of combination administration would be to achieve therapeutic effects at reduced doses, thereby minimizing the toxicity and other side effects associated with high-dose single agents. Sensitivity and synergy are therefore two important indicators for assessing combination dosing. The combined drug synergistic effect evaluation model widely adopted at present comprises the following steps: chou-Talalay merge index CI (Combination index) method, independent model Bliss independence of Bliss, equivalent line addition model Loewe additivity, HAS (Highest single sgent) or ZIP (). However, model selection has become a personal preference due to the lack of practical guidelines, with no clear reason. However, the current common method for evaluating the combined drug only considers the cooperativity of the drug combination and neglects the sensitivity of the drug combination, which can lead to screening false positive drug combinations. It may even occur that a combination of drugs is classified as synergistic according to one model, but antagonistic according to another model, for which it is difficult to choose from. In order to avoid selecting models, however, it has been proposed to use all models for evaluation, for example: zheng Yushu et al, on Nucleic Acids Research, published a "one more comprehensive drug sensitivity data storage and analysis portal" that proposes, for sensitivity, using a dose response curve of IC50 and RI values to describe sensitivity of a single drug, whereas sensitivity of co-administration (or drug combination) uses the CSS (Combination Sensitivity Score) index, i.e., log of the combined dose response curve when one of the two drugs is fixed at its IC50 concentration 10 -transformed normalized area to characterize overall drug response efficacy; aiming at the synergism of the combined drug, a widely adopted combined drug synergistic effect evaluation model at present is proposed: bliss, loewe, HSA and ZIP, the 4 principal mathematical models, provide a score visualization in the dose-response matrix and provide a synergy score called "S score", which is based onDifferences between CSS and RI scores for the combination drug and the single drug, and combination drug with zero synergy score were considered additive, with positive synergy score indicating synergy and negative synergy score indicating antagonism. To ensure clinical transformation of drug combinations, it is advocated to use all the main co-score indicators, i.e. only four models consider co-ordination, and to judge the interaction between the drugs of the combination as co-ordination, and correspondingly, four models consider antagonism.
However, the four mathematical models described above are actually based on different mathematical assumptions, e.g. the Bliss model assumes that the probability of drug non-interactions is independent, while the Loewe model assumes that the efficacy of the non-synergistic drug combination is the same as that of the drug combination itself, and the ZIP model can be considered as an Ensembl model, combining Bliss and Loewe assumptions, the HSA model simply shows that drug combination improves patient survival compared to monotherapy. Thus, the four models do not always produce consistent results, i.e. the probability of simultaneous recognition of synergy is very low, i.e. the accuracy is low, thus causing problems of excessive screening.
Disclosure of Invention
The invention aims to provide a combined drug recommendation method and a device thereof, which partially solve or alleviate the defects in the prior art and can screen out the truly effective optimal drug combination.
In order to solve the technical problems, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a method for recommending combination medication, comprising the steps of: judging a combination mode between two single-component medicines in each combined medicine to be detected, wherein the combined medicine is a double-medicine combination; the combination mode comprises the following steps: the two single component medicines are combined in a non-constant proportion; if the combination is non-constant proportion combination, acquiring a first characterization parameter for representing the actual drug effect corresponding to each concentration combination of the combined drug to be tested; respectively obtaining the actual values of the two single component drugs representing the combined drug to be tested under the independent action of the corresponding concentrationsA first characterization parameter of the drug effect; determining a second characterization parameter S for characterizing the synergy degree of each concentration combination of each to-be-tested combined drug based on a preset first evaluation model and a second evaluation model and combining the first characterization parameter Loewe And a third characterization parameter S Bliss The method comprises the steps of carrying out a first treatment on the surface of the The first evaluation model and the second evaluation model are a Loewe model and a Bliss model respectively; determining a fourth characterization parameter which characterizes the synergy degree of the combined drug based on the first characterization parameter, the second characterization parameter and the third characterization parameter; obtaining a sixth characterization parameter for characterizing the sensitivity of the combined drug to be tested; and screening out the combined drug with the maximum fourth characterization parameter and the maximum sixth characterization parameter from all the combined drugs to be tested as recommended target combined drug.
In some embodiments of the present invention, the combination mode further includes a constant proportion combination, where the constant proportion combination refers to that the concentration of one single component drug in the combination to be tested is fixed and the combination is used with another single component drug that changes in a gradient within a first preset concentration range; alternatively, the two single component drugs are combined in a constant concentration ratio.
In some embodiments of the present invention, the method for recommending combination medication further includes the steps of: if the combination mode of the two single-component drugs in the combined drug to be tested is judged to be the combination mode with a constant proportion, a seventh characterization parameter for representing the actual drug effect of the combined drug to be tested is obtained; respectively obtaining seventh characterization parameters for characterizing respective actual drug use effects of the two single-component drugs; judging whether the seventh characterization parameter of the combined drug to be tested is larger than the seventh characterization parameter corresponding to each of the two single-component drugs, and if so, taking the combined drug as a recommended target combined drug.
In some embodiments of the present invention, the step of determining a fourth characterization parameter that characterizes a degree of synergy of each concentration combination based on the first characterization parameter, the second characterization parameter, and the third characterization parameter, specifically includes the steps of: judging whether the first characterization parameter corresponding to each concentration combination is larger than that of two single-component medicines respectively in the corresponding stateThe minimum value and the maximum value of the first characterization parameters under the concentration action are smaller than the minimum value and the maximum value, and if the minimum value and the maximum value are larger than the minimum value and smaller than the maximum value, a first quantized value is given to a fifth characterization parameter for representing the synergy degree of the concentration combination; if the minimum value of the first characterization parameters corresponding to the two single-component medicines is smaller than the minimum value of the first characterization parameters, a second quantized value is given to the fifth characterization parameters; if the value is larger than the maximum value in the first characterization parameters corresponding to the two single-component medicines, judging the second characterization parameters S Loewe And the third characterization parameter S Bliss If the maximum value of the fifth characterization parameter is smaller than a first preset threshold value, a third quantization value is given to the fifth characterization parameter; if the second characteristic parameter S is larger than the first preset threshold value, judging the second characteristic parameter S Loewe And the third characterization parameter S Bliss Whether the minimum value of (2) is smaller than a second preset threshold value; if the first characteristic parameter is smaller than the second preset threshold value, a fourth quantized value is given to the fifth characteristic parameter, and if the first characteristic parameter is larger than the second preset threshold value, a fifth quantized value is given to the fifth characteristic parameter; and calculating the average value of the fifth characterization parameters corresponding to all concentration combinations of the combined drug to be tested, and taking the average value as the quantized value of the fourth characterization parameters.
In some embodiments of the present invention, the first evaluation model is: s is S Loewe ＝yc-y Loewe The method comprises the steps of carrying out a first treatment on the surface of the Wherein yc is a first characterization parameter of the actual drug effect of the combined drug to be tested under the current concentration combination; y is Loewe A first characterization parameter, y, of the expected drug effect of the combination at the current concentration combination Loewe The conditions are to be satisfied:x 1 the concentration corresponding to a single component drug in the combined drug for the current concentration combination,an inverse function of the dose-response curve for the single component drug alone; x is x 2 Another single component drug in the combination which is the current concentration combinationCorresponding concentration->Is the inverse of the dose-response curve of the individual action of the further single component drug.
In some embodiments of the invention, the second evaluation model is: s is S Bliss ＝yc-[Y 1 (X 1 )+Y 2 (X 2 )-Y 1 (X 1 )Y 2 (X 2 )]The method comprises the steps of carrying out a first treatment on the surface of the Wherein yc is a first characterization parameter of the actual drug effect of the combined drug to be tested under the current concentration combination; y is Y 1 (X 1 ) For a single component of the combination 1 A first characterization parameter of the actual drug effect at the concentration alone; y is Y 2 (X 2 ) For another single component in the combination 2 A first characterization parameter of the actual drug effect at the concentration alone.
In some embodiments of the present invention, the calculation formula of the sixth characterization parameter is: wherein CSS 1 、CSS 2 The concentration of any one of the two single-component medicines is anchored to a first preset concentration, and the sensitivity coefficient under the combined action of the two single-component medicines with the concentration which changes in a gradient within a preset range is used.
In some embodiments of the invention, the first predetermined concentration is the IC50 concentration of the single component drug alone.
In some embodiments of the present invention, the step of screening out the combination with the maximum fourth characterization parameter and the maximum sixth characterization parameter as the recommended combination specifically includes the steps of: judging whether the average value is larger than a third preset threshold value, if so, obtaining a combined medicine subset to be tested; and selecting the combined drug with the largest average value in the combined drug subset and the largest sixth characterization parameter as the recommended combined drug.
Based on the above-mentioned recommendation method of combined medication, the invention also provides a recommendation device of combined medication, which comprises: the first analysis module is used for judging the combination mode between two single-component medicines in each to-be-detected combined medicine for the combination of the two medicines; the combination mode comprises non-constant proportion combination and constant proportion combination; wherein, the constant proportion combination means that two single-component medicines in the combined medicine to be detected are combined in a first preset concentration combination mode; the first preset concentration combination mode comprises the following steps: the concentration of one single-component medicine is fixed and is combined with the other single-component medicine which changes in a gradient way within a first preset concentration range; alternatively, the two single component drugs are combined in a constant concentration ratio; the non-constant proportion combination means that when the combined medicine to be detected is a double medicine combination, two single component medicines are combined in a second preset concentration combination mode, wherein the second preset concentration combination mode comprises that the two single component medicines are combined in irregular concentration; the first data acquisition module is used for acquiring a first characterization parameter for characterizing an actual drug effect corresponding to each concentration combination of the combined drug to be tested when judging that the combination is combined in a non-constant proportion; the second data acquisition module is used for respectively acquiring first characterization parameters for characterizing actual drug use effects of two single-component drugs in the combined drug to be tested under the independent action of corresponding concentrations when judging that the two single-component drugs are combined in a non-constant proportion; the second analysis module is used for determining a second characterization parameter S for characterizing the synergy degree of each concentration combination of the combined drug to be tested based on a preset first evaluation model and a second evaluation model and combining the first characterization parameters Loewe And a third characterization parameter S Bliss The method comprises the steps of carrying out a first treatment on the surface of the The first evaluation model and the second evaluation model are a Loewe model and a Bliss model respectively; the third analysis module is used for determining a fourth characterization parameter for characterizing the synergy degree of the combined drug based on the first characterization parameter, the second characterization parameter and the third characterization parameter; the third data acquisition module is used for acquiring a sixth characterization parameter for characterizing the sensitivity of the combined drug to be tested; the recommendation module is used for screening out from all the combined medicines to be testedAnd the combined drug with the maximum fourth characterization parameter and the maximum sixth characterization parameter is used as a recommended target combined drug.
In some embodiments of the present invention, the third analysis module is specifically configured to determine whether the first characterization parameter corresponding to each concentration combination is greater than a minimum value and less than a maximum value of the first characterization parameters of the two single-component drugs under the respective concentration effects, and if yes, assign a first quantization value to a fifth characterization parameter that characterizes the synergy degree of the concentration combinations; if the minimum value of the first characterization parameters corresponding to the two single-component medicines is smaller than the minimum value of the first characterization parameters, a second quantized value is given to the fifth characterization parameters; if the value is larger than the maximum value in the first characterization parameters corresponding to the two single-component medicines, continuously judging the second characterization parameters S Loewe And the third characterization parameter S Bliss If the maximum value of the fifth characterization parameter is smaller than a first preset threshold value, a third quantization value is given to the fifth characterization parameter; if the second characteristic parameter S is larger than the first preset threshold value, judging the second characteristic parameter S Loewe And the third characterization parameter S Bliss Whether the minimum value of (2) is smaller than a second preset threshold value; if the first characteristic parameter is smaller than the second preset threshold value, a fourth quantized value is given to the fifth characteristic parameter, and if the first characteristic parameter is larger than the second preset threshold value, a fifth quantized value is given to the fifth characteristic parameter; and calculating the average value of the fifth characterization parameters corresponding to all concentration combinations of the combined drug to be tested, and taking the average value as the quantized value of the fourth characterization parameters.
The beneficial effects are that: in the art, when judging the synergy of a combined user to evaluate, a single mathematical model is generally adopted to evaluate the combined drug so as to judge whether each single component drug in the combined drug has the synergy, then, as the departure angle (for example, the premise assumption) of each mathematical model is different, each has emphasis, and the calculation methods are different, one model is generally cooperated, and the other judgment is antagonistic, namely, from the aspect of results, if the single model is adopted to evaluate, misjudgment occurs; from the user's perspective, because of the numerous mathematical models, there is currently no general standard to determine which model to choose specifically is appropriate, thus burdening the model selection. However, in order to avoid this problem, if the four mathematical models are used for evaluation respectively as described in the background art, as described above, the preconditions of the respective mathematical models are assumed to be different, and therefore, the probability of agreement of the determination results of the four models is very low, so that a transitional screening situation occurs, for example, two models of Bliss and Loewe are determined to be synergistic, but the other two models of HAS and ZIP are determined to be non-synergistic, no synergistic effect is determined between the individual component drugs of the combination, and the combination is determined to be a non-optimal drug combination.
However, the two models of Bliss and Loewe (Bliss model assumes similar mechanism of co-administration and Loewe model assumes different mechanism of co-administration) are assumed from two different angles, so if the two models are combined for evaluation, the coverage is very comprehensive, but the assumed angles of the two models are almost opposite, so in order to balance the reliability of the determination result of the model, in the present application, first, initial screening is performed by the inhibition rate under the co-administration, when the initial screening result determines the actual drug effect of the co-administration to be consistent, the degree of co-administration is determined by taking the evaluation result of the two models as a critical value and based on the critical value, that is, the degree of co-administration is characterized according to the consistency of the two mathematical models for the drug combination reaction, so that misjudgment is avoided (for example, even if Min (y) 1 ，y 2 )<y c <Max(y 1 ，y 2 ) S is also present in the case of Bliss > 0, and S Loewe <0, the concentration combination should be judged to be weak antagonistic, but if no preliminary screening is performed, the concentration combination is misjudged to be weak synergistic), and the condition of excessive screening (such as the condition caused by inconsistent judgment results of four models) is avoided, so that the truly effective drug combination is screened, and the method is particularly suitable for the conditions of two-drug combination and three-drug combination.
In the art, only synergy is generally considered when determining the efficacy of a combinationSex or even if both cooperativity and sensitivity are considered (as described in the background), for example: the synergy is determined to be the synergy through four mathematical models at the same time, and then the combined drug is determined to be the synergy; sensitivity, based on the calculated CSS and RI scores (log 10 Normalized area under converted dose-response curve) and then drawing an "S-S" curve based on the quantitative parameter "S" and CSS, i.e., the "S-S" curve is virtually independent of the synergy assessed by the model, i.e., its synergy and sensitivity are virtually independent of each other, there is no combined synergy and sensitivity to be comprehensively considered, and there is no correlation between the assessment results of the four models. In this context, the average value of the quantization parameter under each concentration combination obtained by combining the Bliss model and the Loewe model can directly reflect the synergy degree of the combined drug, and a corresponding curve is drawn based on the synergy degree-sensitivity coefficient, that is, the synergy degree and the sensitivity are truly combined together so as to screen out the combined drug combination with high cooperativity, that is, the cooperativity and the sensitivity are jointly considered. Herein, S avg The mean value of the scores at each concentration combination obtained from the definition rules obtained by combining BLISS and LOEWE models can directly reflect the synergy.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below. Like elements or portions are generally identified by like reference numerals throughout the several figures. In the drawings, elements or portions thereof are not necessarily drawn to scale. It will be apparent to those of ordinary skill in the art that the drawings in the following description are of some embodiments of the invention and that other drawings may be derived from these drawings without inventive faculty.
FIG. 1 is a flow chart of a method of recommending combination medication according to an exemplary embodiment of the present invention;
FIG. 2 is a flow chart of a method of co-medication recommendation for dual drug use in accordance with an exemplary embodiment of the present invention;
FIG. 3 is a flow chart of a method of recommending combination according to yet another exemplary embodiment of the present invention;
FIG. 4 is a functional block diagram of a combination recommendation device according to an exemplary embodiment of the present invention;
FIG. 5 is a graph showing the dose response of combination I of 17-AAG, paclitaxel with a combination of two drugs;
fig. 6a is a dose response curve for Sunitinib alone;
FIG. 6b is a graph showing the dose response of Sunitinib, oxaliplatin in combination II with a combination of two drugs;
FIG. 7a is a schematic representation of a inhibition matrix reflecting combinations of concentrations of combination drug III of Cisplatin in combination with Fulvestat;
FIGS. 7b and 7c are S for combinations of concentrations of combination III calculated using the Bliss model and the Loewe model, respectively Bliss And S is Loewe A matrix schematic;
FIG. 7d is a schematic diagram showing the degree of synergy for each concentration combination of combination III;
FIG. 8a is a schematic representation of a inhibition matrix reflecting combinations of concentrations of combination drug IV in combination of Docetaxel and ifosfamine;
FIGS. 8b and 8c are S for combinations of concentrations of combination IV calculated using the Bliss model and the Loewe model, respectively Bliss And S is Loewe A matrix schematic;
FIG. 8d is a schematic diagram showing the degree of synergy of combination IV reflecting the combination of Docetaxel and Ifosfamide;
FIG. 9 is a graph of dose response with cyclophosphamide drug alone;
FIG. 10 is a schematic diagram showing the degree of synergy of combination V of Doxorubicin, nab-Pclitaxel, cyclophosphamide single and three drug combinations;
Fig. 11 is a graph of dose response with BKM120 single drug action;
fig. 12a is a schematic representation of the inhibition rate matrix for each concentration combination of combination VI for Carboplatin, olaparib in combination with BKM 120;
FIGS. 12b and 12c are S for each concentration combination of combination VI calculated using the Bliss model and the Loewe model, respectively Bliss And S is Loewe A matrix schematic;
FIG. 12d is a schematic diagram showing the degree of synergy for each concentration combination of combination drug VI;
FIG. 13 is a graph showing the dose response of Epirubicin, lobaplatin single and combination drug VII;
fig. 14 shows four combinations I with constant concentration ratios: 17-aag+ptx, combination II: sun+oxp, combination VII: lob+epi combination V: dose effect curve of TAC-100;
FIG. 15 shows seven combinations of CSS-S to be tested avg A scatter plot;
FIG. 16 is a graph showing the change in tumor volume of mice under the combined action of 17-AAG, paclitaxel;
FIG. 17 is a graph showing the change of tumor volume of mice under the combined action of Sunitinib, oxaliplatin and two drugs;
FIG. 18 is a graph showing tumor volume change in mice under the combined action of Cisplatin and Fulvestrent;
FIG. 19 is a graph showing tumor volume change in mice under the combined action of Docetaxel and ifosfamine;
FIG. 20 is a graph showing tumor volume change in mice under the combined action of Doxorubicin, nab-Pclitaxel, cyclophosphamide single drug and three drugs;
FIG. 21 is a graph showing the change in tumor volume in mice under the combined action of Carboplatin, olaparib and BKM 120;
FIG. 22 is a graph showing the change in tumor volume of mice under the combined action of epiubicin and Lobaplatin.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. Based on the practice of the inventionEmbodiments all other embodiments, which can be made by one of ordinary skill in the art without undue burden, are within the scope of the present invention. In this document, suffixes such as "module", "component", or "unit" used to represent elements are used only for facilitating the description of the present invention, and have no particular meaning in themselves. Thus, "module," "component," or "unit" may be used in combination. The terms "upper," "lower," "inner," "outer," "front," "rear," "one end," "the other end," and the like herein refer to an orientation or positional relationship based on that shown in the drawings, merely for convenience of description and to simplify the description, and do not denote or imply that the devices or elements referred to must have a particular orientation, be constructed and operated in a particular orientation, and thus should not be construed as limiting the invention. Furthermore, the terms "first," "second," and the like, are used for descriptive purposes only and are not to be construed as indicating or implying relative importance. The terms "mounted," "configured to," "connected," and the like, herein, are to be construed broadly as, for example, "connected," whether fixedly, detachably, or integrally connected, unless otherwise specifically defined and limited; the two components can be mechanically connected, can be directly connected or can be indirectly connected through an intermediate medium, and can be communicated with each other. The specific meaning of the above terms in the present invention will be understood in specific cases by those of ordinary skill in the art. Herein, "and/or" includes any and all combinations of one or more of the associated listed items. Herein, "plurality" means two or more, i.e., it includes two, three, four, five, etc. The terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the statement "comprises one … …" is not to be construed as an exclusion of any process, method, or apparatus that comprises the element Additional identical elements may be present in an article or apparatus. As used in this specification, the term "about" is typically expressed as +/-5% of the value, more typically +/-4% of the value, more typically +/-3% of the value, more typically +/-2% of the value, even more typically +/-1% of the value, and even more typically +/-0.5% of the value. In this specification, certain embodiments may be disclosed in a format that is within a certain range. It should be appreciated that such a description of "within a certain range" is merely for convenience and brevity and should not be construed as a inflexible limitation on the disclosed ranges. Accordingly, the description of a range should be considered to have specifically disclosed all possible sub-ranges and individual numerical values within that range. For example, a rangeThe description of (c) should be taken as having specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as individual numbers within such ranges, e.g., 1,2,3,4,5, and 6. The above rule applies regardless of the breadth of the range.
Combination drug: in this context, co-administration refers to a plurality of drugs for co-administration, which contain different kinds of drugs depending on how many kinds of drugs are co-administered. When two drugs are combined, the combined drug means two drugs, and the two drugs are two single-component drugs of the combined drug respectively; when three drugs are combined, the combined drug means three drugs, which are three single component drugs of the combined drug respectively; when more than three kinds of medicines are combined, the combined use means more than three kinds of medicines. The terms "combination" and "combination" as used herein refer to the combination of two or more. The combination or dosage groups of different drugs in the following examples are also meant to be combinations of drugs in different combinations (e.g., combinations of different concentrations, or combinations of different dosages). Concentration combination: concentration combinations herein refer to the combination of the individual component drugs (or individual component drugs) in the corresponding dosage (or concentration ) Combinations formed when the combination is performed are also referred to as dose combinations. For example, the combination comprises a first component drug a and a second component drug B, wherein the combination dose (or concentration) of the first component drug a is Am and the combination dose (or concentration) of the second component drug B is Bm, i.e., one concentration combination of the combination is (Am, bm); if the combined dosage (or concentration) of the first component drug A is An, the combined dosage (or concentration) of the second component drug B is Bn, i.e., one concentration combination of the combined drugs is (An, bn). Accordingly, by varying the dosage (or concentration) of any single component drug or of multiple component drugs therein, a dosage matrix (or concentration matrix [ X ] of the combination drug can be obtained A ,X B ]). Drug synegy: drug synergy in this context means whether the effect produced by the combined application of a plurality of drugs is greater than the effect in which the single component drugs are used alone, also referred to as synergy. Specifically, drug cooperativity (synergy) includes: interactions and non-interactions, wherein the interactions include: synergistic and antagonistic. Synergy: the actual drug effect is larger than the additive effect, namely the interaction between the drugs occurs. Antagonizing: it means that the actual drug effect is smaller than the additive effect, i.e. the interaction between the drugs occurs. Non-interacting (or addition): it means that the actual potency is equal to the additive effect, i.e. no interaction or zero interaction between the drugs takes place. Degree of synergy: the synergy is used herein to measure the level of synergy between individual components of the combination and is supported by data analysis, wherein the corresponding synergy is characterized by a quantization parameter S for each concentration combination and the average S of the synergy quantization parameters S for a plurality of concentration combinations for each combination avg To characterize the corresponding degree of synergy of the combination. The synergy degree specifically comprises: strong antagonism, weak antagonism, strong synergy, weak synergy and non-interaction, wherein strong antagonism means that the actual administration effect of the combined administration is smaller than that of each single-component drug/each group drug in the combined administration, and correspondingly, the quantitative parameter S representing the synergy degree of the concentration combination is-2; weak antagonism means that the actual effect of the combination is greater than that of either single drug/eitherThe group drug is simultaneously smaller than the actual drug effect of the other single drug/the other group drug, and correspondingly, the quantitative parameter S representing the synergy degree of the concentration combination is-1; strong synergy means that on the premise that the actual drug effect of the combined drug is larger than the drug effect when two single drugs/two grouping drugs respectively act independently, the consistency of the judging result that the concentration combination is synergistic by the Bliss model and the Loewe model is high, and correspondingly, the quantized parameter S representing the synergy degree of the concentration combination is 2; weak synergy means that on the premise that the actual drug effect of the combined drug is larger than the drug effect when two single drugs act independently, the judging result of the concentration combination by using the Bliss model and the Loewe model is inconsistent, and correspondingly, the quantification parameter S representing the synergy degree of the concentration combination is 1; non-interactive means that both the Bliss and Loewe models delineate the combination as antagonistic under the precondition that the actual drug effect of the combination is greater than the drug effect of the two single drugs acting alone, and that the concentration combination does not produce either synergistic or antagonistic effects in response. Accordingly, the quantization parameter S characterizing the degree of synergy of the concentration combinations is 0. Because the hypothesis preconditions of two mathematical models Bliss, loewe are different, wherein Loewe assumes that the mechanisms of action of the combination drugs are similar, the combined effect (or synergistic effect) is additive, equivalent to the combination of several different doses of the same drug, also called mutual rejection; bliss assumes that the mechanisms of action of the combination drugs are different, and that the effect of one drug on the other drug is not or only little affected, also called as the non-repulsive effect of the drug. Since the departure angles are different, the departure angles are emphasized, and the calculation methods are different, a situation that one model is cooperated and the other judgment is antagonistic, that is, a situation that if a single model is adopted for evaluation, wireless misjudgment is performed, and a situation that a plurality of models (for example, four models in the background art) are adopted for simultaneous evaluation, and the probability of consistency of the judgment results of the plurality of models is very low, so that transition screening is caused. To avoid these two cases, herein, the evaluation is performed using the two mathematical models, and the degree of synergy is determined using the evaluation result of the evaluation of the two models as a cutoff value, that is, based on the two mathematical models The degree of synergy is characterized for consistency of drug combination response. Drug sensitivity (drug sensitivity): drug sensitivity herein refers to the response of a cell to a drug, typically characterized by the percent inhibition of cell growth (or survival of cell growth). The medicine effect is as follows: the drug effect herein refers to a characteristic of inhibition of cell growth (i.e., a first characterization parameter), which is commonly referred to as a drug effect, or simply drug effect. Background medicine: the background drug refers to a single component drug with fixed concentration, which forms combined drug with any other single component drug with gradient concentration or forms combined drug with combined drug of two/more other single component drugs, wherein the single component drug with fixed concentration is the background drug, and any other single component drug or combined drug of other single component drugs is the foreground drug. For example, a combination of two drugs: when the drug II is combined with the drug I with gradient change concentration at a first fixed concentration (for example, IC 50), the combination drug with a plurality of concentration combinations is formed, wherein the drug II is a background drug, and the drug I is a foreground drug. Of course, drug I may be used as the background drug and drug II may be used as the foreground drug in combination to form a plurality of concentration combinations. For example, three drugs are used in combination: when the drug III is used with a second fixed concentration (such as IC 30) and the drug II is used with a first fixed concentration (IC 50) as the background, the drug III and the drug I with gradient concentration are combined to form a combined drug with a plurality of concentration combinations, wherein the drug II is a background drug and the drug I is a foreground drug. Grouping medicines: herein, the group drug means that various single drugs in the combination drug are divided into two groups. For example, when the combination is a dual combination, wherein one of the single component agents I is a group agent and the other single component agent II is a group agent. For another example, when the combination is three-drug combination, wherein the single-component drug I and the single-component drug III form a group drug; the single component drug II and the single component drug III form a group drug. Parameter definition: s: according to the recommendation device, calculating the quantitative parameters of the obtained synergy degree of the corresponding concentration combination of the combined drug; s is S avg : an average or mean value of the quantization parameter of the degree of synergy of the corresponding concentration combinations; yc, Y 1 、y 1 、Y 2 、y 2 、y 1,3 、y 2,3 、y Loewe : inhibition of cell growth; s is S Bliss The synergy score of the combination corresponding concentration combination obtained by the Bliss model calculation; s is S Loewe The synergy score of the corresponding concentration combination of the combined drug obtained by the Loewe model calculation; CSS, CSS 1 、CSS 2 、CSS 1,3 、CSS 2,3 : a coefficient of sensitivity; c 1 -c 2 、c 1 ′-c 2 ': concentration range of drug (in μm); AUC: area under the dose-effect curve; AUC' is a standard value of the AUC after standardization; inh min Is the lowest inhibitory effect of the drug effect; IC50: when the cell growth inhibition rate is 50%, the corresponding medicine or medicine combination concentration is obtained; IC30: at a cell growth inhibition of 30%, the corresponding drug or drug combination concentration.
Example 1: referring to fig. 1, a flowchart of a method for co-administration recommendation according to an exemplary embodiment of the present invention, specifically, the method includes the steps of: s11, respectively obtaining first characterization parameters for characterizing actual drug effects of preset multiple concentration combinations of the combined drug to be tested. In some embodiments, the first characterization parameter is a cell inhibition rate of the combination at a corresponding concentration, and characterizes the effect of the combination at the corresponding concentration. Specifically, the calculation formula is as follows: inhibition yc=100-survival=100- [ (dosing-blank) ]/(negative-blank) ×100%. Wherein, "administered" refers to the OD value corresponding to the combination of concentrations in an actual test (e.g., examples 6-14 herein) when used as the test group; "blank" refers to the OD value corresponding to the cell-free and drug-free media group in this test; "negative" refers to the OD value under the influence of the negative group in the test. In some embodiments, each combination is obtained by combining two or three single-component medicines in a plurality of concentrations, so that the actual administration effect of each combination to be tested under each concentration combination needs to be obtained (or calculated) respectively, so that the subsequent analysis of the synergy degree of the combination based on the actual administration effect is convenient. In some embodiments, the concentration combinations of each single component drug in the combined drug to be tested can be set according to actual needs, and corresponding combined experiments are performed based on in vitro cell lines as disease models, so as to obtain or calculate according to corresponding experimental data to obtain the first characterization parameters.
S12, respectively obtaining first characterization parameters for characterizing actual drug effect of each group drug in the combined drug to be tested under corresponding doses. In some embodiments, the grouping refers to grouping individual components of the combination to obtain a combination. For example, when the combination is a dual drug combination, the two single component drugs are each a single group drug. For another example, when the combination is a combination of three drugs, and one of the three single component drugs is anchored at a second preset concentration (for example, IC30 value) and is used as a background drug, then the remaining two single component drugs I, II (which are graded in a preset concentration range) are respectively combined with the second preset concentration to form two group drugs, namely, the single component drug I and the single component drug III form a first group drug, and the single component drug II and the single component drug III form a second group drug.
S13, determining a second characterization parameter S for characterizing the synergy degree of the combined medication corresponding to each concentration combination based on a preset first evaluation model and a second evaluation model Loewe And a third characterization parameter S Bliss . In some embodiments, the first and second evaluation models are a Loewe model and a Bliss model, respectively, and the second and third characterization parameters are, respectively: s is S Loewe ＝yc-Y 1 (X 1 +X 2 )＝yc-Y 2 (X 1 +X 2 )，S Bliss ＝yc-[Y 1 (X 1 )+Y 2 (X 2 )-Y 1 (X 1 )Y 2 (X 2 )]. In some embodiments, yc is a first characterization parameter (i.e., inhibition rate), Y, of the actual drug effect of the combination at the current concentration combination 1 、Y 2 Respectively, the first characterization parameter (i.e. inhibition rate) of the actual drug effect of the two grouped drugs in the combined drug under the independent action of the corresponding concentration, X 1 、X 2 For the concentration of the corresponding group drug. For example, when the combination is a combination of two drugs, Y 1 (X 1 ) Combination for the combination of the current concentrationsOf the drugs, a single component drug I (i.e. a group of drugs) is shown in X 1 A first characterization parameter of the actual drug effect when the concentration alone is acting; y is Y 2 (X 2 ) Single component drug II (i.e. another group drug) in the combination at the current concentration combination at X 2 A first characterization parameter of the actual drug effect when the concentration alone is acting; y is Y 1 (X 1 +X 2 ) For the single component drug I is shown in (X 1 +X 2 ) A first characterization parameter of the actual drug effect when the concentration alone is acting; y is Y 2 (X 1 +X 2 ) For the single component drug II in (X 1 +X 2 ) A first characterization parameter of the actual drug effect when the concentration alone is acting; yc is the current concentration combination (i.e. the concentrations are X respectively) of the combination 1 And X 2 The combined effect of the single component drug I and the single component drug II). For another example, when the combination is a three-drug combination, Y 1 (X 1 ) Is prepared from single-component medicine III and concentration X 1 A first characterization parameter of the actual drug effect when the first group of single-component drugs I are combined; y is Y 2 (X 2 ) Is prepared from single-component medicine III and concentration X 2 A first characterization parameter of the actual drug effect when the second group of single-component drugs II are combined; y is Y 1 (X 1 +X 2 ) Is a single component drug III and has a concentration of (X 1 +X 2 ) A first characterization parameter of the actual drug effect upon combined action of the single component drug I; y is Y 2 (X 1 +X 2 ) For the single component drug III and the concentration (X) 1 +X 2 ) A first characterization parameter of the actual drug effect during the combination of the single component drugs II; wherein the concentration of the single component drug III is anchored at a second predetermined concentration (e.g., IC 30), i.e., the single component drug III acts as a background drug and the single component drugs I, II act as foreground drugs, respectively. And yc is the combination of the combined medicines at the current concentration (namely, single component medicine III with the second preset concentration and the concentration of X 1 Is a single component drug I with concentration of X 2 A first characterization parameter of the actual drug effect with a single component drug II) combination. In other embodiments, the second characterization parameter is: s is S Loewe ＝yc-y Loewe Wherein yc is a first characterization parameter of the actual drug effect of the combined drug to be tested under the current concentration combination; y is Loewe A first characterization parameter, which is the expected drug effect of the combination at the current concentration combination, which satisfies the condition:x 1 the concentration corresponding to a single component drug in the combined drug of the current concentration combination is +.>An inverse function of a dose-response curve for a first group drug action comprising the single component drug; x is x 2 The concentration corresponding to the other single component drug in the combined drug of the current concentration combination is +.>Is the inverse of the dose-response curve of the effect of the second drug component comprising the further single drug component. For example, when the combination is a combination of two drugs, x 1 For the concentration corresponding to a single component drug I (i.e. the first group drug) in the combined drug of the current concentration combination, +.>An inverse function of the dose-response curve for the single component drug I alone; x is x 2 For the concentration corresponding to the other monocomponent II (i.e. second component) in the combined drug of the current concentration combination, +.>Is the inverse of the dose-response curve of the individual action of the further single-component drug II. For another example, when the combination is a three-agent combination, x 1 The concentration corresponding to a single component drug I in the combined drug of the current concentration combination is +.>Dose-response curves for the combined action of the single-component drug III anchored at the second predetermined concentration with the single-component drug I (i.e., the first group drug) An inverse function; x is x 2 Is the corresponding concentration of another single component drug II in the combined drug of the current concentration combination, ++>An inverse function of the dose-response curve for the combined effect of the one-component drug III anchored at the second predetermined concentration with the other one-component drug II (i.e., the second component drug). Wherein the concentration x of the single component drug I 1 And concentration x of monocomponent II 2 And the gradient changes are carried out in the respective preset concentration ranges.
S14, determining a fourth characterization parameter for characterizing the synergy degree of the combined drug based on the first characterization parameter, the second characterization parameter and the third characterization parameter. In some embodiments, the step S14 specifically includes the steps of: a, judging whether the first characterization parameter corresponding to each concentration combination is larger than the minimum value and smaller than the maximum value in the first characterization parameters of all grouped medicines corresponding to the corresponding concentration combination, if so, giving a first quantized value-1 to a fifth characterization parameter S, and if so, giving a second quantized value-2 to the fifth characterization parameter S; if the value is greater than the maximum value, the step B is executed. B, judging the second characterization parameter S Loewe And a third characterization parameter S Bliss Whether the maximum value of (a) is greater than a first preset threshold: and 0, if yes, giving a third quantized value of 1 to the fifth characterization parameter S, otherwise, executing the step C. C, judging the second characterization parameter S Loewe And a third characterization parameter S Bliss Whether the maximum value of (a) is smaller than a second preset threshold value: 0, if so, giving a fourth quantized value 0 to the fifth characterization parameter S; if the threshold value is larger than a second preset threshold value: and 0, assigning a fifth quantized value of 2 to the fifth characterization parameter S. In some embodiments, the first preset threshold and the second preset threshold are both 0. Of course, the adjustment may be appropriately performed according to actual needs. D, calculating the average value of the fifth characterization parameters corresponding to all concentration combinations, and taking the average value as a fourth characterization parameter S avg Is included in the quantized value of (2).
S15, acquiring a sixth characterization parameter CSS for characterizing the sensitivity of the combined administration. In some embodiments, the calculation formula for the sixth characterization parameter is:in some embodiments, when the combination is two single component pharmaceutical compositions, CSS 1 Anchoring the concentration of one single component medicine to a first preset concentration, and forming a sensitivity coefficient under the action of a medicine combination with the other single component medicine with the concentration changing in a gradient way within a second preset concentration range; CSS 2 The concentration of the other single component drug is anchored to be a first preset concentration, and the sensitivity coefficient under the action of the drug combination formed by the concentration of the other single component drug with gradient change in a third preset concentration range. In some embodiments, when the combination is of three single component pharmaceutical compositions, CSS 1 A sensitivity coefficient under the combined action of a drug formed by a single-component drug III with a concentration anchored to a second preset concentration, a first single-component drug I with a concentration anchored to a first preset concentration and a single-component drug II with a concentration which changes in a gradient within a fourth preset concentration range; CSS 2 The sensitivity coefficient under the combined action of the single-component drug III with the concentration anchored to the second preset concentration, the second single-component drug II with the concentration anchored to the first preset concentration and the drug formed by the first single-component drug I with the concentration changing in a gradient way within the first preset concentration range.
S16, screening out the combined drug with the maximum fourth characterization parameter and the maximum sixth characterization parameter as a recommended target combined drug. In other embodiments, determining whether the average value is greater than a third predetermined threshold (e.g., 1), if so, obtaining a subset of the combination to be tested; and selecting the combined drug with the largest average value in the combined drug subset and the largest sixth characterization parameter as the recommended combined drug. And performing primary screening by using the fourth characterization parameter, and screening the combined medicine with the largest sensitivity coefficient in the primary screening result as the target combined medicine. Of course, in other embodiments, the sensitivity coefficient may be first used for preliminary screening, that is, the sensitivity coefficient of each combination may be first determined, and a value higher than the value of the next quarter point in the sensitivity coefficient set may be selected, where the sixth characterization parameter is also higher than S avg The combination of the values of the lower quartile points in the data set was used as the recommended combination.
Example 2: referring to fig. 2, a flowchart of a method for recommending combined medication when two drugs are combined according to an exemplary embodiment of the present invention is shown, specifically, the method includes the steps of: s21, obtaining a first characterization parameter yc for characterizing actual drug effect of each concentration combination of the combined drug to be tested for the dual drug combination. In some embodiments, the concentration combinations between two single component drugs in the combined drug to be tested can be set according to actual needs, and the double drug combination experiment is performed based on in vitro using the cell line as a disease model, so as to obtain or calculate according to corresponding experimental data to obtain the first characterization parameter.
S22, respectively obtaining first characterization parameters y for characterizing actual drug effect of two single-component drugs I, II in the combined drug to be tested under corresponding concentrations 1 And y 2 . In some embodiments, the combination to be tested is pre-tested on human breast cancer cell lines at different concentration combinations (e.g., 17-AAG and Paclitaxel are combined at 0.05+0.25, 0.5+2.5), while the two single component drugs in the combination are tested on human breast cancer cell lines at their respective concentrations (e.g., 17-AAG is applied on human breast cancer cell lines at concentrations of 0.05, 0.5; paclitaxel is applied on human breast cancer cell lines at concentrations of 0.25, 2.5; respectively); meanwhile, a negative control group (for example, the concentrations of 17-AAG and Paclitaxel are 0) and a blank control group (a culture medium well without cells and liquid medicine) are set, and then, the inhibition rate of each to the cell growth, namely, the first characterization parameter yc, is calculated according to the test result. Specifically, the inhibition ratio=100-survival ratio=100- [ (dosing-blank) ]/(negative-blank) ×100%. In some embodiments, the order between the steps S21 and S22 may be exchanged or performed simultaneously, that is, the order between the steps S21 and S22 does not affect the final result of the present invention, and may be adjusted according to practical situations when the present invention is implemented.
S23, determining a second characterization parameter S for characterizing the synergy degree of each concentration combination of the combined drug based on the Loewe model and the Bliss model respectively Loewe And a third characterization parameter S Bliss . In some embodiments of the present invention, in some embodiments,when the actual drug effect of each of the two single component drugs I, II of the combination is the same (i.e., the dose-effect curves are the same), the second characterization parameter is: s is S Loewe ＝yc-y 1 (x 1 +x 2 )＝yc-y 2 (x 1 +x 2 ). In some embodiments, the third characterization parameter is: s is S Bliss ＝yc-[y 1 (x 1 )+y 2 (x 2 )-y 1 (x 1 )y 2 (x 2 )]. Wherein y is 1 (x 1 ) The single component medicine I in the combined medicine to be tested is x 1 The first characterization parameter of the actual drug effect at the dose alone, i.e. the inhibition rate, y 2 (x 2 ) For another single component drug II at x 2 A first characterizing parameter of the actual drug effect under the individual action of the dose, i.e. the inhibition rate; y is 1 (x 1 +x 2 ) For the single component drug I at x 1 +x 2 A first characterization parameter of the actual drug effect at the dose alone; y is 2 (x 1 +x 2 ) Is a single component drug II in x 1 +x 2 A first characterization parameter of the actual drug effect at the dose alone; yc is the combination of the corresponding concentrations (i.e. the concentrations are x respectively) 1 、x 2 The single component of (a) is to be combined with the single component drug of (II) the first characterizing parameter of the actual drug effect under the action of the combination. In other embodiments, the second characterization parameter may be whether or not the actual drug effect of the two single-component drugs is the same: s is S Loewe ＝yc-y Loewe Wherein y is Loewe For the combination at the current concentration combination (x 1 ，x 2 ) (i.e. the concentration of the single component drug I is x 1 The concentration of the single component drug II is x 2 ) A first characterization parameter of the following expected drug effect, which satisfies a preset condition:wherein (1)>Dose-effect for individual action of monocomponent I in the combinationThe inverse function of the curve can map the actual drug effect of the single component drug I back to the corresponding concentration of the single component drug I; />The actual dosing effect of monocomponent II can be mapped back to the corresponding concentration of monocomponent II as an inverse function of the dose-response curve of monocomponent II alone in the combination.
S14, judging whether a first characterization parameter of the combined drug to be tested meets a first preset condition: min (y) 1 ，y 2 )<yc＜Max(y 1 ,y 2 ) If the first preset condition is satisfied, step S15 is executed, if Min (y 1 ,y 2 ) Step S16 is performed if yc > Max (y 1 ,y 2 ) Step S17 is performed. In some embodiments, when the combination is administered at a concentration of x 1 、x 2 When the single component drug I and the single component drug II are combined, y in the step S14 1 Is y 1 (x 1 ),y 2 Is y 2 (x 2 ). S15, a first quantized value of-1 is given to a fifth characterization parameter, namely a synergy degree quantized parameter S, which characterizes the synergy degree of the corresponding concentration combination. S16, a second quantized value is given to a fifth characterization parameter, namely a synergy degree quantized parameter S, for characterizing the synergy degree of the corresponding concentration combination, wherein the second quantized value is minus 2. S17, judging whether second and third characterization parameters of the combined drug to be tested meet a second preset condition: max (S) Bliss ,S Loewe ) If the value is less than 0, step S18 is executed, and if Max (S Bliss ,S Loewe ) > 0, step S19 is performed. To reduce data throughput, in some embodiments, the first characterization parameter and the first preset condition may be used for initial screening, i.e., only if yc > Max (y 1 ,y 2 ) And when the combined drug to be tested is in a certain period, the step S13 is executed to obtain second and third characterization parameters of the combined drug to be tested; then, step S17 is executed, namely, the second and third characterization parameters are used as cutoff values (or critical values) to determine the quantization parameter S of the degree of synergy, in other words, the quantization parameter S is used to characterize the consistency of the two mathematical models for the combined medication response to be tested to characterize the degree of synergy.
S18, a third quantized value of 0 is given to a fifth characterization parameter-synergy degree quantized parameter S for characterizing the synergy of the corresponding concentration combination of the combined drug. S19, judging whether second and third characterization parameters of the combined drug to be tested meet a third preset condition: min (S) Bliss ,S Loewe ) If the value is less than 0, step S20 is executed, and if Min (S Bliss ,S Loewe ) > 0, step S21 is performed. S20, a fourth quantized value of 1 is given to a fifth characterization parameter-synergy degree quantized parameter S for characterizing the synergy of the corresponding concentration combination of the combined drug. S21, a fifth characterization parameter-synergy degree quantization parameter S for characterizing the synergy of the corresponding concentration combination of the combined drug is provided with a fifth quantization value: 2. s22, calculating average score S under all concentration combinations according to the synergy degree quantification parameter S of different concentration combinations of the combined drug to be tested avg As the quantized value of the fourth characterization parameter, step S26 is performed. In some embodiments, the fourth characterization parameter, S avg I.e. comprehensively characterizing the degree of synergy between the drugs in the combination. In some embodiments, the degree of synergy of the combination may be further determined based on the fourth characterization parameter, in particular: judging whether the fifth characterization parameter meets a fourth preset condition: s is S avg Judging that the synergism of the combined drug to be tested is strong synergism, and taking the combined drug with the concentration combination as recommended combined drug; if S avg Judging whether the fifth characterization parameter meets a fifth preset condition or not is less than or equal to 1: s is S avg If the combination is more than 0, judging that the synergy of the combination to be tested is weak synergy; if S avg =0, judging that the synergy of the combination to be tested is a non-interactive combination; if S avg < 0, judging whether the fifth characterization parameter meets a sixth preset condition: s is S avg More than or equal to-1, judging that the synergistic effect of the combined drug to be tested is weak antagonism; if S avg <-1, determining that the synergy of the combination to be tested is strong antagonism.
S26, obtaining a fifth characterization parameter CSS for characterizing the sensitivity of each concentration combination in the combined drug to be tested. In some embodiments, the two single component agents I, II of the combination to be tested may be the same as each otherBackground drug, therefore, when one of them is used as a background drug (its concentration is fixed, i.e. the IC50 concentration value under the action of its single drug is adopted), and the other single component drug is used as a foreground drug (i.e. the concentration is changed in gradient within the preset concentration range) to be combined with it, it will be obtained respectively: CSS 1 And CSS 2 Thus, the fifth characterization parameter CSS value is defined as the average of two, namely: In the specific implementation, the full matrix drug administration design is adopted, so that no additional experiment is needed, and the full matrix drug administration design is directly extracted from the existing data. Of course, when two single-component drugs are used as the foreground drugs, the corresponding preset concentration ranges are different, namely c 1 、c 2 The values are different; of course, the setting can be performed according to actual needs. In some embodiments, CSS 1 When the single component drug I in the combined drug to be tested is used as a background drug and the other single component drug II is used as a foreground drug, a dose response curve is fitted, and according to the area under the dose response curve AUC (namely the concentration of the single component drug I when the IC50 is adopted and the concentration of the single component drug II is in a second preset concentration range c) 1 ～c 2 (c 1 <c 2 ) The inner part is graded, and then the area under the curve AUC is calculated by fitting a dose effect curve; then, after normalizing it, it gives: />Thereby obtaining CSS 1 =100 AUC'. Accordingly, CSS 2 In order to treat the single component drug I in the combined drug to be tested as a background drug and the other single component drug II as a foreground drug, a dose-response curve is fitted, and the concentration of the single component drug I is within a third preset concentration range c according to the area AUC under the dose-response curve (namely the concentration of the single component drug II when the IC50 is adopted 1 ～c 2 The inner part is graded, and then the area under the curve AUC is calculated by fitting a dose effect curve; then, after normalizing it, it gives: />Thereby obtaining CSS 2 =100 AUC'. Wherein inh min The lowest inhibitory effect (default 10%) of the drug effect; c 2 、c 1 Respectively, the maximum value and the minimum value of a preset concentration range of the foreground medicine. In some embodiments, in order to further reduce the data throughput, when it is determined that the combination to be tested has a synergistic effect (i.e. weak synergistic effect and strong synergistic effect) according to the fourth characterization parameter, the step S26 is executed, that is, the sensitivity coefficient corresponding to each concentration combination having a synergistic effect is calculated.
S27, screening sensitivity coefficients CSS and S from all the combined medicines to be tested avg The highest concentration combination was used as the recommended target combination. In some embodiments, only true positive combinations with good synergy and sensitivity can be used as the final output, thus combining the CSS sensitivity coefficient with S avg Score, CSS sensitivity coefficient and S are obtained through analysis software avg Scoring, drawing an S-S scatter diagram, and screening CSS and S in the diagram avg The highest point, the drug combination corresponding to the point is the preferred combination.
Example 3: the invention also provides a combined drug recommendation method when three drugs of an exemplary embodiment are combined, specifically, the method comprises the steps in the embodiment 1 or 2, except that: 1) Because of the combination of three drugs, when the step S12 or S22 is executed, one single component drug III is used as a background drug, namely, the single component drug III is respectively combined with single component drugs I (foreground drug I) and II (foreground drug II) at a fixed concentration (namely, a second preset concentration, such as IC 30), so that the inhibition rate y when the single component drug III is combined with the single component drug II (namely, the single component drug III and the single component drug II form a single component drug) is respectively obtained 2,3 And inhibition rate y when single component drug I and single component drug III are combined (i.e., single component drug III and single component drug I form another group drug) 1,3 . 2) Accordingly, the above steps S23 or S13 are performed, i.e., when the evaluation is performed using the loew model and the BLISS model, respectively: the second and third characterization parameters are respectively as follows: s is S Loewe ＝yc-y 1,3 (x 1,3 +x 2,3 )＝yc-y 2,3 (x 1,3 +x 2,3 )，S Bliss ＝yc-[y 1,3 (x 1,3 )+y 2,3 (x 2,3 )-y 1,3 (x 1,3 )y 2,3 (x 2,3 )]. Wherein y is 1,3 (x 1,3 ) For single component drug III as background drug at a fixed concentration (e.g. IC 30) with a concentration of x 1,3 A first characterization parameter of the actual drug effect when the single component drugs I are combined; y is 2,3 (x 2,3 ) For single component drug III as background drug at a fixed concentration (e.g. IC 30) with a concentration of x 2,3 A first characterization parameter of the actual drug effect when the single component drug II is combined; y is 1,3 (x 1,3 +x 2,3 ) For single component drug III as background drug at a fixed concentration (e.g. IC 30) with a concentration of x 1,3 +x 2,3 A first characterization parameter of the actual drug effect when the single component drugs I are combined; y is 2,3 (x 1,3 +x 2,3 ) For single component drug III as background drug at a fixed concentration (e.g. IC 30) with a concentration of x 1,3 +x 2,3 A first characterization parameter of the actual drug effect when the single component drug II is combined; yc is a single component drug III as a background drug at a fixed concentration (e.g., IC 30) with a concentration of x 1,3 Is a single component drug I with the concentration x 2,3 A first characterization parameter of the actual drug effect under the combined action of the single component drug II. In general, the second characterization parameter is calculated using the above formula when the actual drug effect of the single component I, II alone is the same, or the actual drug effect of the single component III at the anchor concentration is the same as the actual drug effect of the single component I and single component II, respectively. In other embodiments, the second characterization parameter may be as follows, whether the actual drug effect of the single component drug I, II alone is the same, or whether the actual drug effect of the single component drug III at the anchor concentration is the same as the actual drug effect of the single component drug I and the single component drug II, respectively: s is S Loewe ＝yc-y Loewe The method comprises the steps of carrying out a first treatment on the surface of the Wherein yc is the combination of the combined drug to be tested at the current concentration (i.e. the concentration of the single component drug I is x 1 The method comprises the steps of carrying out a first treatment on the surface of the The concentration of the single component drug II is x 2 The method comprises the steps of carrying out a first treatment on the surface of the First characterization of the actual drug effect of monocomponent III anchored at a fixed concentration, e.g. IC 30)A number; y is Loewe A first characterization parameter, which is the expected drug effect of the combination at the current concentration combination, which satisfies the condition:x 1 the concentration corresponding to a single component drug I in the combined drug of the current concentration combination is +.>An inverse function of the dose-response curve of the combined effect of the single component drug III and the single component drug I anchored at a second predetermined concentration (e.g., IC 30), which inverse function can map the actual drug effect back to the corresponding concentration of single component drug I due to the anchoring of single component drug III concentration; x is x 2 The concentration corresponding to the other single component drug II in the combined drug for the current concentration combination is->Because of the anchoring of the concentration of the one-component drug III, which is the inverse function of the dose-response curve of the combined action of the one-component drug III and the further one-component drug II at the second predetermined concentration, the actual dosing effect can be mapped back to the corresponding concentration of the one-component drug II. And the concentration x of the single component drug I 1 And concentration x of monocomponent II 2 And the gradient changes are carried out in the respective preset concentration ranges. 3) Accordingly, when the step S26 is executed, the sixth characterization parameter is obtained as follows: />Because of the combination of three drugs, the sensitivity coefficient is calculated by using the single component drug III anchored at a second preset concentration (for example, the IC30 concentration value under the single drug action) and the single component drug I anchored at a first preset concentration (for example, the IC50 concentration under the single drug action) as the background and a fourth preset concentration (for example, c 1 -c 2 ) Single component medicine II with inner gradient change is combined; and anchoring with a single component drug III at a second predetermined concentration (e.g., IC30 concentration under single drug action) and anchoring with a single component drug II at a first predetermined concentration (e.g., IC50 under single drug action)Concentration) is used as background, and is within a first preset concentration range (e.g., c 1 ′-c 2 ') combination of single component drugs I with gradient changes in the interior; the area under the curve AUC was then calculated by fitting the corresponding dose-response curves, respectively, and normalized. That is, since the single-component drug I and the single-component drug II can be background drugs with each other on the basis of the fixed concentration of the single-component drug III as the background, two are obtained: CSS 1,3 、CSS 2,3 Thus, CSS is an average of two. That is, a combination in which one single component drug and the other two single component drugs of fixed concentrations are respectively regarded as two group drugs, and then performed with reference to the corresponding steps in the above-described example 2. In specific implementation, the inhibition rate y of the combination of the single component drug I and the single component drug III at corresponding concentration 1,3 And the inhibition rate y of the single component drug II and the single component drug III when combined at corresponding concentrations 2,3 And S Loewe 、S Bliss The principle of obtaining these four characterization parameters is the same as that of the above-described embodiment 2, and will not be described here again. When the three medicines are combined, any one of the single-component medicines can be selected as a background medicine, and any one of the other two single-component medicines is used as a foreground medicine, so that the concentration combination matrix of the two single-component medicines is intersected or positively intersected or cross-combined under the background of the half-inhibitory concentration (namely IC 30) of the third single-component medicine.
Example 4: referring to fig. 3, a flowchart of a combined medication recommendation method according to an exemplary embodiment of the present invention is shown, specifically, the method according to the present embodiment includes steps of any one of the foregoing embodiments 1 to 3, except that in the step of executing the foregoing step S11 or S21, the method according to the present embodiment needs to distinguish a combination form of each single component drug in the combined medication, and provides different collaborative degree analysis methods according to different combination forms, specifically, the method includes steps of: s41, judging the combination mode of the combined medicine, if the combination mode is the first preset combination mode, executing the step S42 or S43, and if the combination mode is the second preset combination mode, executing the step S11 or S21. In some embodiments, the first coupling means comprises: the concentration of one single component medicine in the double medicine combination is fixed and is matched with the other single component medicine Gradient change (i.e. increasing by a fixed factor, e.g. concentration change of another single component drug: c) 0 Concentration 2c of 2 times 0 Concentration 3c of 3 times 0 Form of (a); the concentration ratio of the two single component drugs in the double-drug combination is constant (namely, the two drugs are diluted according to the same fixed multiple, and the concentration of the two drugs has a constant multiple relationship; namely, the ratio of each concentration combination in the drug combination is constant, for example, A:10,1,0.1; B drug 50,5,0.5, and the concentration combination of the two single component drugs in the matrix is 1:5); in the three-drug combination, the concentration of one single-component drug is fixed (i.e., the anchoring concentration), while the other two single-component drugs are combined with each other in a constant ratio. In some embodiments, the second linkage comprises: the two single component drugs in the double-drug combination are combined in irregular concentration (namely, the concentration of the two drugs has no multiple relation); in the three-component combination, the concentration of one single-component medicine is fixed, and the other two single-component medicines are combined with the three-component combination in a non-constant proportion. In some embodiments, the order of addition of the individual components can be adjusted according to actual needs, whether dual or triple drug combinations are used. S42, respectively obtaining a seventh characterization parameter IC50 for characterizing the drug effect of the to-be-tested dual-drug combination and a seventh characterization parameter IC50 for characterizing the drug effect of each of the two single-component drugs. S43, obtaining a seventh characterization parameter IC50 for characterizing the drug effect of the three-drug combination and a seventh characterization parameter IC50 for characterizing the drug effect of each of the three single-component drugs. S44, judging whether the seventh characterization parameter of the combined drug is larger than the seventh characterization parameter of each single component drug, if so, taking the combined drug as a recommended target combined drug; otherwise, the combination is not used as the recommended target combination.
In this embodiment, the combination modes of the combination are pre-determined, so that the combination of the different combination modes is recommended according to different characterization parameters, for example, when the combination modes are first preset, the combination is recommended according to the IC50, and when the combination modes are second preset, the combination is recommended based on the sensitivity coefficient and the fourth characterization parameter; of course, in other embodiments, the combination may be recommended based entirely on the sensitivity coefficient and the fourth characterization parameter, without distinguishing the combination, and according to any of the recommended methods of embodiments 1 to 3.
Example 5: based on the combined medication recommendation method, the invention further provides a combined medication recommendation device, and the combined medication recommendation device is described in detail below with reference to specific embodiments and drawings. Referring to fig. 4, a functional block diagram of a medication combination recommendation device according to an exemplary embodiment of the present invention, specifically, the medication combination recommendation device includes: the first data acquisition module is used for acquiring a first characterization parameter for characterizing an actual drug effect corresponding to each concentration combination of the combined drug to be tested; the second data acquisition module is used for respectively acquiring first characterization parameters for characterizing the actual drug effect of each group drug in the combined drug to be tested under the action of the corresponding concentration; specifically, when the combination is a dual-drug combination, two single-component drugs are respectively one group drug, and when the combination is a three-drug combination, the combination comprises two group drugs, namely: 1) With a single component drug III anchored at a second predetermined concentration (e.g., IC30 concentration) as a background drug, respectively associated with a single component drug III within a first predetermined concentration range (e.g., c 1 ′-c 2 ' the specific concentration range can be set according to actual needs), and single-component drugs I (namely, the single-component drugs I are used as foreground drugs) which are in gradient change are combined to form a first group drug; 2) With a single component drug III anchored at a second predetermined concentration (e.g. the concentration at IC 30) as a background drug, respectively corresponding to a single component drug III in a fourth predetermined concentration range (e.g. c 1 -c 2 The specific concentration range can be set according to actual needs), and single-component drugs II (namely, the single-component drugs II are used as foreground drugs) in a gradient way to form a second component drug; the second analysis module is used for determining a second characterization parameter S for characterizing the synergy degree of each concentration combination of the combined drug to be tested based on a preset first evaluation model and a second evaluation model and combining the first characterization parameters Loewe And a third characterization parameter S Bliss The method comprises the steps of carrying out a first treatment on the surface of the The first evaluation model and the second evaluation model are a Loewe model and a Bliss model respectively; a third analysis module for determining a fourth characterization parameter S for characterizing the synergy degree of the combination drug based on the first characterization parameter, the second characterization parameter and the third characterization parameter avg The method comprises the steps of carrying out a first treatment on the surface of the The third data acquisition module is used for acquiring a sixth characterization parameter CSS for characterizing the sensitivity of the combined drug to be tested; and the recommending module is used for screening out the combined drug with the maximum fourth characterization parameter and the maximum sixth characterization parameter from all the combined drugs to be detected as recommended target combined drug.
In some embodiments, if the third analysis module is specifically configured to determine whether the first characterizing parameter corresponding to each concentration combination is greater than a minimum value and less than a maximum value of the first characterizing parameters of each single component drug/group drug under the action of the corresponding concentration, and if greater than the minimum value and less than the maximum value, assign a first quantized value to a fifth characterizing parameter S that characterizes the degree of synergy of the concentration combinations (e.g., -1); if less than the minimum value, assigning a second quantization value (e.g., -2) to the fifth characterization parameter S; if the second characteristic parameter S is larger than the maximum value, continuing to judge the second characteristic parameter S Loewe And the third characterization parameter S Bliss If the maximum value of (a) is smaller than a first preset threshold (e.g., 0), and if the maximum value is smaller than the first preset threshold, a third quantized value (e.g., 0) is given to the fifth characterization parameter S; if the second characteristic parameter S is larger than the first preset threshold value, judging the second characteristic parameter S Loewe And the third characterization parameter S Bliss Whether the minimum value of (a) is less than a second preset threshold (e.g., 0); assigning a fifth quantization value (e.g., 1) to the fifth characterization parameter S if less than the second preset threshold, and assigning a fifth quantization value (e.g., 2) to the fifth characterization parameter S if greater than the second preset threshold; calculating the average value of the fifth characterization parameters S corresponding to all concentration combinations of the combined drug to be tested as the fourth characterization parameters S avg Is included in the quantized value of (2). In some embodiments, the quantized value of the fifth characterization parameter S may be set according to actual needs. In some embodiments, the first preset threshold and the second preset threshold are the same, for example, both are 0. Of course, the fifth characterization parameter S may be appropriately adjusted according to the quantized value of the fifth characterization parameter S and the actual test situation.
In some embodiments, the second characterization parameter and the third characterization parameter are each: s is S Loewe ＝yc-Y 1 (X 1 +X 2 )＝Y 2 (X 1 +X 2 )；S Bliss ＝yc-[Y 1 (X 1 )+Y 2 (X 2 )-Y 1 (X 1 )Y 2 (X 2 )]The method comprises the steps of carrying out a first treatment on the surface of the Wherein yc is a first characterization parameter of the combined drug under the combined action of the current concentration; y is Y 1 For a group of drugs in the combination, the corresponding concentration in the current concentration combination (e.g., when two drugs are combined, single-component drug I is at X 1 Or X 1 +X 2 Concentration; or three medicines are combined, and the prospect medicine in one group of medicines is X1 or X 1 +X 2 Concentration) of the first characterization parameter; y is Y 2 For the corresponding concentration of the other drug group in the current concentration combination in the combination (e.g., single-component drug II in X when the two drugs are combined 2 Or X 1 +X 2 Concentration; or when the three medicines are combined, the prospect medicine in the other group medicine is X 2 Or X 1 +X 2 Concentration) is used. In other embodiments, the second characterization parameter is: s is S Loewe ＝yc-y Loewe The method comprises the steps of carrying out a first treatment on the surface of the Wherein yc is a first characterization parameter of the actual drug effect of the combined drug to be tested under the current concentration combination; y is Loewe A first characterization parameter, which is the expected drug effect of the combination at the current concentration combination, which satisfies the condition:x 1 the concentration corresponding to a single component drug in the combined drug of the current concentration combination is +.>An inverse function of a dose-response curve for a first group drug action comprising the single component drug; x is x 2 The concentration corresponding to the other single component drug in the combined drug of the current concentration combination is +.>Is the inverse of the dose-response curve of the effect of the second drug component comprising the further single drug component.
In other embodiments, the recommending apparatus further includes: the fourth data acquisition module is used for acquiring a seventh characterization parameter IC50 for characterizing the actual drug effect of the combined drug to be tested; respectively obtaining a seventh characterization parameter IC50 for characterizing the actual drug effect of each of the two single-component drugs; the first analysis module is also used for judging the combination mode of single component medicines in each combination to be tested; if the combination is non-constant proportion combination, triggering the first acquisition module to acquire first characterization parameters for characterizing actual drug effect corresponding to each concentration combination of the combined drug to be tested; triggering the second data acquisition module to respectively acquire first characterization parameters for characterizing actual drug effects of two single-component drugs in the combined drug to be tested under the independent action of corresponding concentrations; if the combination is the constant proportion combination, triggering a fourth data acquisition module to acquire the seventh characterization parameter; and the second analysis module is used for judging whether the seventh characterization parameter IC50 of the combined drug to be detected is larger than the seventh characterization parameter IC50 corresponding to each of the two single-component drugs when the seventh characterization parameter is acquired by the fourth data acquisition module, and if so, taking the combined drug as a recommended target combined drug.
In some embodiments, if the combination to be tested is a dual combination, the constant ratio combination refers to: the two single component medicines are combined in a first preset concentration combination mode; the first preset concentration combination mode comprises the following steps: the concentration of one single-component medicine is fixed and is combined with the other single-component medicine which changes in a gradient way within a first preset concentration range; alternatively, the two single component drugs are combined in a constant concentration ratio; the non-constant proportion combination means that when the combined drug to be tested is a double-drug combination, two single-component drugs are combined in a second preset concentration combination mode, and the second preset concentration combination mode comprises that the two single-component drugs are combined in irregular concentration. In other embodiments, the first analysis module is further configured to determine a combination mode between single component drugs in the combination to be tested for each of the three drug combinations; if the combination is non-constant proportion combination, the first acquisition module is triggered to acquire a first actual medication effect corresponding to each concentration combination representing the combined medication to be testedCharacterizing parameters; triggering the second data acquisition module to respectively acquire first characterization parameters for characterizing actual drug effects of two grouped drugs in the combined drug to be tested under the action of corresponding concentrations; if the combination is in constant proportion, triggering the fourth data acquisition module to acquire a seventh characterization parameter of the combination, and respectively acquiring seventh characterization parameters of three single-component drugs I, II and III in the combination; correspondingly, the second analysis module is further configured to determine whether the seventh characterization parameter of the combined drug is greater than the seventh characterization parameter of each single component drug, and if so, take the combined drug as a recommended target combined drug. In some embodiments, if the combination to be tested is a combination of three drugs, the constant ratio combination refers to: one of the single component drugs is anchored at a second predetermined concentration (e.g., the concentration at IC 30) and is used in combination with the other two single component drugs in a constant ratio combination; the non-constant ratio combination mentioned above means: one of the single component drugs is anchored at a second predetermined concentration (e.g., the concentration at IC 30) and is used in combination with the other two single component drugs in a non-constant ratio. Of course, in other embodiments, the above analysis module is further configured to directly determine the number of single component drugs in the combined drug to be tested, and then determine a specific combination mode of the dual drug combination, so as to trigger the corresponding data acquisition model to acquire the corresponding characterization parameters. In some embodiments, when the combined drug to be tested is a dual drug combination, the third data acquisition module is specifically configured to acquire a sensitivity coefficient under the action of a drug combination formed by anchoring the concentration of any one of the two single component drugs to a first preset concentration and another single component drug whose concentration changes in a gradient within a third preset range. In some embodiments, when the combination to be tested is a three-drug combination, the third data acquisition module is specifically configured to acquire a third single-component drug III anchored at a first predetermined concentration (e.g., IC 30), the first single-component drug I anchored at a second predetermined concentration (e.g., IC 50) being used as a background, and a third single-component drug III anchored at a third predetermined concentration range (e.g., c 1 -c 2 ) The sensitivity coefficient of the second single component drug II which is changed in a gradient way is used together; and a third single component drug III anchored at a first predetermined concentration (e.g., IC 30), anchored at a firstA second single component drug II of a second predetermined concentration (e.g., IC 50) as background, and a second single component drug II of a second predetermined concentration range (e.g., C 1 ′-c 2 ') the sensitivity coefficient of the first single component drug I in gradient. Specifically, the third data acquisition module can automatically judge whether the combined drug to be detected is used in combination of two drugs or three drugs, or the first analysis module can trigger the third data acquisition model after judging.
And calculating the synergy score based on the two models according to the data obtained by the drug test so as to comprehensively evaluate the synergy effect, thereby evaluating the combined drug effect. Meanwhile, the tumor size of mice after in-vivo administration is compared, and the reliability of the evaluation method is verified. Specifically, taking a human breast cancer cell line as an example for verification, the cell line and the drug combination can be replaced according to specific situations when the implementation is carried out.
Example 6: combination of two drugs for human breast cancer cell lines
1. Selecting human breast cancer cell line, culturing, digesting when the cell growth reaches logarithmic phase and fusion rate reaches 80%, plating in 96-well plate according to 1000-5000 cells/well, 37 deg.C, 5%, CO 2 After 24h incubation, the effect of the four concentrations of single drug or the four concentrations of combination drug was administered for 72 hours, and cell viability and inhibition were determined using a CCK 8-based assay. 2. Different combinations of drugs were selected for testing, and the experimental groups were divided into four groups, including group a: single component drug group I, B: single component drug II, group C: single component drug I + single component drug II, group D: blank (i.e., cell-free, medium alone, and no drug, for baseline) group E: DMSO control. The breast cancer cell lines were tested at 4 concentrations each for single and combination drug administration. 3. Cell suspension of human breast cancer cell line is adjusted to 5-10×10 6 cells/mL，0.2mL(1-2×10 6 cells) cell suspension was inoculated into the mammary glands of 12 immunocomplex-deficient female mice when the tumor volume reached 100mm 3 At the time, the medicine is randomly divided into 4 groups, the physiological saline is injected into the tail vein of a control group (group D) daily, the single component medicine I is injected into the tail vein of a group A daily, and the tail vein of a group B dailyThe single component drug II is injected, and the single component drug I+the single component drug II is injected into the tail vein of the group C every day. Mice tumor volumes were measured every two days following 25 consecutive days of injection. Mice were sacrificed 27 days later, tumors were dissected, tumor sizes were measured and recorded.
Example 7: combination of three drugs for human breast cancer cell lines
In this embodiment, the experimental principle is the same as that of the combination of the two drugs in the above embodiment, so each step can refer to each step in the above embodiment, except that in this embodiment, since three drugs are combined, the experimental components are adaptively divided into five groups, including group a: single component drug group I, B: single component drug II, group C: single component drug III, group D: single component drug i+single component drug ii+single component drug III, E group: blank, F: DMSO control, and correspondingly, cell suspension was inoculated into the mammary gland of 15 immunocomplex-deficient female mice when the tumor volume reached 100mm 3 At the time, the medicine is randomly divided into 4 groups, wherein the physiological saline is injected into the tail vein of a control group (group E) at 0.2mL, the single component medicine is injected into the tail vein of a group A at daily, the single component medicine is injected into the tail vein of a group B at daily, the single component medicine is injected into the tail vein of a group C at daily, and the single component medicine is injected into the tail vein of a group D at daily, and the single component medicine is combined with the single component medicine I, the single component medicine II and the single component medicine III. The invention will be further illustrated with reference to specific examples. The examples are not intended to limit the present patent in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art. Unless otherwise indicated, all reagents and materials used in this patent are commercially available.
Example 8: sensitivity test of breast cancer triple negative MDA-MB-231 cells to combination drug I of single drug and combination drug of paclitaxel and tamspiramycin.
1. MDA-MB-231 cell suspensions were seeded into 96-well plates at a ratio of 3000 cells/well, 100. Mu.L of cell-containing medium was added to each well, and the group planning was performed as follows. The addition of 200 μl PBS to the edge wells avoids edge effects.
Form 17-AAG, paclitaxel grouping plan for single and combination I
2. After the plating is finished, the mixture is put back to 37 ℃ and 5 percent CO 2 The incubator is incubated for 24 hours for standby, each medicine is diluted according to the table, 100 mu L of medicine liquid with different concentrations is added into each hole after 24 hours, and the concentration in the hole is enabled to reach the working concentration. After the addition, the pore plate is put back into the incubator to make the medicine act for 72 hours. After 3.72h, 20 mu LCCK8 reagent is added into the pore plate, the pore plate is incubated for 4h in a dark place, an enzyme-labeled instrument detects OD value at the wavelength of 450nm, the survival rate under the action of 17-AAG, paclitaxel and the combined drug I and the survival rate under the combined drug I are respectively obtained through the values of a blank control group, and corresponding dose curves are drawn, as shown in FIG. 5 (the abscissa is 17-AAG concentration, and the ordinate is cell survival rate). Wherein, the survival rate= (administration-blank)/(negative-blank) ×100%. Wherein, negative refers to the OD value under the action of the negative group (i.e. the combination of the concentrations of the two single component drugs in the group C when the two single component drugs are orthogonalized is 0. Mu.M). 4. By the method described in the above example 4, since the concentration ratio of the two single component drugs in the combination I in this example was constant at 1:2, IC50 values of each single component drug Paclitaxel (Paclitaxel), tamspiramycin (17-AAG) and the combination I were obtained according to the dose curve analysis shown in FIG. 5, as shown in Table II below.
List of IC50 for 17-AAG, paclitaxel single and combination I
| 17-AAG | Paclitaxel | Combination I | |
| IC50(μM) | 4.206 | 0.2793 | 0.02103 |
Experimental results show that the combination drug I: the IC50 value of the Paclitaxel+17-AAG is smaller than that of the single drug 17-AAG, and is also smaller than that of the single drug Paclitaxel, that is, the combined drug effect is better than that of the two single drugs.
Example 9: sensitivity test of breast cancer triple negative MDA-MB-231 cells to single drug sunitinib, oxaliplatin, and combination II of both drugs.
1. MDA-MB-231 cell suspensions were seeded into 96-well plates at a ratio of 3000 cells/well, 100. Mu.L of cell-containing medium was added to each well, and the group planning was performed according to Table three below. The addition of 200 μl PBS to the edge wells avoids edge effects.
Table three Sunitinib, oxaliplatin grouping plan table for single and combined drug II
2. After plating, the mixture was returned to 37℃and incubated in a 5% CO2 incubator for 24 hours, and after 24 hours, the respective drugs were diluted according to the above table, and the IC30 concentration of sunitinib was selected as a fixed concentration to be combined with oxaliplatin, and since the IC30 concentration was 1.23. Mu.M and approximately 1. Mu.M, 1. Mu.M was selected to be combined with oxaliplatin. 100 mu L of liquid medicine with different concentrations is added into each hole, so that the concentration in the hole reaches the working concentration. After the addition, the pore plate is put back into the incubator to make the medicine act for 72 hours. After 3.72h, 20 μl of CCK8 reagent was added to the well plate, incubated for 4h in the dark, the microplate reader detected the OD at 450nm wavelength, and the cell viability was calculated for each single-component drug and drug combination II by the blank control values, respectively, to obtain the corresponding dose profile, as shown in fig. 6 b. Survival = (dosing-blank)/(negative-blank) ×100%.4. According to the method described in example 4, the combination of the gradient change of one drug and the concentration of the other drug in the combination II is fixed, and the analysis of FIG. 6a and FIG. 6b using GraphPad Prism7 software is performed to compare the IC50 of two single drugs Sunitinib, oxaliplatin with the IC50 of the combination II shown in Table four below.
List of IC50 for table four Sunitinib, oxaliplatin single and combination II
| Sunitinib | Oxaliplatin | Combination II | |
| IC50(μM) | 1.44 | 13.73 | 45.28 |
Experimental results show that the combination drug II: the IC50 under the action of sun+oxa is greater than that under the action of Sunitinib alone (see fig. 6a and table four below), and also greater than that under the action of oxailitin alone, that is, the combination is inferior to the effect of the single drug in that the combination cannot effectively inhibit the activity of tumor cells.
Example 10: sensitivity test of breast cancer triple negative MDA-MB-231 cells on single drug cisplatin and fulvestrant and combined drug III applied by combining the two drugs
1. MDA-MB-231 cell suspensions were seeded into 96-well plates at a ratio of 3000 cells/well, 100. Mu.L of cell-containing medium was added to each well, and the group planning was performed according to Table five below. The addition of 200 μl PBS to the edge wells avoids edge effects.
Table five Cisplatin, fulvestrant group plan table for single and combined drug III
| Group of | Drug name | Concentration (mu M) | Number of multiple holes n |
| Group A | Cisplatin (cisplatin) | 0.16、0.8、4、20、0 | 3 |
| Group B | Fulvestrant | 0.01、0.1、1、10、0 | 3 |
| Group C | Cisplatin + fulvestrant | Concentration orthogonality | 3 |
| Group D | Blank control group | - | 3 |
| Group E | DMSO control group | - | 3 |
2. After the plating is finished, the mixture is put back to 37 ℃ and 5 percent CO 2 The incubator is incubated for 24 hours for standby, each medicine is diluted according to the table, 100 mu L of medicine liquid with different concentrations is added into each hole after 24 hours, and the concentration in the hole is enabled to reach the working concentration. After the addition, the pore plate is put back into the incubator to make the medicine act for 72 hours. After 3.72h, 20 μl of CCK8 reagent was added into the well plate, incubated for 4h in the dark, the microplate reader detected the OD at 450nm wavelength, the inhibition ratios of the cells were calculated by the values of the blank control group, and the corresponding drug concentration-inhibition ratio matrix was plotted as shown in fig. 7 a. Inhibition = 100-survival = 100- [ (dosing-blank) ]/(negative-blank) ×100%. As can be seen from fig. 7a, single drug cispratin acts alone: the inhibition rate to cells is negative when the dosage is 0.16 mu M, and the inhibition rate to cells is positive under the action of the rest dosage; single drug fu l alone: the inhibition rate to cells is negative when the dosage is 0.01 mu M, and the inhibition rate to cells is positive under the action of the rest dosage; the inhibition rate corresponding to the 4×4 concentration matrix combination of the combination drug III applied by the two drugs is positive, and when the concentration combination of the combination drug III is: cisplatin-20. Mu.M and FUL-10. Mu.M showed the highest inhibition rate on cells: 76%; and when the combination of the concentrations of the combination drugs III are as follows:cisplatin-20. Mu.M, FUL-1. Mu.M, has a cell inhibition of 50%, when combined at the concentration of III: the inhibition rate of Cisplatin-4. Mu.M and FUL-0.01. Mu.M was 2% at the lowest level. 4. According to the method described in the above example 4, since the concentrations of the two single component drugs Cisplatin, fulvestrant in the combination drug III in this example are not constant, the analysis was performed by the above method, and the experimental results are shown in FIGS. 7b to 7 d: wherein, FIG. 7b and FIG. 7c respectively reflect the S corresponding to each concentration combination in the concentration matrix of the combination drug III calculated by using the Bliss model and the Loewe model respectively Bliss And S is Loewe . While FIG. 7d reflects S based on the Bliss model evaluation shown in FIGS. 7b and 7c Loewe And S obtained by Loewe model Loewe The quantized parameter S of the synergy degree corresponding to each concentration combination calculated by the synergy degree characterization method in the above embodiment is utilized to calculate a corresponding average mean (i.e. the quantized parameter S for comprehensively evaluating the synergy degree between the drugs in the combination III) avg ). As can be seen from FIG. 7a, when the concentration combination of the combination III is Cisplatin-20. Mu.M and FUL-0.01. Mu.M, the inhibition rate yc=14% corresponding to the concentration combination is greater than the inhibition rate y corresponding to the concentration (0.01. Mu.M) corresponding to the single drug Ful alone 1 = -8.9% (shown in fig. 7 a), but less than the corresponding inhibition y with single drug cis corresponding concentration (20 μm) alone 2 =30.6% (shown in fig. 7 a), and therefore, the quantization parameter S of the synergy degree of the concentration combination is-1. As can be seen from FIG. 7a, when the concentration combination of the combination drug III is Cisplatin-4. Mu.M and FUL-0.01. Mu.M, the inhibition rate yc=2% corresponding to the concentration combination is larger than the inhibition rate y corresponding to the concentration (0.01. Mu.M) corresponding to the single drug Ful 1 = -8.9% (shown in fig. 7 a), but less than the corresponding inhibition y at the concentration corresponding to cis-single drug (4 μm) 2 =5.24% (shown in fig. 7 a), and therefore, the quantization parameter S of the synergy degree of the concentration combination is-1. As can be seen in fig. 7a, when the concentrations of combination III are combined: the inhibition rate yc=47% (shown in fig. 7 a) of the concentration combination at Cisplatin-0.16 μm and FUL-10 μm is greater than the inhibition rate y of the single drug Ful at the concentration (10 μm) 1 =6.79% (shown in fig. 7 a), also greater than the corresponding inhibition rate y at the concentration corresponding to cis-alone (0.16 μm) 2 -2.15 (% shown in fig. 7 a); as can be seen from FIGS. 7b and 7c, the concentration combinations (Cisplatin-0.16. Mu.M, FUL-10. Mu.M) were calculated to obtain the corresponding S using the Bliss model Bliss :42.21 > 0 (see FIG. 7 b), and the corresponding S of the concentration combination (Cisplatin-0.16. Mu.M, FUL-10. Mu.M) calculated using the Loewe model Loewe :39.95 > 0 (see fig. 7 c), and therefore the quantitative parameter S of the degree of synergy of the concentration combination is 2, see fig. 7d. Similarly, the quantization parameter S of the synergy degree of the other concentration combinations was obtained according to the method in the above-described example 4. Finally, average value calculation is carried out on the synergy degree quantization parameters of all concentration combinations shown in fig. 7d to obtain S avg The method comprises the following steps: [ (2*13) -3]/16= 1.4375 due to S avg And more than 1, therefore, the synergistic degree of the combined drug III is judged to be strong, and the activity of tumor cells can be effectively inhibited.
Example 11: sensitivity test of breast cancer triple negative MDA-MB-231 cells to single drug docetaxel and ifosfamide and combined drug IV of combined application of two drugs
1. MDA-MB-231 cell suspensions were seeded into 96-well plates at a ratio of 3000 cells/well, 100. Mu.L of cell-containing medium was added to each well, and the group planning was performed according to the following Table six. The addition of 200 μl PBS to the edge wells avoids edge effects.
Table six grouping plan table of Docetxel and Ifosfamine single and combination IV
2. After the plating is finished, the mixture is put back to 37 ℃ and 5 percent CO 2 The incubator is incubated for 24 hours for standby, each medicine is diluted according to the table, 100 mu L of medicine liquid with different concentrations is added into each hole after 24 hours, and the concentration in the hole is enabled to reach the working concentration. After the addition, the pore plate is put back into the incubator to make the medicine act for 72 hours.
After 3.72h, 20 mu LCCK8 reagent is added into the pore plate, the pore plate is incubated for 4h in a dark place, an enzyme-labeled instrument detects OD values at the wavelength of 450nm, the inhibition rate of cells is calculated through the values of a blank control group respectively, and a corresponding concentration-inhibition rate matrix diagram is drawn, as shown in FIG. 8 a. Wherein inhibition = 100-survival = 100- [ (dosing-blank) ]/(negative-blank) ×100%. As can be seen from fig. 8a, under the action of the single drug Docetaxel, the inhibition rate of the single drug ifosfamine on cells is negative, while under the action of the single drug ifosfamine, the inhibition rate of the single drug ifosfamine on cells is positive, and under the combined action of most of the concentrations of the combined drug IV, the inhibition rate of the combined drug IV on cells is negative, and only four concentration combinations are provided: the inhibition rate of the cells is positive when the Docetixel is 0.04 mu M, the Ifosfamine is 0.1 mu M, docetaxel to 0.04 mu M, the Ifosfamine is 100 mu M, docetaxel to 0.008 mu M, the Ifosfamine is 10 mu M, docetaxel to 0.0016 mu M and the Ifosfamine is 1 mu M, and the inhibition rate is 38.00 percent at most; and when the combination of concentrations of combination IV are: the inhibition rate of cells was-8.83% at 0.0016. Mu.M for Docetxel and 100. Mu.M for Ifosfamide.
4. According to the method of the above embodiment 4, the concentration combinations of the two drugs in the combination IV in this embodiment are analyzed according to the synergy degree analysis method in a non-constant ratio, and the experimental results are shown in fig. 8 b-8 d: wherein, FIG. 8b and FIG. 8c respectively reflect the S corresponding to each concentration combination of the combination drug IV calculated by using the Bliss model and the Loewe model respectively Bliss And S is Loewe . While FIG. 8d reflects S calculated based on the Bliss model shown in FIGS. 8b and 8c Bliss And S calculated by Loewe model Loewe The synergy degree quantization parameter S corresponding to each concentration combination calculated by the synergy degree analysis mode in the embodiment is utilized to calculate the average mean (namely the quantization parameter S representing the synergy degree among the medicines in the combined medicine IV) avg )。
As can be seen in conjunction with fig. 8a, when the combination IV concentrations are combined: when the concentration of Docetaxel is 0.04 mu M and the concentration of Ifosfamine is 100 mu M, the inhibition rate yc=38.00% corresponding to the concentration combination is larger than the inhibition rate y corresponding to the concentration (0.04 mu M) corresponding to the single-drug Docetaxel 1 = -7.08%, which is smaller than the inhibition rate y corresponding to the concentration (100 mu M) of the single drug Ifosfamine 2 = 41.50%; namely, min (y 1 ，y 2 )＜yc＜Max(y 1 ,y 2 ) Accordingly, the quantization parameter S of the synergy degree of the concentration combination is-1, as shown in fig. 8 d.
As can be seen in conjunction with fig. 8a, when the combination IV concentrations are combined: when the concentration of the Docetaxel is 0.04 mu M and the concentration of the Ifosfamine is 1 mu M, the inhibition rate yc= -7.91% corresponding to the concentration combination is smaller than the inhibition rate y corresponding to the concentration (0.04 mu M) corresponding to the single-drug Docetaxel 1 = -7.08%, and is also smaller than the inhibition rate y corresponding to the concentration (1 mu M) of the single drug Ifosfamine 2 =9.50%, i.e. yc < Min (y 1 ,y 2 ) Therefore, the synergy degree quantization parameter s= -2 corresponding to the concentration combination is shown in fig. 8 d. As can be seen in conjunction with fig. 8a, when the combination IV concentrations are combined: when the concentration of Docetaxel is 0.008 mu M and the concentration of Ifosfamine is 1 mu M, the inhibition rate yc= -7.28% corresponding to the concentration combination is smaller than the inhibition rate y corresponding to the concentration (0.008 mu M) corresponding to the single-drug Docetaxel 1 = -7.16%, and is also smaller than the inhibition rate y corresponding to the concentration (1 mu M) of the single drug Ifosfamine 2 =9.50%, i.e. yc < Min (y 1 ,y 2 ) Therefore, the synergy degree quantization parameter s= -2 corresponding to the concentration combination is shown in fig. 8 d. As can be seen in conjunction with fig. 8a, when the combination IV concentrations are combined: when the concentration of Docetaxel is 0.04 mu M and the concentration of Ifosfamine is 10 mu M, the inhibition rate yc= -1% corresponding to the concentration combination is larger than the inhibition rate y corresponding to the concentration (0.04 mu M) corresponding to the single-drug Docetaxel 1 = -7.08%, which is smaller than the inhibition rate y corresponding to the concentration (10 mu M) of the single drug Ifosfamine 2 =21.40%, i.e. Min (y 1 ，y 2 )＜yc＜Max(y 1 ,y 2 ) Therefore, the synergy degree quantization parameter s= -1 corresponding to the concentration combination is shown in fig. 8 d. As can be seen in fig. 8a, when the combination IV concentrations are combined: when the concentration of the Docetaxel is 0.04 mu M and the concentration of the Ifosfamine is 0.1 mu M, the inhibition rate yc=9.88% corresponding to the concentration combination is larger than the inhibition rate y corresponding to the concentration (0.04 mu M) corresponding to the single-drug Docetaxel 1 = -7.08%, which is larger than the corresponding inhibition rate y of the single drug ifosfamine under the action of the corresponding concentration (0.1 mu M) 2 =0.73%, i.e. yc > Max (y 1 ,y 2 ) And, seeFIGS. 8b and 8c show that the synergistic score S of the concentration combination (Docetixel-0.04. Mu.M, ifosfamide-0.1. Mu.M) was calculated using the Bliss model and the Loewe model Bliss ：16.18＞0、S Loewe :7.31 > 0, and therefore, the synergy degree quantization parameter s=2 corresponding to the concentration combination, as shown in fig. 8 d.
As can be seen in fig. 8a, when the combination IV concentrations are combined: when the concentration of Docetaxel is 0.008 mu M and the concentration of Ifosfamine is 10 mu M, the inhibition rate yc=24% corresponding to the concentration combination is larger than the inhibition rate y corresponding to the concentration (0.008 mu M) corresponding to the single-drug Docetaxel 1 = -7.16%, which is larger than the corresponding inhibition rate y of the single drug ifosfamine under the action of the corresponding concentration (10 mu M) 2 =21.4%, i.e. yc > Max (y 1 ,y 2 ) And, referring to FIGS. 8b and 8c, it can be seen that the synergy score S of the concentration combination (Docetaxel-0.008. Mu.M, ifosfamide-10. Mu.M) was calculated using the Bliss model and the Loewe model Bliss ：8.23＞0、S Loewe :2.34 > 0, and thus the synergy degree quantization parameter s=2 corresponding to the concentration combination, as shown in fig. 8 d. Similarly, the quantization parameter S of the synergy degree of the other concentration combinations was obtained according to the method in the above-described example 4. Finally, the synergy scores for all concentration combinations shown in FIG. 8d are averaged to obtain S avg The method comprises the following steps: [ (2+2) + (-2*4) + (-1*10)]With a ratio of +16= -0.875, due to-1<S avg And < 0, therefore, the synergistic effect of the combination IV is judged to be weak antagonistic effect, and the activity of tumor cells cannot be effectively inhibited.
Example 12: sensitivity test of breast cancer triple negative MDA-MB-231 cell to single drug albumin taxol+doxorubicin+cyclophosphamide and combined drug V for combined application of three drugs
1. Before combined administration, the concentration to be measured of cyclophosphamide was tested for single component drug to obtain a dose curve, and the IC30 of cyclophosphamide was calculated to be 1.47 μm, as shown in fig. 9.
2. Cyclophosphamide with a fixed concentration of 1.47 mu M is used as a background drug when the combination V is applied, and the other two drugs are combined in a constant ratio (1:1).
3. MDA-MB-231 cell suspensions were seeded into 96-well plates at a ratio of 3000 cells/well, 100. Mu.L of cell-containing medium was added to each well, and the group planning was performed according to Table seven below. The addition of 200 μl PBS to the edge wells avoids edge effects.
Grouping planning table for seven-Doxorubicin, nab-Pclitaxel, cyclophosphamide single drug and combined drug V
4. After the plating is finished, the mixture is put back to 37 ℃ and 5 percent CO 2 The incubator is incubated for 24 hours for standby, each medicine is diluted according to the table, 100 mu L of medicine liquid with different concentrations is added into each hole after 24 hours, and the concentration in the hole is enabled to reach the working concentration. After the addition, the pore plate is put back into the incubator to make the medicine act for 72 hours. After 5.72h, 20 mu L of CCK8 reagent is added into the pore plate, the pore plate is incubated for 4h in a dark place, an enzyme-labeled instrument detects the OD value at the wavelength of 450nm, the cell survival rate of each single-component drug and each combined drug V is calculated respectively through the values of a blank control group, and a dose curve chart 10 is drawn. Wherein survival = (dosing-blank) -/(negative-blank) ×100%.6. According to the above-described method for analyzing the degree of synergy, since the concentration of CTX of one drug in combination V is fixed and the other two drugs are combined at a constant ratio (1:1), analysis was performed according to the graph shown in fig. 10, and the IC50 under each single drug and combination is shown in the following table eight.
Table eight Doxorubicin, nab-Pclitaxel, cyclophosphamide list of IC50 s for drug combination V (TAC-100)
As can be seen from the following table eight, the IC50 value of combination V: 0.1352 μm, less than IC50 value with Doxorubicin alone: 0.5607. Mu.M, which is smaller than the IC50 value under the action of Nab-Pclitaxel as a single drug, and also smaller than the IC50 value under the action of Cyclophosphamide as a single drug: 33.18 μm, as shown in table eight below, i.e., the combination V is superior to the single action effect.
Example 13: sensitivity test of breast cancer triple negative MDA-MB-231 cells to single drug Olaparib, carboplatin and BKM120 and combined drug VI applied by combining the three drugs
1. Before combined administration, the concentration to be measured of single drug BKM 120: 0.01 Individual drug tests were performed on (μm), 0.1 (μm), 1 (μm), 10 (μm), 100 (μm) pairs, a dose curve was obtained for single drug BKM120, and IC30 for BKM120 was calculated to be 5 μm, as shown in fig. 11.
2. BKM120 at a fixed concentration (or dose) of 5 μm was used as a background drug for combination VI application, while the other two drugs were combined in a non-constant ratio.
3. MDA-MB-231 cell suspensions were seeded into 96-well plates at a ratio of 3000 cells/well, 100. Mu.L of cell-containing medium was added to each well, and the group planning was performed according to Table nine below. The addition of 200 μl PBS to the edge wells avoids edge effects.
Grouping planning table for table nine Carboplatin, olaparib and BKM120 single drug and combined drug VI
4. After the plating is finished, the mixture is put back to 37 ℃ and 5 percent CO 2 The incubator is incubated for 24 hours for standby, each medicine is diluted according to the table, 100 mu L of medicine liquid with different concentrations is added into each hole after 24 hours, and the concentration in the hole is enabled to reach the working concentration. After the addition, the pore plate is put back into the incubator to make the medicine act for 72 hours. After 5.72h, 20 μl of CCK8 reagent was added into the well plate, incubated for 4h in the dark, the OD values at 450nm were detected by the microplate reader, the inhibition ratios of the cells were calculated by the values of the blank control group, and the corresponding concentration-inhibition ratio matrix was plotted as shown in fig. 12 a. Wherein inhibition = 100-survival = 100- [ (dosing-blank)]/(negative-blank) ×100%. FIG. 12a shows the inhibition ratios of the other two drugs added alone in the case of a BKM120 at a fixed concentration of 5. Mu.M, as shown in the leftmost column in FIG. 12a (i.e., the inhibition ratio of the single drug Olaparib was added in the case of a BKM120 at a fixed concentration of 5. Mu.M) and the bottom column (i.e., the inhibition ratio of the other two drugs added in the case of a BKM120 at a fixed concentration of 5. Mu.M)Inhibition by Carboplatin alone). As can be seen from fig. 12a, in the background of BKM120 at a fixed concentration of 5 μm, the inhibition rate against cells was negative only at a dose of 0.15 μm, positive at the rest of the doses, and maximum at a dose of 35.0% at 150 μm, by the addition of Olaparib alone; under the action of adding single-drug Carboplatin under the background that BKM120 is 5 mu M with fixed concentration, the inhibition rate of the single-drug Carboplatin on cells is positive, and when the dose is 80 mu M, the maximum inhibition rate is 66%; when the three drugs are combined, the inhibition rate of the drugs to cells is positive, and when BKM120 is in a background with a fixed concentration of 5 mu M, the concentration combination of Olaparib and Carboplatin is as follows: the inhibition rate of cells was at most 63.81% at Olaparib-0.15. Mu.M, carboplatin-80. Mu.M, whereas the concentration combination (or dose combination) of Olaparib and Carboplatin in the background where BKM120 was at a fixed concentration of 5. Mu.M was: the inhibition rate of cells was 1% at the time of Olaparib-0.15. Mu.M and Carboplatin-0.68. Mu.M. According to the above analysis method, in this embodiment, the concentration of BKM120d is fixed in the combination VI, and the other two drugs Olaparib, carboplatin are combined in a non-constant ratio, so that the analysis is performed according to the above analysis method, and the experimental results are shown in fig. 12b-12 d: wherein, fig. 12b and fig. 12c respectively reflect the calculation of each concentration combination of the combination drug VI by using the Bliss model and the Loewe model, respectively, and the obtained S corresponding to each concentration combination Bliss And S is Loewe . While FIG. 12d reflects S calculated based on the Bliss model shown in FIGS. 12b and 12c Bliss And S obtained by Loewe model evaluation Loewe And calculating the corresponding synergy degree quantization parameter S of each concentration combination by using the synergy degree analysis mode in the embodiment, and calculating the average mean according to the synergy degree quantization parameter S. As can be seen from FIG. 12d, the inhibition ratio yc of the combination of concentrations corresponding to the combination drug VI was greater than that of the combination drug of BKM120 and Olaparib at a fixed concentration of 5. Mu.M and also greater than that of the combination drug of BKM120 and Carboplatin at a fixed concentration of 5. Mu.M, and S was calculated by using the Bliss model using the two mathematical models as the background drug for the BKM120 at a fixed concentration of 5. Mu.M Bliss And S obtained by Loewe model evaluation Loewe When the concentration combinations are all larger than 0, the corresponding synergy degree quantification is carried outThe parameter S is given a quantization value of 2. Referring to fig. 12a, the concentration combinations are: bKM 120-5. Mu.M, olaparib-150. Mu.M, carboplatin-14.8. Mu.M in combination with VI corresponding to a cell inhibition rate yc= 61.10%, which is greater than the inhibition rate y of 5. Mu.M of BKM120 in combination with 150. Mu.M Olaparib 1 Inhibition y of BKM120, also greater than 5 μm, when used in combination with 14.8 μm Carboplatin =35.00: 2 =32.00%; and, referring to fig. 12b and 12c, S corresponding to the concentration combination calculated using the Bliss model Bliss :5.3 > 0; s corresponding to the concentration combination calculated by using Loewe model Loewe :23.66 > 0, i.e.: max (y) 1 ,y 2 ) < yc, and Min (S) Bliss ,S Loewe ) > 0, thus the synergy degree quantization parameter s corresponding to the concentration combination is 2, see fig. 12d. Referring to fig. 12a, concentration combinations of combination VI: BKM120-5 μm, olaparib-0.15 μm, carboplatin-0.68 μm corresponding to a cell inhibition yc=1%, which is greater than inhibition y when used in combination with Olaparib at 0.15 μm in a background BKM120 at a dose of 5 μm 1 -1.10%; bKM120, also greater than 5. Mu.M, was used as background to inhibit y in combination with 0.68. Mu.M Carboplatin 2 =0.46%; and referring to fig. 12b and 12c, the concentration combined drug combination VI is calculated using the Bliss mathematical model to obtain S Bliss :1.63 > 0, and S calculated by Loewe mathematical model Loewe : -1.3 < 0, i.e. Max (y 1 ,y 2 ) < yc, and Max (S) Bliss ,S Loewe )＞0，Min(S Bliss ,S Loewe )<0, thus, the concentration combination corresponds to a synergy score of 1, see fig. 12d. Referring to fig. 12a, the concentration combinations of combination VI are: bKM 120-5. Mu.M, olaparib-15. Mu.M, carboplatin-2.74. Mu.M, corresponding to a cell inhibition yc=15%, which is greater than the inhibition y of 5. Mu.M of BKM120 in combination with 15. Mu.M Olaparib 1 Inhibition y of BKM120, also greater than 5 μm, with 2.74 μm Carboplatin =14% 2 =10%; however, referring to FIGS. 12b and 12c, the concentration combined combination VI is calculated using the Bliss mathematical model to obtain S Bliss : -7.6 < 0, and S calculated using Loewe mathematical model Loewe : -4.43 < 0, i.e. Max (y 1 ,y 2 ) < yc, but Max (S Bliss ,S Loewe ) And < 0, therefore, the synergy score for this concentration combination is 0, see fig. 12d. Referring to fig. 12a, the concentration combinations of combination VI are: bKM 120-5. Mu.M, olaparib-150. Mu.M, carboplatin-0.68. Mu.M, corresponding to a cell inhibition yc=31.01%, which is less than the inhibition y of 5. Mu.M of BKM120 in combination with 150. Mu.M Olaparib 1 Inhibition y of BKM120 greater than 5 μm in combination with 0.68 μm Carboplatin =35% 2 =0.46%, i.e. Min (y 1 ,y 2 )＜yc＜Max(y 1 ,y 2 ) Thus, the synergy degree quantization parameter S corresponding to the concentration combination is-1, see fig. 12d. Similarly, the quantization parameter S of the synergy degree of the other concentration combinations was obtained according to the method in the above-described example 4. Finally, the synergy scores for all concentration combinations shown in FIG. 12d are averaged to obtain S avg The method comprises the following steps: [ (2*8) +1+0-1*6]V16=0.6875, since 1 > S avg And more than 0, therefore, the synergy degree of the combined drug VI is judged to be weak synergy, and compared with the action effect of the combination of BKM120 and any one of the other two single drugs, the three-drug combination can partially and effectively inhibit the activity of tumor cells.
Example 14: sensitivity test of breast cancer triple negative MDA-MB-231 cells to single drug epirubicin, platinum complex, and combination of both drugs VII.
1. MDA-MB-231 cell suspensions were seeded into 96-well plates at a ratio of 3000 cells/well, 100. Mu.L of cell-containing medium was added to each well, and the group planning was performed according to the following table. The addition of 200 μl PBS to the edge wells avoids edge effects.
Table ten Epirubicin, lobaplatin grouping planning table for single drug and combined drug VII
2. After the plating is finished, the mixture is put back to 37 ℃ and 5 percent CO 2 The incubator is incubated for 24 hours for standby, and after 24 hours, each medicine is diluted according to the table, 10 mu L of 0 mu L of medicine liquid with different concentrations is added into each hole, so that the concentration in the hole reaches the working concentration. After the addition, the pore plate is put back into the incubator to make the medicine act for 72 hours. After 3.72h, 20 μl of CCK8 reagent was added into the well plate, incubated for 4h in the dark, the microplate reader detected the OD at 450nm wavelength, and the cell viability was calculated for each single drug and combination II by the blank control values, respectively, to obtain the corresponding dose profile, as shown in fig. 13. Survival = (dosing-blank)/(negative-blank) ×100%.4. By the method described in example 4, since the concentration ratio of the two single-component drugs in the combination I in this example was constant, IC50 values of each single-component drug Epirubicin (Epirubicin), cisplatin (Lobaplatin) and the combination vii were obtained by analysis of the dose curve described in fig. 13, as shown in the following table eleven.
Table eleven Epirubicin, lobaplatin list of IC50 s for single and combination VII
| Epirubicin | Lobaplatin | Combined medication VII | |
| IC50(μM) | 1.395 | 16.74 | 1.271 |
Experimental results show that the combination drug VII: the IC50 value of Epirubicin and Lobaplatin is smaller than that of single-drug Epirubicin and smaller than that of single-drug Lobaplatin, that is, the combined drug effect is better than that of two single-drug single-action effects. The above 4 drug combinations with constant concentration ratios were summarized and the dose curves were plotted to obtain the optimal drug combination as the 17-aag+ptx combination (i.e., with the lowest IC50 value) as shown in fig. 14 and table twelve below.
Table twelve IC50 lists for combinations I, II, VII, V with constant concentration ratios
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Summarizing the sensitivity coefficient and the synergy degree quantization parameter S of each of the seven combined medicines I-VII avg Thirteen of the following table was made and an S-S scatter plot was obtained as shown in fig. 15.
Table thirteen sensitivity coefficients CSS and S for various combinations avg Summary
According to the thirteenth content of the table and the S-S scatter diagram results of each combined drug shown in FIG. 15, the lower quartile (or quartile) in the data set is taken as the sensitive drug combination cutoff value to obtain the sensitivity coefficient and S avg The S-S scatter plot of FIG. 15 shows that the paclitaxel combination is the optimal combination, i.e., combination I. The results of the above experiments were verified in conjunction with animal experiments.
Verification test 1: evaluation of therapeutic Effect of combination of paclitaxel and Tencellmycin I on triple negative breast cancer in mice
1. Human breast cancer triple negative cell line MDA-MB-231 cell suspension is regulated to 5 multiplied by 10 6 cells/mL，0.2mL(1×10 6 cells) cell suspension was inoculated into the mammary gland of 12 immunocomplex-deficient female mice (six weeks old) when the tumor volume reached 100mm 3 At this time, the mice were randomly divided into 4 groups (experimental group consisting of group A, B for single drug, group C for combined drug, and blank control group), each group of 3 mice. 2. The blank group (Vehicle group) was injected with 0.2mL of physiological saline by tail vein daily, 20mg/kg of paclitaxel by tail vein daily, 20mg/kg of tamsulosin by tail vein daily, and 20mg/kg of paclitaxel +20mg/kg of tamsulosin by tail vein daily. 3. Mice tumors were measured using vernier calipers 2 times a week for 27 days following injection, and tumor growth curves were recorded and plotted. Mice were sacrificed 27 days later, tumors were dissected and tumor volumes were measured (v=pi/6×l×w×h). 4. Relative tumor volume of mice vr=vt/V0, where Vt is the tumor volume of mice measured post-drug administration and V0 is the tumor volume of mice at the time of group administration. The evaluation index of the antitumor activity was relative tumor proliferation rate (T/C%). T/C% = Vr (Drug)/Vr (Vehicle) ×100%. Where Vr (Drug) is the relative tumor volume of the Drug group and V (NS) is the relative tumor volume of the Vehicle group. The evaluation criteria of the curative effect are as follows: T/C% > 60% is null; T/C% is less than or equal to 60%, and P is less than 0.05 after statistical analysis to represent effectiveness. The change in tumor volume in mice with the 5.17-AAG single drug, the Paclitaxel single drug, and combination I is shown in FIG. 16. As can be seen from FIG. 16, the tumor volume of the mice was increased from the initial 100mm under the action of the Vehicle group 3 Proliferate to nearly 1500mm 3 The method comprises the steps of carrying out a first treatment on the surface of the The tumor volume proliferation of mice exceeds 500mm under the action of single medicine PTX or 17-AAG 3 Under the action of the combined drug I (namely, the combined application of 17-AAG and Paclitaxel), the tumor volume proliferation of the mice is less than 500mm 3 That is, although the single drug group inhibited tumor growth to a different extent, the combination drug group significantly inhibited tumor growth in animals compared to the single drug group. 6. Mouse tumor volume data are presented as mean values, and multiple comparisons of mean values for each group of single-factor samples employ single-factor anova and LSD-t-test. Analysis with SPSS10.0 softwareAs a result, the results are shown in Table fourteen below.
Fourteen groups of mice have initial tumor volume V0, tumor volume after drug action, relative tumor volume, relative tumor proliferation rate and actual tumor volume
As can be seen from the above table, the average tumor volume of each treatment group is significantly lower than that of the blank control group (P < 0.05), and T/C% of the paclitaxel and tamsulosin group is significantly lower than that of the paclitaxel or tamsulosin single drug group (P < 0.05). The animal experiment result verifies the synergistic effect evaluation result of the combined drug I, and proves the accuracy and reliability of an evaluation technical system of the multi-drug combined experiment effect taking a cell line as a disease model in vitro.
Verification test 2: evaluation of treatment effect of Sunitinib, oxaliplatin combination II on mouse triple negative breast cancer
1. Human breast cancer triple negative cell line MDA-MB-231 cell suspension is regulated to 5 multiplied by 10 6 cells/mL，0.2mL(1×10 6 cells) cell suspension was inoculated into mammary glands (six weeks old) of 12 immunocomplex-deficient female mice, and tumor volumes reached 100mm 3 At this time, the mice were randomly divided into 4 groups of 3 mice each. 2. A blank (Vehicle) was given 0.2mL of physiological saline by tail vein daily, 30mg/kg of sunitinib by tail vein daily, 15mg/kg of oxaliplatin by tail vein daily, and 30mg/kg of sunitinib+15 mg/kg of cyclophosphamide by tail vein daily. And a group animal experiment was performed by the method of the above-mentioned evidence experiment 1. The tumor volume changes of mice under the action of Sunitinib single drug, oxaliptin single drug and combined drug II of the two drugs are shown in figure 17. Referring to FIG. 17, the tumor volume of mice was measured from the initial 100mm under the action of the vehicle group 3 Proliferate to nearly 1500mm 3 The method comprises the steps of carrying out a first treatment on the surface of the Under the action of Sunitinib, the medicine is smallThe volume proliferation of the mouse tumor is less than 1000mm 3 Under the action of single medicine Oxaliptin and under the action of combined medicine II (namely Sunitinib+Oxaliptin combined application), the tumor volume proliferation of mice is 1000mm 3 Left and right, as shown in table twelve below. That is, the group a of the single drug Sunitinib inhibited the tumor growth to some extent, while the group B of the single drug Oxaliplatin and the group C of the combination drug II did not inhibit the tumor growth significantly, i.e., the group C of the combination drug II failed to inhibit the tumor growth significantly in animals compared to the two group A, B of the single drug. 4. Mouse tumor volume data are presented as mean values, and multiple comparisons of mean values for each group of single-factor samples employ single-factor anova and LSD-t-test. The results were analyzed using SPSS10.0 software and are shown in the following table fifteen:
fifteen groups of mice were shown to have an initial tumor volume V0, tumor volume after drug action, relative tumor volume, relative tumor proliferation rate, and actual tumor volume
5. As can be seen from the above table, the average tumor volume of each treatment group was consistently lower to some extent than that of the blank group (P < 0.05), and T/C% was significantly higher for the sunitinib + oxaliplatin group than for the Yu Suni tinib or oxaliplatin single drug group (P < 0.05). The animal experiment result verifies the evaluation result of the synergistic effect of the combined drug II, and proves the accuracy and reliability of an evaluation technical system of the double drug combined experiment effect taking a cell line as a disease model in vitro.
Evidence experiment 3: evaluation of treatment effect of combination III of Cisplatin and Fulvestrant on triple negative breast cancer in mice
1. Human breast cancer triple negative cell line MDA-MB-231 cell suspension is regulated to 5 multiplied by 10 6 cells/mL，0.2mL(1×10 6 cells) cell suspension was inoculated into mammary glands (six weeks old) of 12 immunocomplex-deficient female mice, and tumor volumes reached 100mm 3 At this time, the mice were randomly divided into 4 groups of 3 mice each. 2. Blank control group (Vehicle group) daily Tail intravenous injection physiological saline 0.2mL, group A daily tail intravenous injection 4mg/kg cisPlatinum, 0.5mg/kg fulvestrant daily for tail vein injection in group B, 4mg/kg cisplatin +0.5mg/kg fulvestrant daily for tail vein injection in group C, and group animal experiments were conducted as sixteen in the following table using the procedure described above in evidence test 1. The tumor volume changes in mice under the action of Cisplatin single drug, fulvestrant single drug, and combination III of the two drugs are shown in figure 18. Referring to FIG. 18, the tumor volume of mice was measured from the initial 100mm under the action of the vehicle group 3 Proliferate to nearly 1500mm 3 The method comprises the steps of carrying out a first treatment on the surface of the Under the action of Fulvestrant, the tumor volume of the mice is proliferated to 1004mm 3 The method comprises the steps of carrying out a first treatment on the surface of the Under the action of Fulvestrant, the tumor volume of the mice is proliferated to 684mm 3 The method comprises the steps of carrying out a first treatment on the surface of the Under the action of the combined drug III, the tumor volume of the mice is proliferated to 387mm 3 . That is, A, B groups administered alone inhibited tumor growth to varying degrees, and group C, in combination, significantly inhibited tumor growth in animals compared to the group administered alone. 4. Mouse tumor volume data are presented as mean values, and multiple comparisons of mean values for each group of single-factor samples employ single-factor anova and LSD-t-test. The results were analyzed using SPSS10.0 software. The experimental results are shown in Table sixteen:
sixteen groups of mice are shown with initial tumor volume V0, tumor volume after drug action, relative tumor volume, relative tumor proliferation rate and actual tumor volume
From the sixteen above tables, the average tumor volume of each treatment group was significantly lower than that of the blank group (P < 0.05), and the T/C% of cisplatin plus fulvestrant group was significantly lower than that of cisplatin or fulvestrant single drug group (P < 0.05). The animal experiment results prove the synergistic effect evaluation result of the combined drug III in the embodiment, and the accuracy and the reliability of an evaluation technical system of the double drug combined experiment effect taking a cell line as a disease model in vitro are proved.
Evidence experiment 4: evaluation of therapeutic Effect of combination IV of Docetxel and Ifosfamine on triple negative breast cancer in mice
1. Human breast cancer triple negative cell line MDA-MB-231 fine Cell suspension was adjusted to 5X 10 6 cells/mL，0.2mL(1×10 6 cells) cell suspension was inoculated into mammary glands (six weeks old) of 12 immunocomplex-deficient female mice, and tumor volumes reached 100mm 3 At this time, the mice were randomly divided into 4 groups of 3 mice each. 2. The blank (Vehicle group) was given 0.2mL of physiological saline by tail vein, 7mg/kg of docetaxel by tail vein, 50mg/kg of ifosfamide by tail vein, 7mg/kg of docetaxel +50mg/kg of ifosfamide by tail vein, and seventeen of animals were grouped in accordance with the following table by the method in the above-mentioned evidence test 1. 3. The results of tumor volume change in mice with Docetaxel, ifosfamine, and combination IV are shown in fig. 19. Referring to FIG. 19, the tumor volume of mice was measured from the initial 100mm under the action of the vehicle group 3 Proliferate to nearly 1500mm 3 The method comprises the steps of carrying out a first treatment on the surface of the Under the action of single drug Docetaxel, the tumor volume of the mice is proliferated to 1244mm 3 The method comprises the steps of carrying out a first treatment on the surface of the Under the action of the single drug Ifosfamine, the tumor volume of the mice is proliferated to 902mm 3 The method comprises the steps of carrying out a first treatment on the surface of the Under the action of the combined drug IV, the tumor volume of the mice is proliferated to 1105mm 3 . That is, the group B of the single drug ifesfamine inhibited the growth of the tumor to some extent, while the group a of the single drug Docetaxel and the group C of the combination IV did not significantly inhibit the growth of the tumor, i.e., the group C of the combination IV failed to significantly inhibit the growth of the tumor in the animals compared to the two group A, B of the single drug. 4. Mouse tumor volume data are presented as mean values, and multiple comparisons of mean values for each group of single-factor samples employ single-factor anova and LSD-t-test. The results were analyzed using SPSS10.0 software and are shown in the following table seventeen:
Initial tumor volume V0, tumor volume after drug action, relative tumor volume, relative tumor proliferation rate, and actual tumor volume of seventeen groups of mice
5. As shown in the table above, the average tumor volume of each treatment group is significantly lower than that of the blank control group (P < 0.05), the T/C% of docetaxel+ifosfamide group is significantly higher than that of the ifosfamide single drug group (P < 0.05), and the T/C% is not less than 60. The animal experiment results prove the evaluation result of the synergistic effect of the combined drug in the embodiment 4, and prove the accuracy and the reliability of an evaluation technical system of the double drug combined experiment effect taking a cell line as a disease model in vitro.
Evidence experiment 5: evaluation of treatment effect of combination V of Doxorubicin, nab-Pclitaxel, cyclophosphamide on triple negative breast cancer in mice
1. Human breast cancer triple negative cell line MDA-MB-231 cell suspension is regulated to 5 multiplied by 10 6 cells/mL，0.2mL(1×10 6 cells) cell suspension was inoculated into mammary glands (six weeks old) of 15 immunocomplex-deficient female mice, and tumor volumes reached 100mm 3 At this time, the mice were randomly divided into 5 groups of 3 mice each. 2. A blank (Vehicle) was given 0.2mL of physiological saline by tail vein daily, 80mg/kg of albumin paclitaxel by tail vein daily, 10mg/kg of doxorubicin by tail vein daily, 75mg/kg of cyclophosphamide by tail vein daily, 80mg/kg of albumin paclitaxel +10mg/kg of doxorubicin +75mg/kg of cyclophosphamide by tail vein daily, and a group animal experiment was conducted according to eighteen of the following table by the method in the evidence test 1. 3. The tumor volume change of mice under the combined action of the single drug Doxokumicin, the single drug Nab-Pclaxel and the single drug Cyclophosphamide, namely the combined drug V of the three drugs is shown in figure 20. Referring to FIG. 20, the tumor volume of mice was measured from the initial 100mm under the action of the vehicle group 3 Proliferation to 1202mm 3 The method comprises the steps of carrying out a first treatment on the surface of the Under the action of single-drug Doxorubicin, the tumor volume of the mice is proliferated to 804mm 3 Under the action of single drug Nab-Pclitaxel, the tumor volume of the mice is proliferated to 542mm 3 Under the action of single-drug Cyclophosphamide, the tumor volume of the mice is proliferated to 986mm 3 Under the action of the combined application V (namely, the combined application of Doxorubicin, nab-Pclaxel and Cyclophosphamide), the tumor volume of the mice is increased to 409mm 3 As shown in the following table eighteen. That is, group A, B, C alone inhibited tumor growth to some extent, while group D in combination V significantly inhibited tumor growth in animals compared to the single administration group. 4. Tumor volume data of mice are represented by average values, and multiple comparison of average values of samples of each group of single factors is adoptedOne-way analysis of variance and LSD-t test were used. The results were analyzed using SPSS10.0 software, eighteen in the following table:
initial tumor volume V0, tumor volume after drug action, relative tumor volume, relative tumor proliferation rate and actual tumor volume of eighteen groups of mice
As can be seen from the above table, the average tumor volume of each treatment group was significantly lower than that of the blank group (P < 0.05), the T/C% of albumin paclitaxel + doxorubicin + cyclophosphamide was significantly lower than that of each single drug group (P < 0.05), and the T/C% < 60. The animal experiment results prove the evaluation result of the synergistic effect of the combined drug in the embodiment 5, and prove the accuracy and the reliability of an evaluation technical system of the double drug combined experiment effect taking a cell line as a disease model in vitro.
Evidence experiment 6: evaluation of treatment effect of combination therapy VI of Carboplatin, olaparib and BKM120 on triple negative breast cancer of mice
1. Human breast cancer triple negative cell line MDA-MB-231 cell suspension is regulated to 5 multiplied by 10 6 cells/mL，0.2mL(1×10 6 cells) cell suspension was inoculated into mammary glands (six weeks old) of 15 immunocomplex-deficient female mice, and tumor volumes reached 100mm 3 At this time, the mice were randomly divided into 5 groups (experimental group consisting of group A, B, C for single drug, group D for combined drug, and blank group), each group of 3 mice. 2. A blank (Vehicle) was given a daily tail vein of 0.2mL of normal saline, a daily tail vein of 50mg/kg of Olaparib, a daily tail vein of 60mg/kg of carboplatin, a daily tail vein of 30mg/kg of BKM120, a daily tail vein of 50mg/kg of Olaparib+60 mg/kg of carboplatin+30 mg/kg of BKM120, and a group animal experiment was conducted in accordance with nineteenth of the following table by the method of the above-mentioned evidence experiment 1. The change in tumor volume in mice under the action of combination VI of carboplatin single drug, olaparib single drug, BKM120 single drug and the combination of the three drugs is shown in FIG. 21. Referring to FIG. 21 and nineteen tables below, the tumor volume of mice was measured from the initial 100mm under the action of the Vehicle group 3 Proliferation to 1200mm 3 The method comprises the steps of carrying out a first treatment on the surface of the Under the action of single medicine Olaparib, the tumor volume of the mice is proliferated to 981mm 3 Under the action of single-drug Carboplatin, the tumor volume of the mice is proliferated to 753mm 3 Under the action of single drug BKM120, the tumor volume of the mice is proliferated to 705mm 3 On the other hand, under the action of the combined drug VI, the tumor volume of the mice is proliferated to 647mm 3 . That is, the group C of the single drug BKM120 inhibits the growth of the tumor to a certain extent, the inhibition capacity of the group D of the combined drug VI on the tumor is not obvious, but the effect is relatively better compared with the group A, B. 4. Mouse tumor volume data are presented as mean values, and multiple comparisons of mean values for each group of single-factor samples employ single-factor anova and LSD-t-test. Analysis of the results using SPSS10.0 software gave sixteen of the following tables:
sixteen groups of mice are shown with initial tumor volume V0, tumor volume after drug action, relative tumor volume, relative tumor proliferation rate and actual tumor volume
5. As can be seen from the above table, the average tumor volume of each treatment group is significantly lower than that of the blank control group (P < 0.05), and the T/C% of the combined drug VI (Olaparib+carboplatin+BKM120) is relatively higher than that of each single drug group (P < 0.05), and the T/C% is more than or equal to 60. The animal experiment result verifies the evaluation result of the synergy effect of the combined drug VI, and proves the accuracy and the reliability of an evaluation technical system of the double drug combined experiment effect taking a cell line as a disease model in vitro.
Evidence experiment 7: evaluation of treatment effect of combination medication VII of Epirubicin and Lobaplatin on triple negative breast cancer of mice
1. Human breast cancer triple negative cell line MDA-MB-231 cell suspension is regulated to 5x10 6 cells/mL，0.2mL(1x10 6 cells) cell suspension was inoculated into mammary glands (six weeks old) of 12 immunocomplex-deficient female mice, and tumor volumes reached 100mm 3 At this time, the mice were randomly divided into 4 groups (experimental group consisting of A, B groups for single drug, C group for combination drug, and blank control group) with 3 mice each.
2. The blank (Vehicle) was given 0.2mL of physiological saline by tail vein daily, 3.5mg/kg epirubicin by tail vein daily, 5mg/kg platinum complex by tail vein daily, 3.5mg/kg epirubicin +5mg/kg platinum complex by tail vein daily, and the group animal experiments were conducted in accordance with the following Table seventeen using the method in the above-mentioned evidence experiment 1.
The change of the tumor volume of mice under the action of the combined drug VII of the Epirubicin single drug and the Lobaplatin single drug and the double drug combination is shown in figure 22. Referring to FIG. 22 and Table twenty below, the tumor volume of mice was measured from an initial 100mm under the action of the Vehicle group 3 Proliferation to 1267mm 3 The method comprises the steps of carrying out a first treatment on the surface of the Under the action of single drug Epirubicin, the tumor volume of the mice is proliferated to 631mm 3 Under the action of the single medicine Lobaplatin, the tumor volume of the mice is proliferated to 839mm 3 Under the action of the combined drug VII, the tumor volume of the mice is proliferated to 607mm 3 . That is, the group A of the single drug Epirubicin inhibits the growth of the tumor to a certain extent, and the inhibition capacity of the group D of the combined drug VII on the tumor is similar to the degree of the group A, but the effect is relatively better compared with the group A, B of the single drug.
4. Mouse tumor volume data are presented as mean values, and multiple comparisons of mean values for each group of single-factor samples employ single-factor anova and LSD-t-test. Analysis of the results using SPSS10.0 software gave the following table twenty:
initial tumor volume V0, tumor volume after drug action, relative tumor volume, relative tumor proliferation rate, and actual tumor volume of each group of twenty mice
5. As can be seen from the above table, the average tumor volume of each treatment group is significantly lower than that of the blank control group (P < 0.05), and the T/C% of the combined drug VII (epirubicin+platinum) is relatively lower than that of each single drug group (P < 0.05), and the T/C% < 60. The animal experiment results prove the synergistic effect evaluation result of the combined drug VII, and prove the accuracy and the reliability of an evaluation technical system of the double drug combined experiment effect taking a cell line as a disease model in vitro. The results of the seven combinations used in animal evidence tests 1-7 are shown in Table twenty-one below:
Animal test structure statistics for twenty-seven combinations of table
As can be seen from the above table, combination I (i.e., paclitaxel + tamsulosin combination) is the optimal combination for all examples. The results show that the comprehensive standard for evaluating the synergistic effect of the combined drug and the evaluation technology system based on the in-vitro double-drug combined experimental effect taking the cell line as a disease model can obtain the evaluation of the combined drug effect with comprehensiveness, objectivity and reliability. It should be noted that, in this document, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising one … …" does not exclude the presence of other like elements in a process, method, article, or apparatus that comprises the element. From the above description of the embodiments, it will be clear to those skilled in the art that the above-described embodiment method may be implemented by means of software plus a necessary general hardware platform, but of course may also be implemented by means of hardware, but in many cases the former is a preferred embodiment. Based on such understanding, the technical solution of the present invention may be embodied essentially or in a part contributing to the prior art in the form of a software product stored in a storage medium (e.g. ROM/RAM, magnetic disk, optical disk) comprising several instructions for causing a computer terminal (which may be a mobile phone, a computer, a server, or a network device, etc.) to perform the method according to the embodiments of the present invention. The embodiments of the present invention have been described above with reference to the accompanying drawings, but the present invention is not limited to the above-described embodiments, which are merely illustrative and not restrictive, and many forms may be made by those having ordinary skill in the art without departing from the spirit of the present invention and the scope of the claims, which are to be protected by the present invention.
Claims (9)
1. A method of recommending combination medication, comprising the steps of:
judging a combination mode between two single-component medicines in each combined medicine to be detected, wherein the combined medicine is a double-medicine combination; the combination mode comprises the following steps: the two single component medicines are combined in a non-constant proportion;
if the combination is non-constant proportion combination, acquiring a first characterization parameter for representing the actual drug effect corresponding to each concentration combination of the combined drug to be tested;
respectively obtaining first characterization parameters for characterizing actual drug effects of two single-component drugs in the combined drug to be tested under the independent action of corresponding concentrations;
determining a second characterization parameter S for characterizing the synergy degree of each concentration combination of each to-be-tested combined drug based on a preset first evaluation model and a second evaluation model and combining the first characterization parameter Loewe And a third characterization parameter S Bliss The method comprises the steps of carrying out a first treatment on the surface of the The first evaluation model and the second evaluation model are a Loewe model and a Bliss model respectively;
determining a fourth characterization parameter which characterizes the synergy degree of the combined drug based on the first characterization parameter, the second characterization parameter and the third characterization parameter;
obtaining a sixth characterization parameter for characterizing the sensitivity of the combined drug to be tested;
Screening out the combined drug with the maximum fourth characterization parameter and the maximum sixth characterization parameter from all the combined drugs to be tested as recommended target combined drug;
wherein, the step of determining the fourth characterization parameter specifically includes:
a, judging whether the first characterization parameter corresponding to each concentration combination is larger than the minimum value and smaller than the maximum value in the first characterization parameters of all grouped medicines corresponding to the corresponding concentration combination, if so, giving a first quantized value to a fifth characterization parameter S, and if so, giving a second quantized value to the fifth characterization parameter S; if the value is greater than the maximum value, executing the step B;
b, judging the second characterization parameter S Loewe And a third characterization parameter S Bliss If the maximum value of the characteristic parameters is larger than the first preset threshold value, a third quantized value is given to the fifth characteristic parameters S, otherwise, the step C is executed;
c, judging the second characterization parameter S Loewe And a third characterization parameter S Bliss If the maximum value of the characteristic parameter S is smaller than a second preset threshold value, a fourth quantization value is given to the fifth characteristic parameter S; if the characteristic parameter S is larger than the second preset threshold value, a fifth quantized value is given to the fifth characteristic parameter S;
d, calculating the average value of the fifth characterization parameters corresponding to all concentration combinations, and taking the average value as a fourth characterization parameter S avg Is included in the quantized value of (2).
2. The method for recommending combination according to claim 1, wherein the combination further comprises a constant ratio combination, wherein the constant ratio combination means that the concentration of one single component drug in the combination to be tested is fixed and the combination is used with another single component drug which changes in a gradient within a preset concentration range; alternatively, the two single component drugs are combined in a constant concentration ratio.
3. The method of claim 2, further comprising the step of:
if the combination mode of the two single-component drugs in the combined drug to be tested is judged to be the combination mode with a constant proportion, a seventh characterization parameter for representing the actual drug effect of the combined drug to be tested is obtained;
respectively obtaining seventh characterization parameters for characterizing respective actual drug use effects of the two single-component drugs;
judging whether the seventh characterization parameter of the combined drug to be tested is larger than the seventh characterization parameter corresponding to each of the two single-component drugs, and if so, taking the combined drug as a recommended target combined drug.
4. The method of claim 1, wherein the step of determining a fourth characterization parameter that characterizes a degree of synergy for each concentration combination based on the first characterization parameter, the second characterization parameter, and the third characterization parameter, comprises the steps of:
Judging whether the first characterization parameter corresponding to each concentration combination is larger than the minimum value and smaller than the maximum value in the first characterization parameters of the two single-component medicines under the action of the corresponding concentrations,
if the value is larger than the minimum value and smaller than the maximum value, a first quantized value is given to a fifth characterization parameter which characterizes the synergy degree of the concentration combination
If the minimum value of the first characterization parameters corresponding to the two single-component medicines is smaller than the minimum value of the first characterization parameters, a second quantized value is given to the fifth characterization parameters;
if the value is larger than the maximum value in the first characterization parameters corresponding to the two single-component medicines, judging the second characterization parameters S Loewe And the third characterization parameter S Bliss Whether the maximum value of (c) is less than a first preset threshold,
if the first characteristic parameter is smaller than the first preset threshold value, a third quantized value is given to the fifth characteristic parameter;
if the second characteristic parameter S is larger than the first preset threshold value, judging the second characteristic parameter S Loewe And the third characterization parameter S Bliss Whether the minimum value of (2) is smaller than a second preset threshold value;
if the value is smaller than the second preset threshold value, a fourth quantized value is given to the fifth characterization parameter,
if the characteristic parameter is larger than the second preset threshold value, a fifth quantized value is given to the fifth characteristic parameter;
And calculating the average value of the fifth characterization parameters corresponding to all concentration combinations of the combined drug to be tested, and taking the average value as the quantized value of the fourth characterization parameters.
5. A method of co-administration recommendation according to any one of claims 1 to 4, wherein said second characterization parameters are:
S Loewe ＝yc-y Loewe ，
wherein yc is a first characterization parameter of the actual drug effect of the combined drug to be tested under the current concentration combination; y is Loewe A first characterization parameter for the expected drug effect of the combination at the current concentration combination, which satisfies the condition:x 1 f, the concentration corresponding to a single component drug in the combined drug for the current concentration combination 1 -1 An inverse function of the dose-response curve for the single component drug alone; x is x 2 A concentration corresponding to another single component drug in the combined drug for the current concentration combination, f 2 -1 An inverse function of the dose-response curve for the individual action of the further single component drug; and/or the number of the groups of groups,
the third characterization is:
S Bliss ＝yc-[Y 1 (X 1 )+Y 2 (X 2 )-Y 1 (X 1 )Y 2 (X 2 )]；
wherein yc is a first characterization parameter of the actual drug effect of the combined drug to be tested under the current concentration combination; y is Y 1 (X 1 ) For a single component of the combination 1 A first characterization parameter of the actual drug effect at the concentration alone; y is Y 2 (X 2 ) For another single component in the combination 2 A first characterization parameter of the actual drug effect at the concentration alone.
6. The method of claim 1 to 4, wherein the sixth characterization parameter is calculated according to the formula:
wherein CSS 1 、CSS 2 The concentration of any one of the two single-component medicines is anchored to a first preset concentration, and the sensitivity coefficient under the combined action of the two single-component medicines with the concentration which changes in a gradient within a preset range is used.
7. The method of claim 6, wherein the first predetermined concentration is an IC50 concentration of the single component drug alone.
8. The method for recommending combined use according to claim 4, wherein the step of screening out the combined use with the maximum fourth characterization parameter and the maximum sixth characterization parameter as the recommended combined use specifically comprises the steps of:
judging whether the average value is larger than a third preset threshold value, if so, obtaining a combined medicine subset to be tested; and selecting the combined drug with the largest average value in the combined drug subset and the largest sixth characterization parameter as the recommended combined drug.
9. A recommendation device for combination use, comprising:
the first analysis module is used for judging the combination mode between two single-component medicines in each to-be-detected combined medicine for the combination of the two medicines; the combination mode comprises non-constant proportion combination and constant proportion combination; wherein, the constant proportion combination means that two single-component medicines in the combined medicine to be detected are combined in a first preset concentration combination mode; the first preset concentration combination mode comprises the following steps: the concentration of one single-component medicine is fixed and is combined with the other single-component medicine which changes in a gradient way within a first preset concentration range; alternatively, the two single component drugs are combined in a constant concentration ratio; the non-constant proportion combination means that when the combined medicine to be detected is a double medicine combination, two single component medicines are combined in a second preset concentration combination mode, wherein the second preset concentration combination mode comprises that the two single component medicines are combined in irregular concentration;
the first data acquisition module is used for acquiring a first characterization parameter for characterizing an actual drug effect corresponding to each concentration combination of the combined drug to be tested when judging that the combination is combined in a non-constant proportion;
The second data acquisition module is used for respectively acquiring first characterization parameters for characterizing actual drug use effects of two single-component drugs in the combined drug to be tested under the independent action of corresponding concentrations when judging that the two single-component drugs are combined in a non-constant proportion;
the second analysis module is used for determining a second characterization parameter S for characterizing the synergy degree of each concentration combination of the combined drug to be tested based on a preset first evaluation model and a second evaluation model and combining the first characterization parameter Loewe And a third characterization parameter S Bliss The method comprises the steps of carrying out a first treatment on the surface of the The first evaluation model and the second evaluation model are a Loewe model and a Bliss model respectively;
the third analysis module is used for determining a fourth characterization parameter for characterizing the synergy degree of the combined drug based on the first characterization parameter, the second characterization parameter and the third characterization parameter;
the third data acquisition module is used for acquiring a sixth characterization parameter for characterizing the sensitivity of the combined drug to be tested;
the recommending module is used for screening out the combined drug with the maximum fourth characterization parameter and the maximum sixth characterization parameter from all the combined drugs to be detected as recommended target combined drug;
the third analysis module is specifically configured to determine whether the first characterization parameter corresponding to each concentration combination is greater than a minimum value and less than a maximum value of the first characterization parameters of the two single-component drugs under the respective concentration effects, and if so, assign a first quantization value to a fifth characterization parameter representing the synergy degree of the concentration combinations; if the value is smaller than the minimum value in the first characterization parameters corresponding to the two single-component drugs Assigning a second quantization value to the fifth characterization parameter; if the value is larger than the maximum value in the first characterization parameters corresponding to the two single-component medicines, continuously judging the second characterization parameters S Loewe And the third characterization parameter S Bliss If the maximum value of the fifth characterization parameter is smaller than a first preset threshold value, a third quantization value is given to the fifth characterization parameter; if the second characteristic parameter S is larger than the first preset threshold value, judging the second characteristic parameter S Loewe And the third characterization parameter S Bliss Whether the minimum value of (2) is smaller than a second preset threshold value; if the first characteristic parameter is smaller than the second preset threshold value, a fourth quantized value is given to the fifth characteristic parameter, and if the first characteristic parameter is larger than the second preset threshold value, a fifth quantized value is given to the fifth characteristic parameter; and calculating the average value of the fifth characterization parameters corresponding to all concentration combinations of the combined drug to be tested, and taking the average value as the quantized value of the fourth characterization parameters.
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