CN115845254A - Small cell lung cancer treatment system and alternating electric field generating device - Google Patents
Small cell lung cancer treatment system and alternating electric field generating device Download PDFInfo
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Abstract
The invention relates to the technical field of tumor medical treatment, in particular to a small cell lung cancer treatment system and an alternating electric field generating device. The system comprises a patient information processing module and an output module; the patient information processing module is used for receiving information of a small cell lung cancer patient treated by a medicament, wherein the information at least comprises medication information of the small cell lung cancer patient receiving the medicament; the drug is selected from etoposide-platinum drug combination, irinotecan-platinum drug combination, TIC10 or docetaxel; the output module is used for receiving the information output by the patient information processing module and guiding the adjustment of the application parameters and/or the adjustment of the drug delivery mode of the tumor electric field treatment of the small cell lung cancer patient.
Description
Technical Field
The invention relates to the technical field of tumor medical treatment, in particular to a small cell lung cancer treatment system and an alternating electric field generating device.
Background
Lung cancer is the most common cause of tumor death worldwide. Small Cell Lung Cancer (SCLC) is a highly aggressive and fatal malignancy characterized by rapid proliferation, high growth rate and extensive metastasis with early development, accounting for approximately 15-20% of all cases diagnosed with lung cancer. Survival rates of SCLC patients are less than 7% 5 years after definitive diagnosis, and Overall Survival (OS) is poor. SCLC comprises an estimated 250,000 new cases and at least 200,000 deaths worldwide per year. The extensive SCLC (ES-SCLC) accounts for about two-thirds of all SCLC cases.
Clinically, in the treatment of small cell lung cancer, surgery and chemoradiotherapy are common treatment methods for treating small cell lung cancer, but the surgery and the chemoradiotherapy are just like a double-edged sword, can damage normal cells while killing tumors, can generate a series of side effects, cause the reduction of immunity and resistance of a patient, provide a basis for the recurrence and metastasis of cancer, and influence the treatment effect and the life cycle of the patient. Although first-line platinum chemotherapy, which is commonly used in combination with etoposide, often responds significantly (response rates up to 80%), the response is transient, recurrence of the disease is fatal, and rapidly metastasizes. In addition, despite the primary efficacy of first line therapy, these drugs often cause toxicity in patients, including alopecia, high fatigue, cytopenia, nausea, and diarrhea, making treatment more difficult and potentially recurrent in those facing a poor prognosis. Due to the relative limitation of the effect of the existing treatment means, the whole patient faces the outstanding problems of short survival time, quick tumor recurrence, poor curative effect and the like. The effective rate of the platinum refractory patients is only 5%, and the survival rate of the platinum refractory patients is only 9% in 1 year, so that the great demand for improving the first-line treatment is particularly urgent.
The tumor electric field therapy (TTfields) is a novel tumor therapy method, transmits an alternating electric field with medium frequency (100-300 kHz) and low field intensity (1-3V/cm) to a focus in vivo through an externally applied electrode slice to destroy tumor cells in a rapid division state, and is a novel portable, effective and low-side-effect therapy mode. TTFields represents a new therapeutic approach that has been FDA approved for newly diagnosed glioblastomas and recurrent glioblastomas, among others.
The basic principle of TTFields' action is based on the fact that the polar molecules in tumor cells are pulled by alternating electric fields of medium and low intensity, mitotic activity is hindered, and ultimately tumor cell death is induced, while non-rapidly dividing cells and normal tissues are unaffected. TTFields is a physical rather than chemical modality, which is well tolerated with little to no toxicity. The only side effect is contact dermatitis under the electrode, which may also be the result of a combination of factors.
Disclosure of Invention
The invention relates to a small cell lung cancer treatment system, comprising:
a patient information processing module and an output module;
the patient information processing module is used for receiving information of a small cell lung cancer patient treated by a medicament, wherein the information at least comprises medication information of the small cell lung cancer patient receiving the medicament; the drug is selected from etoposide-platinum drug combination, irinotecan-platinum drug combination, TIC10 or docetaxel;
the output module is used for receiving the information output by the patient information processing module and guiding the adjustment of the application parameters and/or the adjustment of the drug delivery mode of the tumor electric field treatment of the small cell lung cancer patient.
According to another aspect of the invention, the invention also relates to the application of etoposide-platinum drug combination, irinotecan-platinum drug combination and TIC10 or docetaxel in preparing small cell lung cancer drugs;
the subject of the small cell lung cancer medicament is a small cell lung cancer patient treated by an electric field tumor treatment.
According to the other aspect of the invention, the alternating electric field generating device for treating the small cell lung cancer comprises electrodes, when the electrodes act on a subject, an alternating electric field can be applied to tumor cells of the subject, the frequency of the alternating electric field is 150 kHz-250 kHz, the field strength is more than or equal to 1.5Vpeak/cm, and the intervention time of the alternating electric field is more than or equal to 72h; the subject is a small cell lung cancer patient and is drug treated; the drug is selected from etoposide-platinum drug combination, irinotecan-platinum drug combination, TIC10 or docetaxel.
The treatment scheme provided by the invention can be used as a substitute scheme of the traditional treatment method, can effectively reduce the use of chemotherapeutic drugs, enhance the treatment effect, reduce the possibility of drug resistance of the chemotherapeutic drugs, reduce the side effect of the traditional chemoradiotherapy on patients and improve the life quality of the patients.
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, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a graph of the frequency of an electric field versus the effectiveness of treatment provided by one embodiment of the present invention: small cell lung cancer cell lines H1048 (a), DMS114 (b), KP3 (c); the frequency is 100-300kHz, and the processing time is 72h.
FIG. 2 is a graph of electric field strength versus treatment effectiveness provided by one embodiment of the present invention: small cell lung cancer cell lines H1048 (a), DMS114 (b), KP3 (c); frequency 200kHz, field strength 1.0-2.2v/cm (peak value), and processing time 72h.
In fig. 3, a is a graph of the therapeutic effect of the combination of an electric field and etoposide-platinum provided by one embodiment of the invention: b is a graph of the therapeutic effect of the electric field in combination with irinotecan-platinum, provided by one embodiment of the invention:
all treatment objects are small cell lung cancer cell lines (KP 3), the frequency is 200kHz, and the treatment time is 72h;
FIG. 4 is a graph of the therapeutic effect of an electric field in combination with etoposide-platinum according to one embodiment of the present invention: a small cell lung cancer cell line (KP 3), the frequency is 200kHz, and the treatment time is 72h;
CTL: a control group; TEFTS: electric field treatment of tumors; TEFTS + Eto: the electric field treatment of the tumor is combined with etoposide, and the drug concentration of Eto is 0.5 mu M; TEFTS + Cis: the tumor electric field treatment is combined with platinum, and the drug concentration of Cis is 0.5 mu M; TEFTS + Eto-Cis: the drug concentration of the electric field treatment of the tumor combined with etoposide-platinum, eto and Cis is 0.5 mu M.
Figure 5 is a graph of the therapeutic effect of an electric field in combination with irinotecan-platinum species provided by one embodiment of the present invention: a small cell lung cancer cell line (KP 3), the frequency is 200kHz, and the treatment time is 72h;
CTL: a control group; TEFTS: electric field treatment of tumors; TEFTS + Iri: the electric field treatment of the tumor is combined with irinotecan, and the drug concentration of Iri is 0.5 mu M; TEFTS + Cis: the tumor electric field treatment is combined with platinum, and the drug concentration of Cis is 0.5 mu M; TEFTS + Iri-Cis: the drug concentration of the electric field treatment of tumor combined with irinotecan-platinum, eto and Cis is 0.5 mu M.
FIG. 6 is a graph of the therapeutic effect of an electric field in combination with TIC10 provided by one embodiment of the present invention: a small cell lung cancer cell line (KP 3), the frequency is 200kHz, and the treatment time is 72h;
CTL: a control group; TEFTS: electric field treatment of tumors; TIC10: TIC10 alone; TEFTS + TIC10: tumor electric field therapy in combination with TIC10; the drug concentration of TIC10 was 10. Mu.M.
Figure 7 is a graph of the therapeutic effect of electric field in combination with docetaxel provided in accordance with one embodiment of the present invention: a small cell lung cancer cell line (KP 3) with the frequency of 200kHz and the treatment time of 72h;
CTL: a control group; TEFTS: electric field treatment of tumors; and Doc: docetaxel alone; TEFTS + Doc: electric field treatment of tumors in combination with docetaxel; the drug concentration of docetaxel was 0.5 μ M as described above.
Detailed Description
Reference will now be made in detail to embodiments of the invention, one or more examples of which are described below. Each example is provided by way of explanation, not limitation, of the invention. Indeed, it will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. For instance, features illustrated or described as part of one embodiment, can be used on another embodiment to yield a still further embodiment.
Unless otherwise defined, all terms (including technical and scientific terms) used in disclosing the invention are to be interpreted as commonly understood by one of ordinary skill in the art to which this invention belongs. The following definitions serve to better understand the teachings of the present invention by way of further guidance. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The term "and/or", "and/or" as used herein is intended to be inclusive of any one of the two or more items listed in association, and also to include any and all combinations of the items listed in association, including any two or more of the items listed in association, any more of the items listed in association, or all combinations of the items listed in association. It should be noted that when at least three items are connected by at least two conjunctive combinations selected from "and/or", "or" and/or ", it should be understood that in this application, the technical solutions unquestionably include the technical solutions all connected by" logical and ", and also unquestionably include the technical solutions all connected by" logical or ". For example, "A and/or B" includes three parallel schemes of A, B and A + B. For example, a reference to "a, and/or, B, and/or, C, and/or, D" includes any one of a, B, C, and D (i.e., all references connected by "logical or"), any and all combinations of a, B, C, and D (i.e., any two or any three of a, B, C, and D), and four combinations of a, B, C, and D (i.e., all references connected by "logical and").
As used herein, the terms "comprising," "including," and "comprising" are synonymous, inclusive or open-ended, and do not exclude additional, unrecited members, elements, or method steps.
The recitation of numerical ranges by endpoints herein includes all numbers and fractions subsumed within that range, as well as the recited endpoints.
The present invention relates to concentration values, which include fluctuations within a certain range. For example, it may fluctuate within a corresponding accuracy range. For example, 2%, may be allowed to fluctuate within ± 0.1%. For values that are larger or do not require more fine control, the meaning is also allowed to include greater fluctuations. For example, 100mM, may allow fluctuations within the range of. + -. 1%,. + -. 2%,. + -. 5%, etc. The molecular weight is referred to, allowing the meaning to include fluctuations of ± 10%.
In the present invention, the terms "plurality", and the like mean, unless otherwise specified, 2 or more in number.
In the present invention, the technical features described in the open type include a closed technical solution composed of the listed features, and also include an open technical solution including the listed features.
In the present invention, "preferably", "better" and "preferable" are only embodiments or examples with better description, and it should be understood that the scope of the present invention is not limited by them. In the present invention, "optionally", "optional" and "optional" refer to the presence or absence, i.e., to any one of two juxtapositions selected from "present" and "absent". If multiple optional parts appear in one technical scheme, if no special description exists, and no contradiction or mutual constraint relation exists, each optional part is independent.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. The citation referred to herein is incorporated by reference in its entirety for all purposes unless otherwise in conflict with the present disclosure's objectives and/or technical solutions. Where a citation is referred to herein, the definition of a reference in the document, including features, terms, nouns, phrases, etc., that is relevant, is also incorporated by reference. In the present invention, when the citation is referred to, the cited examples and preferred embodiments of the related art features are also incorporated by reference into the present application, but the present invention is not limited to the embodiments. It should be understood that where the citation conflicts with the description herein, the application will control or be adapted in accordance with the description herein.
A first aspect of the invention relates to a small cell lung cancer treatment system, the system comprising:
a patient information processing module and an output module;
the patient information processing module is used for receiving information of a small cell lung cancer patient treated by a medicament, wherein the information at least comprises medication information of the small cell lung cancer patient receiving the medicament; the drug is selected from etoposide-platinum drug combination, irinotecan-platinum drug combination, TIC10 or docetaxel;
the output module is used for receiving the information output by the patient information processing module and guiding the adjustment of the application parameters and/or the adjustment of the drug delivery mode of the tumor electric field treatment of the small cell lung cancer patient.
The alternating electric field is combined with etoposide/irinotecan-platinum drugs, TIC10 or docetaxel to inhibit the rapid proliferation of small cell lung cancer cells, so as to achieve the purpose of treating the small cell lung cancer. This not only improves the prognosis of the patient, but also improves the quality of life of the patient. In the present invention, etoposide, platinoids, irinotecan, TIC10 or docetaxel are understood to comprise pharmaceutically acceptable salts or solvates thereof, according to the general knowledge of a person skilled in the art.
The content of the adjustment of the application parameters of the tumor electric field treatment can comprise electric field frequency, field intensity, intervention time, the number of times of electric field stimulation, the interval time of two adjacent electric field stimulation, the application of the electric field stimulation and the position on the body of the patient and the like. The adjusted result can be presented in a mode of reporting a main interface by the system, and an operator operates the system through the guidance information; but it is more preferable to directly control the electric field generating means.
The content of the adjustment of the administration mode can comprise administration type, administration amount, administration times, administration interval, medication contraindications (such as drug cross-reaction indications) and side effect indications, etc.
In some embodiments, the electric field used for electric field treatment of tumors is an alternating electric field.
In some embodiments, the output module is configured to adjust the frequency of the alternating electric field to be 150kHz to 250kHz, such as 160kHz, 170kHz, 180kHz, 190kHz, 200kHz, 210kHz, 220kHz, 230kHz, 240kHz, and preferably 150kHz to 220kHz, 150kHz to 210kHz, or 150kHz to 200kHz.
The optimal frequency may be determined for each individual's own circumstances, such as the degree of sensitivity and tolerance to frequency. Preferably, care is taken to ensure that the alternating electric field at the selected frequency does not adversely heat a part of the subject's body.
In some embodiments, the output module is used for adjusting the field intensity of the alternating electric field to be more than or equal to 1.5Vpeak/cm; preferably 1.5 to 2.5Vpeak/cm, for example 1.7Vpeak/cm, 2.0Vpeak/cm, 2.2Vpeak/cm, 2.3Vpeak/cm.
In some embodiments, the output module is used to adjust the intervention time of the alternating electric field ≧ 72h, such as 76h, 80h, 92h, 100h.
The intervention time may be continuous or intermittent (but the cumulative time should reach the intervention time). For example, when the total intervention time is 72 hours, the intervention may be performed in 6 sessions having a duration of 12 hours each, with, for example, 2 hour intervals between sessions. The term "interval" refers to a time interval in which no electric field is applied. Again, care is preferably taken here to ensure that the alternating electric field at the selected intervention time does not adversely heat a part of the subject's body.
The parameters of the alternating electric field are set for the target region, in particular the region that acts on the tumor cells and the tissue in the vicinity thereof.
Platinum drugs act in a similar manner-these agents do not have alkyl groups, but nevertheless damage DNA. They permanently coordinate to DNA to interfere with DNA repair, and are therefore described as "alkylation-like". Some non-limiting examples of platinum analogs of the invention are one or more of the following: platinum, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate.
In some embodiments, the drug is an etoposide-platinum drug combination, and the concentration of both the etoposide and the platinum drug is between 0.5 μ M and 4.0 μ M, such as 1.0 μ M, 1.5 μ M, 2.0 μ M, 2.5 μ M, 3.0 μ M, or 3.5 μ M.
In some embodiments, the agent is an irinotecan-platinum-drug combination and the concentration of both irinotecan and platinum-drug is 0.5 μ M to 8.0 μ M, e.g., 1.0 μ M, 1.5 μ M, 2.0 μ M, 2.5 μ M, 3.0 μ M, 4.0 μ M, 5.0 μ M, 6.0 μ M, or 7.0 μ M.
In some embodiments, the drug is TIC10 and the concentration of TIC10 is 10 μ Μ to 80 μ Μ, such as 10 μ Μ, 15 μ Μ,20 μ Μ, 25 μ Μ, 30 μ Μ, 40 μ Μ, 50 μ Μ,60 μ Μ or 70 μ Μ.
In some embodiments, the drug is docetaxel and the concentration of docetaxel is 0.5 μ M to 8.0 μ M each, e.g., 1.0 μ M, 1.5 μ M, 2.0 μ M, 2.5 μ M, 3.0 μ M, 4.0 μ M, 5.0 μ M, 6.0 μ M, or 7.0 μ M.
The drug concentration herein refers to an effective concentration range when the above drug is brought into contact with target cells, and when the drug is administered in vivo, those skilled in the art can instruct the dose to be administered to a patient based on the concentration.
In some cases, the tumor is treated with an electric field (at least part of the treatment is completed) after administration of the drug and before the drug is eliminated from the subject's body. The term "eliminated from the body of a subject" refers to, for example, (1) metabolism of one or more of the drugs in the liver or elsewhere in the body, resulting in the excretion of substantially all of the one or more drugs from the body, or (2) reduction of the concentration of one or more of the drugs in the blood stream of the subject such that the drugs no longer provide substantially all of their therapeutic effect. The term "substantially" as used herein means greater than about 50%, 60%, 70%, 80%, 90%, or 100%.
In some embodiments, the medication information includes one or more of a type of the drug, a mode of administration, a time to start and stop of administration, and a side effect after administration.
The most common post-administration side effects of chemotherapy include nausea, vomiting, diarrhea or constipation, weakness, fatigue, mucositis, hair loss, respiratory and cognitive disorders. The electric field strength can be adjusted as appropriate by the severity of the side effect.
In some embodiments, the information further comprises one or more of a photograph, age, gender, height, weight, eating habits, medication history, mood status, time to visit with a symptom, family genetic history, frequency of smoking, type of exercise, and frequency of the patient.
The second aspect of the invention relates to the combined use of etoposide-platinum drugs, the combined use of irinotecan-platinum drugs and the application of TIC10 or docetaxel in the preparation of small cell lung cancer drugs;
the subject of the small cell lung cancer medicament is a small cell lung cancer patient treated by an electric field tumor treatment.
The third aspect of the invention relates to an alternating electric field generating device for treating small cell lung cancer, which comprises electrodes, wherein when the electrodes act on a subject, an alternating electric field can be applied to tumor cells of the subject, the frequency of the alternating electric field is 150 kHz-250 kHz, the field intensity is more than or equal to 1.5Vpeak/cm, and the intervention time of the alternating electric field is more than or equal to 72h; the subject is a small cell lung cancer patient and is drug treated; the drug is selected from etoposide-platinum drug combination, irinotecan-platinum drug combination, TIC10 or docetaxel.
The fourth aspect of the present invention also relates to a method of treating small cell lung cancer in a subject, the method comprising: administering a drug to a subject; and applying an alternating electric field to a target region of the subject;
wherein the subject is a small cell lung cancer patient undergoing electric field treatment for the tumor; the drug is selected from etoposide-platinum drug combination, irinotecan-platinum drug combination, TIC10 or docetaxel.
The preferred frequency of the alternating electric field is 150kHz to 250kHz.
The preferred field intensity of the alternating electric field is more than or equal to 1.5Vpeak/cm.
The preferred intervention time of the alternating electric field is more than or equal to 72h.
In some cases, the tumor is treated with an electric field (at least part of the treatment is completed) after administration of the drug and before the drug is eliminated from the subject's body.
It is to be understood that contemplated methods of treatment will also include administration of other tumor treatment entities, including CAR-T therapy, viral cancer vaccines (e.g., adenoviral vectors encoding cancer-specific antigens), bacterial cancer vaccines (e.g., non-pyrogenic e.coli expressing one or more cancer-specific antigens), yeast cancer vaccines, N-803 (also known as ALT-803, altor biosciences), chemotherapeutic drugs, antibodies (e.g., binding to a tumor-associated antigen or a patient-specific tumor neoantigen), stem cell grafts (e.g., allogeneic or autologous), and tumor-targeting cytokines (e.g., NHS-IL12, IL-12 conjugated to a tumor-targeting antibody or fragment thereof). In some embodiments, contemplated methods of treatment further comprise subjecting the patient to radiation therapy. In some embodiments, contemplated methods of treatment further comprise performing surgery on the patient, such as a tumor resection procedure.
In the present invention, a "patient" or "subject" is a mammal, including, but not limited to, humans, monkeys, pigs and other farm animals, sports animals, pets, primates, horses, dogs, cats, pandas, rodents (including mice, rats, guinea pigs), and the like.
The description and illustration of the first aspect of the invention also applies to the second, third and fourth aspects of the invention.
Embodiments of the present invention will be described in detail with reference to examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures for the conditions not specified in the following examples, preferably with reference to the guidelines given in the present invention, may also be performed according to the experimental manual or the conventional conditions in the art, and may also be performed according to other experimental procedures known in the art, or according to the conditions suggested by the manufacturer.
In the following specific examples, the measurement parameters relating to the components of the raw materials, if not specified otherwise, may be subject to slight deviations within the accuracy of the weighing. Temperature and time parameters are involved to allow for acceptable deviation due to instrument test accuracy or operational accuracy.
Examples
The effects of electric field and treatment of etoposide/irinotecan-platinum species or TIC10 or docetaxel alone or in combination were tested using small cell lung cancer cell lines (H1048/DMS 114/KP 3). All cells were supplied with 5% CO 2 Grown in a humidified cell incubator. Cell culture medium was purchased from Gibco and 10% fetal bovine serum and 1% penicillin and streptomycin were added before culturing the cells.
Cell proliferation assay
And (3) interfering the small cell lung cancer cell by using an alternating electric field (100-300 kHz, 1-3 v/cm). Preparing cell suspension, and regulating cell concentration. The slide with the diameter of phi 20mm is placed in a ceramic culture dish, and an in vitro cell experiment tumor electric field intervention device is used. 100-150 mul of cell suspension is added to each slide, so that the cell suspension is uniformly distributed on the surface of the slide. Placing in a 37 ℃ saturated humidity incubator for 4-6h, supplementing 4ml of culture medium after the cells are completely attached to the wall, and placing in the 37 ℃ saturated humidity incubator for overnight culture. The cells were divided into two groups, one group with and one without an electric field. The electric field adding group adjusts the electric field parameters of the instrument to required frequency according to experimental conditions, and sets corresponding cell culture box temperature according to different frequency parameters so as to ensure that the temperature in the quadrilateral culture dish is always kept at 37 ℃ in the whole electrifying process. The electric field is applied for 72h. And taking out all the slides after the electric field treatment is finished, and carrying out cell counting and subsequent experiments. The experiment was repeated 3 times.
CCK-8 cytotoxicity assays
The CCK-8 cytotoxicity detection kit contains WST-8 (2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfophenyl) -2H-tetrazole monosodium salt), and in the presence of an electron carrier, WST-8 is oxidized and reduced by intracellular dehydrogenase to generate water-soluble orange formazan dye which can be dissolved in a tissue culture medium, and the amount of the generated formazan is in direct proportion to the number of living cells. The CCK-8 method is a highly sensitive, radioactivity-free colorimetric assay for determining the number of viable cells in a cell assay. Using small cell lung cancer cell line (H1048/DMS 114/KP 3); the frequency is 200kHz, the field intensity is 2.2v/cm, and the electric field treatment time is 72h. Wherein the concentrations of etoposide, platinum (cisplatin), irinotecan, TIC10 and docetaxel are respectively 0.5 μ M,1 μ M,0.5 μ M,10 μ M and 0.5 μ M in sequence, and the treatment is carried out by simultaneous administration during the electric field treatment period. And collecting the cell suspension, adding 10 mu l of CCK-8 solution into each hole, continuously incubating for 1.5-2 hours in a cell incubator, and measuring the absorbance of each hole by using an enzyme-labeling instrument at 450 nm.
Data statistics
Experimental data were statistically analyzed using Graphpad Prism software, comparisons between groups were performed using t-test, and all data are expressed as mean ± standard deviation, # P < 0.05, # P < 0.01, # P < 0.001.* Represent the statistical comparison of each experimental group with the control group.
2. Results of the experiment
2.1 electric field intervention Small cell Lung cancer cell proliferation has frequency (kHz) dependency
The relationship between the electric field frequency and the intervention effect is shown in FIG. 1, after the electric fields of 100kHz, 150kHz and 200kHz respectively intervene in the small-cell lung cancer cell lines H1048 (a), DMS114 (b) and KP3 (c) 72H, the relative number of the cells at 200kHz is minimum, which indicates that the electric field intervenes in the small-cell lung cancer cells and has frequency dependence, and the inhibition effect of 200kHz is optimal; and secondly 150kHz.
2.2 electric field intervention Small cell Lung cancer cell proliferation has field intensity (V/cm) dependence
The relationship between the electric field intensity and the intervention effect is shown in FIG. 2, after 1.0-2.2V/cm (peak value) and 200kHz electric field intervene in small cell lung cancer cell lines H1048 (a), DMS114 (b) and KP3 (c) for 72H respectively, the relative number of cells at 2.2V/cm is the smallest, which indicates that the electric field intervenes in small cell lung cancer cells and has field intensity dependence, and the larger the field intensity, the better the inhibition effect.
2.3 the synergistic effect of the combination of the electric field and etoposide/irinotecan-platinum or TIC10 or docetaxel
1) First, the inventors examined the conditions of etoposide-platins, irinotecan-platins, TIC10 or docetaxel in combination with electric field at different concentrations to screen the optimal administration concentrations of each drug.
Exemplary experimental results are shown in fig. 3. In fig. 3A, after the small cell lung cancer cell line (KP 3) was treated with different concentrations of etoposide-platinum combined electric field for 72h, it was found that the relative number of cells was significantly decreased and the difference was statistically significant (P < 0.05, P < 0.01) after the electric field combined etoposide-platinum acting small cell lung cancer cell line (KP 3) was used at drug concentrations ranging from 0.5 μ M to 4.0 μ M, compared to the etoposide-platinum alone.
Furthermore, this synergy is also exhibited on the electric field in combination with irinotecan-platinum based small cell lung cancer cell line (B in FIG. 3), at least in the drug concentration range of 0.5. Mu.M to 8.0. Mu.M.
In the same manner, TIC10 and docetaxel were tested to determine the range of drug concentrations for synergy. For TIC10, the concentration of the drug with synergistic effect is 10-80 μ M, and for docetaxel, the concentration of the drug with synergistic effect is 0.5-8.0 μ M.
2) In order to compare the synergistic effect of the combination of the electric field and the drugs more intuitively, the inventors carried out further comparison and detection respectively under the drug concentration with better synergistic effect.
As shown in fig. 4, after the small cell lung cancer cell line was treated with the etoposide-platinum combined electric field for 72h, the relative number of cells was found to be 63.96% compared with the small cell lung cancer cell line treated with the etoposide-platinum combined electric field alone, and after the small cell lung cancer cell was treated with the electric field combined with the etoposide-platinum two drugs, the relative number of cells was clearly seen to drop to 42.37% (. P < 0.01). Furthermore, this synergy was also shown on the electric field in combination with irinotecan-platinum based small cell lung cancer cell lines (results shown in FIG. 5, 60.99% vs 40.44%,. P < 0.01). In addition, electric field combination TIC10: as shown in fig. 6, the electric field in combination with TIC10 decreased the relative number of cells from 67.83% to 38.71% (. X.p < 0.001) compared to TIC10 alone; similarly, the electric field in combination with docetaxel reduced the relative number of cells from 69.57% to 55.92% (P < 0.01) compared to docetaxel alone (fig. 7). The results show that the electric field combined with etoposide/irinotecan-platinum or TIC10 or docetaxel can obviously improve the proliferation inhibition rate of small cell lung cancer cells, and can reduce the dosage of the medicament under the action of achieving the same curative effect, thereby reducing the systemic toxicity. The data show that the combination of the medicine and the tumor electric field treatment produces synergistic effect on the proliferation inhibition of the small cell lung cancer cells, and the result proves that the combination of the electric field combination medicine is effective treatment aiming at the small cell lung cancer cells, wherein the combination effect of TIC10 and the electric field is the best, and secondly, etoposide/irinotecan-platinum provides reference basis for improving the life cycle of the small cell lung cancer patients.
The results show that the electric field combined with etoposide/irinotecan-platinum or TIC10 can obviously improve the proliferation inhibition rate of small cell lung cancer cells, and can reduce the dosage of the medicament under the action of achieving the same curative effect, thereby reducing the systemic toxicity.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the patent of the present invention should be subject to the appended claims, and the description and the drawings can be used for explaining the contents of the claims.
Claims (10)
1. A small cell lung cancer treatment system, the system comprising:
a patient information processing module and an output module;
the patient information processing module is used for receiving information of a small cell lung cancer patient treated by a medicament, wherein the information at least comprises medication information of the small cell lung cancer patient receiving the medicament; the drug is selected from etoposide-platinum drug combination, irinotecan-platinum drug combination, TIC10 or docetaxel;
the output module is used for receiving the information output by the patient information processing module and guiding the adjustment of the application parameters and/or the adjustment of the drug delivery mode of the tumor electric field treatment of the small cell lung cancer patient.
2. The small cell lung cancer treatment system of claim 1, wherein the electric field used for electric field treatment of tumor is an alternating electric field.
3. The small cell lung cancer treatment system of claim 2, wherein the output module is configured to adjust the frequency of the alternating electric field to be 150kHz to 250kHz.
4. The small cell lung cancer treatment system of claim 3, wherein the output module is configured to adjust the frequency of the alternating electric field to be 150 kHz-220 kHz.
5. The small cell lung cancer treatment system of claim 2, wherein the output module is configured to adjust the field strength of the alternating electric field to be greater than or equal to 1.5Vpeak/cm.
6. The small cell lung cancer treatment system of claim 2, wherein the output module is used for adjusting the intervention time of the alternating electric field to be more than or equal to 72h.
7. The small cell lung cancer treatment system according to any one of claims 1 to 6, wherein the platinum drug is selected from one or more of platinum, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin and triplatin tetranitrate.
8. The small cell lung cancer treatment system according to any one of claims 1 to 6, wherein the administration information includes one or more of a type of the drug, an administration mode, a start/stop time of administration, and a side effect after administration.
9. The combination of etoposide-platinum drugs, the combination of irinotecan-platinum drugs and the application of TIC10 or docetaxel in preparing small cell lung cancer drugs;
the subject of the small cell lung cancer medicament is a small cell lung cancer patient treated by an electric field tumor treatment.
10. An alternating electric field generating device for treating small cell lung cancer comprises electrodes, when the electrodes act on a subject, an alternating electric field can be applied to tumor cells of the subject, the frequency of the alternating electric field is 150 kHz-250 kHz, the field intensity is more than or equal to 1.5Vpeak/cm, and the intervention time of the alternating electric field is more than or equal to 72h; the subject is a small cell lung cancer patient and is drug treated; the drug is selected from etoposide-platinum drug combination, irinotecan-platinum drug combination, TIC10 or docetaxel.
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