CN109481454A - Anti-tumor compositions and its application in terms of preparing antitumor or inhibition cancer cell drug, anti-tumor drug - Google Patents
Anti-tumor compositions and its application in terms of preparing antitumor or inhibition cancer cell drug, anti-tumor drug Download PDFInfo
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- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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Abstract
Application, anti-tumor drug the present invention relates to a kind of anti-tumor compositions and its in terms of preparing antitumor or inhibition cancer cell drug, belong to field of medicine preparing technology.Anti-tumor compositions of the invention include including the first Studies on Anticancer Components and the second Studies on Anticancer Components, and the first Studies on Anticancer Components is the combination of one or more of capecitabine, fludarabine, hydroxycarbamide or the salt of one or more of capecitabine, fludarabine, hydroxycarbamide；Second Studies on Anticancer Components is dihydroartemisinine, and the molar ratio of the first Studies on Anticancer Components and dihydroartemisinine is 1:1-20；Or second Studies on Anticancer Components be artemisinin derivatives, first Studies on Anticancer Components and qinghaosu or the molar ratio for being metabolized the dihydroartemisinine generated are 1:1-20, and the antitumoral compounds that metabolism generates dihydroartemisinine are the combination of one or more of Artesunate, Artemether, arteether.The component of anti-tumor compositions of the invention has synergistic function.
Description
Technical field
The present invention relates to a kind of anti-tumor compositions and its prepare it is antitumor or inhibit cancer cell drug in terms of application,
Anti-tumor drug belongs to field of medicine preparing technology.
Background technique
Malignant tumour can not still cure so far, it has also become current whole world public health problem outstanding.The World Health Organization
Claim, just there is 1 people to die of cancer in average every 8 deaths in the whole world at present, than death caused by AIDS, malaria and tuberculosis
Number summation is taller.International Cancer Research Center (IARC) statistics indicate that, whole world malignant tumour new cases in 2002
About 10,900,000, dead 6,700,000.The research report that IARC is provided is shown, increases cancer patient newly every year to the year two thousand twenty whole world
Number is up to 15,000,000 people.WHO statistics shows that surprising increasing occur in global cancer new cases in 2012 and death toll
Long, China is even more to rank first.A newest phase " Chinese Incidence and the Study on mortality report of National Cancer Center publication
Accuse " display, national de novo malignancy case about 380.4 ten thousand, death 229.6 ten thousand in 2014.China accounts for about respectively
The 21.8% and 27% of global malignant tumour new cases and death occupies medium on the upper side in 184 countries and regions
It is horizontal.This means that average minute clock has 7 people to be diagnosed as cancer, 4 people are because of cancer mortality.The mode for the treatment of of cancer at present is main
There are operative treatment, radiotherapy, chemotherapy, biological therapy etc., wherein chemotherapy is still main therapeutic modality.
In the chemicals for the treatment of cancer, capecitabine (Capecitabine) is that one kind can be transformed into 5-FU in vivo
Antimetabolic fluoropyrimidine deoxyribonucleoside carbamates drug, product name is Xeloda, is able to suppress cell division and dry
Disturb RNA and protein (protein) synthesis.It is mainly used for advanced primary or metastatic breast cancer, the carcinoma of the rectum, colon cancer stomach function regulating
The treatment of cancer, be particularly suitable for taxol and include the invalid advanced primary of anthracycline antibiotic chemotherapy regimen treatment or
The further treatment of metastatic breast cancer.
Fludarabine (Fludarabine) is the fluorination nucleotide derivative of cytarabine, certain pharmacological actions and arabinose
Cytidine is similar.Cytarabine is acted on by adenosine deaminase quickly and is inactivated, and fludarabine is without by this enzyme-deactivating.Phosphoric acid fluorine
Up to drawing shore to become 2F-ara-A by rapidly dephosphorylation in vivo, then the latter can be taken off by cellular uptake by intracellular
Become active triphosphate after oxygen cytidine tyrosine phosphorylation, can inhibit DNA synthesis.To the white blood of B- Cell chronic lymphocytic
Sick (CLL) is significant in efficacy.
Hydroxycarbamide (Hydroxycarbamide) is a kind of ribonucleoside diphosphate reductase inhibitor, can prevent nucleotide
It is reduced to deoxynucleotide, thus selectively inhibits the synthesis of DNA, thymidylic acid can be inhibited to mix DNA, and can be straight
Damage dna is connect, but inhibiting effect is had no to the synthesis of RNA and protein.The S phase is acted on, and part cell block can be made in G1/
The edge of S phase effectively to chronic myelocytic leukemia (CML), and can be used for CML drug resistant to busulfan；To melanoma, kidney
Cancer, head-neck carcinoma have certain curative effect, effective to incidence and cervical squamous cell carcinoma with chemotherapy combined radiotherapy.
Sweet wormwood is conventional Chinese medicine, is the drying overground part of annual compositae plant artemisia annua (Aretemisiaannua L.)
Point." the careless wormwood artemisia " and " sweet wormwood " that ancient herbal medicine describes is no different with " artemisia annua ", and Chinese medicine, which is practised, claims " sweet wormwood ", and botany is commonly referred to as
" artemisia annua ".
Chinese medicine sweet wormwood has effects that clearind deficient heat, except hectic fever due to yin, solution hot summer weather, preventing malaria, removing jaundice, has answer within more than 2,000 years in China
Use history.It slaughters cry of a deer research team and has extracted qinghaosu from Chinese medicine plant Artemisia annua for the first time in China in 1971
(Artemisinin, ART), and its determining chemical structure was sesquiterpenoids in 1972.Qinghaosu be China it is pioneering,
The antimalarial agent of international endorsement.On the basis of qinghaosu, researcher retains peroxide bridge active structure, develops sweet wormwood in succession
A series of artemisinin derivatives such as amber ester, Artemether, arteether, dihydroartemisinine, maleic acid arteether amine (SM934).
The chemical structure of qinghaosu and several frequently seen artemisinin derivative is as follows:
Multinomial research confirms that qinghaosu and its derivative pharmacological action are extensive, not only post malaria, toxoplasma etc. in recent years
Infested disease has therapeutic effect, also has anti-inflammatory, antitumor and immunoregulatory function, has to lupus erythematosus, rheumatism etc.
Significant curative effect, to leukaemia, non-small cell lung cancer, liver cancer, gastric cancer, colon cancer, cancer of pancreas, breast cancer, cervical carcinoma, prostate cancer
Deng there is therapeutic effect.Its mechanism of action is mainly shown as the cell for inhibiting the cell cycle, Apoptosis, iron ion being promoted to mediate
Toxic action, anti-angiogenetic therapy, chemicotherapy enhanced sensitivity and reverse effect of multidrug resistance tumor cells etc..Dihydroartemisinine
(Dihydroartemisinin, DHA) is compound of the qinghaosu through sodium borohydride reduction, is that the active metabolism of qinghaosu produces
Object.DHA anti-tumor activity is good；It is worth noting that, DHA is the shared active metabolite of above-mentioned artemisinin derivatives,
It is the Typical Representative of existing artemisinin derivatives.Potentially clinical new indication meets Present Global for qinghaosu and its derivative
Spectrum of disease development law designs such medicinal application composition and contains for current recruit's entity medicament research and development weakness status
Huge potentiality to be exploited.The pharmaceutical composition of capecitabine, fludarabine, hydroxycarbamide and qinghaosu and its derivative is applied to tumour
Treatment has not been reported.
Summary of the invention
The purpose of the present invention is to provide a kind of anti-tumor compositions that can be synergistic.The present invention also aims to
One kind is provided and is capable of application of the synergistic anti-tumor compositions in terms of preparing drug that is antitumor or inhibiting cancer cell.This
The purpose of invention, which also resides in, provides a kind of anti-tumor drug with synergistic function.
To achieve the goals above, The technical solution adopted by the invention is as follows:
A kind of anti-tumor compositions, including the first Studies on Anticancer Components and the second Studies on Anticancer Components, described first antitumor group
Be divided into one or more of capecitabine, fludarabine, hydroxycarbamide combination or capecitabine, fludarabine, in hydroxycarbamide
One or more of salt；Second Studies on Anticancer Components is dihydroartemisinine, first Studies on Anticancer Components and double hydrogen sweet wormwoods
The molar ratio of element is 1-10:1-20；Or second Studies on Anticancer Components for qinghaosu or can be metabolized generation dihydroartemisinine
Antitumoral compounds, the dihydroartemisinine that first Studies on Anticancer Components and qinghaosu or the metabolism of the second Studies on Anticancer Components generate
Molar ratio be 1-10:1-20, it is described can be metabolized generate dihydroartemisinine antitumoral compounds be Artesunate, Hao Jia
The combination of one or more of ether, arteether.
The first Studies on Anticancer Components that anti-tumor compositions of the invention use is in capecitabine, fludarabine, hydroxycarbamide
One or more of combinations, the second Studies on Anticancer Components is that dihydroartemisinine or qinghaosu or metabolic energy generate dihydroartemisinine
Antitumoral compounds enable two kinds of Studies on Anticancer Components mutually to cooperate with when acting on tumour cell, improve thin to tumour
The inhibiting effect of born of the same parents.First Studies on Anticancer Components is that DNA is inhibited to synthesize anti-tumor compounds, derivative with qinghaosu or qinghaosu
Object synergy can have complementary advantages, and reduce single survival dose and avoid toxic reaction, improve anti-tumor activity, expand clinical adapt to
Disease range reduces or slows down the risk for generating drug resistance.
First Studies on Anticancer Components is hydroxycarbamide, and the second Studies on Anticancer Components is dihydroartemisinine, and hydroxycarbamide and double hydrogen are green
The molar ratio of artemisin is 10:1.Hydroxycarbamide in anti-tumor compositions and dihydroartemisinine collaboration at this time has good collaboration
Synergistic effect has good effect to inhibition liver cancer cells.
First Studies on Anticancer Components is hydroxycarbamide, and the second Studies on Anticancer Components is qinghaosu, Artesunate, Artemether, arteether
One or more of combination, mole for the dihydroartemisinine that hydroxycarbamide and qinghaosu or the metabolism of the second Studies on Anticancer Components generate
Than for 10:1.The second Studies on Anticancer Components in anti-tumor compositions at this time for qinghaosu or can be metabolized the double hydrogen sweet wormwoods of generation
Element, cooperateing with hydroxycarbamide has good synergistic function, has good effect to inhibition liver cancer cells.
First Studies on Anticancer Components is capecitabine, and the second Studies on Anticancer Components is dihydroartemisinine, capecitabine and double
The molar ratio of hydrogen arteannuin is 1:2.Capecitabine in anti-tumor compositions and dihydroartemisinine collaboration at this time has good
Synergistic function, have good therapeutic effect to leukaemia.
First Studies on Anticancer Components is capecitabine, and the second Studies on Anticancer Components is qinghaosu, Artesunate, Artemether, wormwood artemisia second
The dihydroartemisinine that the combination of one or more of ether, capecitabine and qinghaosu or the metabolism of the second Studies on Anticancer Components generate
Molar ratio is 1:2.The second Studies on Anticancer Components in anti-tumor compositions at this time for qinghaosu or can be metabolized the double hydrogen blueness of generation
Artemisin, cooperateing with capecitabine has good synergistic function, has good therapeutic effect to leukaemia.
First Studies on Anticancer Components is fludarabine, and the second Studies on Anticancer Components is dihydroartemisinine, fludarabine and double
The molar ratio of hydrogen arteannuin is 1:10-20.Fludarabine is cooperateed with dihydroartemisinine with good in anti-tumor compositions at this time
Good synergistic function, has preferable therapeutic effect to leukaemia, breast cancer, colon cancer.
First Studies on Anticancer Components is fludarabine, and the second Studies on Anticancer Components is qinghaosu, Artesunate, Artemether, wormwood artemisia second
The dihydroartemisinine that the combination of one or more of ether, fludarabine and qinghaosu or the metabolism of the second Studies on Anticancer Components generate
Molar ratio is 1:10-20.The second Studies on Anticancer Components for qinghaosu or can be metabolized the double hydrogen of generation in anti-tumor compositions at this time
Qinghaosu, cooperateing with fludarabine has good synergistic function, has preferably to leukaemia, breast cancer, colon cancer
Therapeutic effect.
A kind of application of above-mentioned anti-tumor compositions in terms of preparing anti-tumor drug.Due to above-mentioned antineoplastic combinations
Two kinds of Studies on Anticancer Components in object have synergistic function, which are used to prepare anti-tumor drug, to swollen
Oncocyte has good inhibiting effect, has good antitumous effect.
A kind of application of above-mentioned anti-tumor compositions in terms of preparation inhibits cancer cell drug, the cancer cell are white blood
At least one of disease, colon cancer, liver cancer, breast cancer cell.Anti-tumor compositions of the invention are to leukaemia, colon cancer, liver
Cancer, breast cancer cell have apparent effect, can be used to prepare the drug for inhibiting cancer cell.
A kind of anti-tumor drug, including main ingredient and auxiliary material, the main ingredient include that the first Studies on Anticancer Components and second are antitumor
Component, first Studies on Anticancer Components are combination or the Ka Peita of one or more of capecitabine, fludarabine, hydroxycarbamide
The salt of one or more of shore, fludarabine, hydroxycarbamide；Second Studies on Anticancer Components be dihydroartemisinine, described first
The molar ratio of Studies on Anticancer Components and dihydroartemisinine is 1:1-20；Or second Studies on Anticancer Components is qinghaosu or being capable of generation
It thanks the antitumoral compounds for generating dihydroartemisinine, first Studies on Anticancer Components and qinghaosu or the second Studies on Anticancer Components is metabolized
The molar ratio of the dihydroartemisinine of generation is 1:1-20, and the antitumoral compounds that can be metabolized generation dihydroartemisinine are blueness
The combination of one or more of artemisic succinate, Artemether, arteether.Anti-tumor drug of the invention has good antitumor work
With.
Detailed description of the invention
Fig. 1 is that the embodiment 1 of anti-tumor compositions of the invention acts on the examination of chronic myelocytic leukemia K562 cell
Test result schematic diagram；
Fig. 2 is that the embodiment 2 of anti-tumor compositions of the invention acts on the examination of chronic myelocytic leukemia K562 cell
Test result schematic diagram；
Fig. 3 is that the embodiment 4 of anti-tumor compositions of the invention acts on the examination of chronic myelocytic leukemia K562 cell
Test result schematic diagram；
Fig. 4 is that the embodiment 3 of anti-tumor compositions of the invention acts on the test result schematic diagram of breast cancer cell；
Fig. 5 is that the embodiment 3 of anti-tumor compositions of the invention acts on the test result schematic diagram of colon cancer cell；
Fig. 6 is that the embodiment 3 of anti-tumor compositions of the invention acts on the test result schematic diagram of liver cancer cells.
Specific embodiment
Anti-tumor compositions of the invention include the first Studies on Anticancer Components and the second Studies on Anticancer Components, and described first is antitumor
Group is divided into combination or the capecitabine, fludarabine, hydroxycarbamide of one or more of capecitabine, fludarabine, hydroxycarbamide
One or more of salt；Second Studies on Anticancer Components is dihydroartemisinine, and first Studies on Anticancer Components and double hydrogen are green
The molar ratio of artemisin is 1-10:1-20；Or second Studies on Anticancer Components for qinghaosu or can be metabolized the double hydrogen sweet wormwoods of generation
Double hydrogen sweet wormwoods that the antitumoral compounds of element, first Studies on Anticancer Components and qinghaosu or the metabolism of the second Studies on Anticancer Components generate
The molar ratio of element is 1-10:1-20, and the antitumoral compounds that can be metabolized generation dihydroartemisinine are Artesunate, Hao Jia
The combination of one or more of ether, arteether.
Anti-tumor drug of the invention includes main ingredient and auxiliary material, and wherein main ingredient is above-mentioned anti-tumor compositions.Of the invention
The second Studies on Anticancer Components in anti-tumor compositions and anti-tumor drug can be dihydroartemisinine or metabolism generates double hydrogen sweet wormwoods
The antitumoral compounds of element, when the second Studies on Anticancer Components is dihydroartemisinine, the first Studies on Anticancer Components and second antitumor group
The molar ratio divided directlys adopt the mol ratio of the first Studies on Anticancer Components and dihydroartemisinine.When the second Studies on Anticancer Components is not
Dihydroartemisinine but metabolism be when can generate the compound of dihydroartemisinine, the dihydroartemisinine generated with the compound metabolism
Molal quantity measured.When the second Studies on Anticancer Components is qinghaosu, directly measured with the molal quantity of qinghaosu.
One of capecitabine, fludarabine, hydroxycarbamide in anti-tumor compositions and anti-tumor drug of the invention
Or several salt is hydrochloride, oxalates, citrate or mesylate, or sodium salt, sylvite or magnesium salts.
Anti-tumor drug of the invention includes main ingredient and auxiliary material.Auxiliary material can be according to the dosage form of pharmaceutical preparation, and use is existing
Auxiliary material in technology, such as filler, wetting agent, adhesive.For example, auxiliary material can be when dosage form is tablet or capsule
Dextrin, starch, sucrose etc..
There is no limit can directly mix two kinds of Studies on Anticancer Components and be made into the preparation method of anti-tumor drug of the invention
Preparation, or respectively with or corresponding auxiliary material mixing be made into preparation respectively, be then packaged in one according still further to this field usual manner
It rises, or mixes and then remix with corresponding auxiliary material respectively and be made into preparation.
Anti-tumor drug of the invention can be the pharmaceutical preparation suitable for gastrointestinal administration, or parenteral administration
Pharmaceutical preparation.The preferably pharmaceutical preparation of gastrointestinal administration.
The first Studies on Anticancer Components and the second Studies on Anticancer Components in anti-tumor compositions and anti-tumor drug of the invention exist
It can be administered simultaneously, can also be separately administered with any sequencing when administration.The mode of separated administration, the two are administered
Time interval does not specially require, it is preferred that the time interval of the two administration is no more than one day.Or two kinds of groups can also be taken
Divide the mode of alternating delivery.
In the scheme that the first Studies on Anticancer Components and the second Studies on Anticancer Components in anti-tumor drug of the invention are administered simultaneously,
The same preparation comprising both components can be made in first Studies on Anticancer Components and the second Studies on Anticancer Components, such as tablet or glue
Capsule.Two kinds of components can also be made to the two different pharmaceutical preparations for separately including both components, such as tablet or capsule, this
When two kinds of preparations conventionally can be packed or be combined, patient can according to package insert prompt and meanwhile take
With.
It, can in the scheme of first Studies on Anticancer Components of anti-tumor drug of the invention and the second Studies on Anticancer Components consecutive administration
The first Studies on Anticancer Components and the second Studies on Anticancer Components to be made to the two different pharmaceutical preparations for separately including both components,
Such as tablet or capsule, two kinds of preparations conventionally can be packed or be combined at this time, patient can say according to drug
The sequencing of bright book prompt is successively taken.Above two component can also will be made to a kind of system of controlled release using conventional method
Agent first discharges a kind of component, then discharges another component again, and patient only needs to take the controlled release preparation.
It, can in the scheme of first Studies on Anticancer Components of anti-tumor drug of the invention and the second Studies on Anticancer Components alternating delivery
Different preparations is respectively prepared in the first Studies on Anticancer Components and the second Studies on Anticancer Components, two kinds of preparations are conventionally wrapped
It fills or combines, patient can take according to the chi sequence that package insert prompts.Or by above two component
The controlled release preparation for intersecting release is made, patient only needs to take the controlled release preparation.
When anti-tumor drug of the invention is solution, solvent can be castor oil, medical corn oil, ethyl alcohol, Tween-80
One of.Preferably, when the second Studies on Anticancer Components is Artesunate, Studies on Anticancer Components is mixed into system with bicarbonate, water
At injection.
Technical solution of the present invention is further detailed combined with specific embodiments below.
The experimental material and instrument used in following example is as follows:
1) experimental material.
Cell strain:
Tumor cell line chronic myelocytic leukemia K562 cell and human breast cancer cell line Bcap-37 of the present invention,
Purchased from Institute of Basic Medical Sciences, China Concord Medical Science University preclinical medicine cell centre；Human liver cancer cell HepG2, the colon of use
Cancer cell HT29 is given by Institute Of Chinese Materia Medica Of China Academy of Chinese Medical Sciences professor Li Qi.
2) laboratory apparatus:
Carbon dioxide incubator of the present invention is produced by Thermo company, and multi-function microplate reader is by Molecular
The production of Devices company.
3) experiment reagent:
Cell culture medium and fetal calf serum (FBS) of the present invention are purchased from Gibco company, 0.25% pancreatin, blueness
Streptomysin is purchased from Hyclone company, and CCK8 detection reagent is purchased from Japanese colleague chemical reagents corporation.
Dihydroartemisinine (DHA) is purchased from Chongqing Huafang Wulingshan Pharmaceutical Co., Ltd..
Capecitabine (2C), fludarabine (4F), hydroxycarbamide (5H) are purchased from the limited public affairs of Shanghai Aladdin biochemical technology share
Department.
The embodiment 1 of anti-tumor compositions
The anti-tumor compositions of the present embodiment are made of the first Studies on Anticancer Components and the second Studies on Anticancer Components, and first is antitumor
Group is divided into capecitabine (2C), and the second Studies on Anticancer Components is dihydroartemisinine (DHA), the first Studies on Anticancer Components and second antitumor
The molar ratio of component is 1:2.
The embodiment 2 of anti-tumor compositions
The anti-tumor compositions of the present embodiment are made of the first Studies on Anticancer Components and the second Studies on Anticancer Components, and first is antitumor
Group is divided into fludarabine (4F), and the second Studies on Anticancer Components is dihydroartemisinine (DHA), the first Studies on Anticancer Components and second antitumor
The molar ratio of component is 1:20.
The embodiment 3 of anti-tumor compositions
The anti-tumor compositions of the present embodiment are made of the first Studies on Anticancer Components and the second Studies on Anticancer Components, and first is antitumor
Group is divided into fludarabine (4F), and the second Studies on Anticancer Components is dihydroartemisinine (DHA), the first Studies on Anticancer Components and second antitumor
The molar ratio of component is 1:10.
The embodiment 4 of anti-tumor compositions
The anti-tumor compositions of the present embodiment are made of the first Studies on Anticancer Components and the second Studies on Anticancer Components, and first is antitumor
Group is divided into hydroxycarbamide (5H), and the second Studies on Anticancer Components is dihydroartemisinine (DHA), the first Studies on Anticancer Components and second antitumor group
The molar ratio divided is 10:1.
The embodiment 1 of anti-tumor drug
The anti-tumor drug of the present embodiment is mixture, is resisted by first in the embodiment 1-4 of above-mentioned anti-tumor compositions
Tumour component and the second Studies on Anticancer Components obtain after directly mixing according to corresponding molar ratio.
The embodiment 2 of anti-tumor drug
The anti-tumor drug of the present embodiment is tablet, including main ingredient and auxiliary material, and main ingredient is the reality of above-mentioned anti-tumor compositions
The anti-tumor compositions in a 1-4 are applied, auxiliary material is auxiliary material commonly used in the prior art.
Test example
Dihydroartemisinine (DHA) solution, capecitabine (2C) solution, fludarabine (4F) solution, hydroxyl in test example below
Base urea (5H) solution is culture medium solution, and DMSO percent by volume is not more than 0.5% in culture medium solution.
(1) test of chronic myelocytic leukemia K562 cell is acted on
Take the chronic myelocytic leukemia K562 cell mycillin of FBS, 100U/mL containing 10% (mass fraction)
DMEM culture medium is at a temperature of 37 DEG C, the CO of 5% (percent by volume)2It is cultivated in incubator, grows to logarithmic growth to cell
Phase, single cell suspension is prepared with 0.25% pancreatin digestive juice digestion, 96 orifice plates are inoculated in the concentration of every 8000 cells in hole
In.
Culture 12 hours after with 50 μm of ol/L, 25 μm of ol/L, 12.5 μm of ol/L, 6.25 μm of ol/L, 3.125 μm of ol/L,
Dihydroartemisinine (DHA) solution and 12.5 μm of ol/L, 6.25 μm of ol/L, 3.125 μ of 1.562 μm of ol/L, 0.781 μm of ol/L
Capecitabine (2C) solution, the 2.5 μm of ol/ of mol/L, 1.56 μm of ol/L, 0.78 μm of ol/L, 0.39 μm of ol/L, 0.195 μm of ol/L
L, 1.25 μm of ol/L, 0.63 μm of ol/L, 0.31 μm of ol/L, 0.156 μm of ol/L, 0.078 μm of ol/L, 0.039 μm of ol/L fluorine reach
Draw shore (4F) solution, 500 μm of ol/L, 250 μm of ol/L, 125 μm of ol/L, 62.5 μm of ol/L, 31.25 μm of ol/L, 15.62 μm of ol/
L, hydroxycarbamide (5H) solution of 7.81 μm of ol/L is respectively acting on the cell after culture, and molten with above-mentioned dihydroartemisinine (DHA)
Liquid and capecitabine (2C) cooperate with the cell after culture, molten with above-mentioned dihydroartemisinine (DHA) respectively with molar ratio 2:1
Liquid and fludarabine (4F) cooperate with the cell after culture, with above-mentioned dihydroartemisinine (DHA) with molar ratio 20:1 respectively
Solution and hydroxycarbamide (5H) cooperate with the cell after culture respectively with molar ratio 1:10.With the DMSO of same volume score by
Grade doubling dilution is as control.
After acting on 48h, the CCK8 detection reagent of 10 μ L is added in every hole, continues to cultivate 2h.It is detected with all-wave length microplate reader
Light absorption value at OD450nm, then calculates inhibiting rate according to the following formula:
Inhibiting rate (GI)=(C-T)/C*100%, wherein C is control group activity of tumor cells, and T is medication therapy groups tumour
Cell activity.
Drug combination index (Combination Index, CI) is calculated using Calcusyn software, according to Chou-
Talaly definition, CI < 1 indicate that two medicines (component) is synergistic, and CI=1 indicates that two medicines (component) has synergistic effect, CI > 1
Indicate that two medicines (component) has antagonism.
It is CI=(D) that two medicines, which are combined Chou-Talaly formula,1/(Dx)1+(D)2/(Dx)2(meaning of formula and each parameter can
Bibliography: Chou T C.Theoretical basis, experimental design, and computerized
simulation of synergism and antagonism in drug combination studies[J]
.Pharmacological Reviews, 2006,58 (3): 621-681.).
As a result as shown in table 1 and Fig. 1, Fig. 2, Fig. 3.
Table 1 acts on the test result of chronic myelocytic leukemia K562 cell
| Medication classification | Concentration (μM) | Inhibiting rate (%) | CI |
| DHA | 1.563 | 34.17 | - |
| 2C | 0.781 | 3.63 | - |
| DHA+2C | 1.563+0.781 | 43.18 | 0.392 |
| DHA | 6.25 | 51.94 | - |
| 2C | 3.125 | 3.95 | - |
| DHA+2C | 6.25+3.125 | 54.43 | 0.536 |
| DHA | 3.125 | 43.4 | - |
| 2C | 1.563 | 2.15 | - |
| DHA+2C | 3.125+1.563 | 48.31 | 0.479 |
| DHA | 6.25 | 51.94 | - |
| 2C | 3.125 | 3.95 | - |
| DHA+2C | 6.25+3.125 | 54.43 | 0.536 |
| DHA | 1.563 | 34.17 | - |
| 4F | 0.078 | 0.1 | - |
| DHA+4F | 1.563+0.078 | 40.84 | 0.492 |
| DHA | 3.125 | 43.4 | - |
| 4F | 0.156 | 1.47 | - |
| DHA+4F | 3.125+0.156 | 51.15 | 0.366 |
| DHA | 3.125 | 43.4 | - |
| 5H | 31.25 | 8.8 | - |
| DHA+5H | 3.125+31.25 | 47.48 | 0.554 |
By table 1 and Fig. 1, Fig. 2, Fig. 3 it is found that capecitabine (2C), fludarabine (4F), hydroxycarbamide (5H) are in debita spissitudo
There is apparent synergistic function with DHA in range.
(2) test of breast cancer cell is acted on
Take the MCF-7 Human Breast Cancer Cells DMEM training of the mycillin of FBS, 100U/mL containing 10% (mass fraction)
Base is supported at a temperature of 37 DEG C, the CO of 5% (percent by volume)2It is cultivated in incubator, grows to logarithmic growth phase to cell, used
0.25% pancreatin digestive juice digestion prepares single cell suspension, is inoculated in 96 orifice plates with the concentration of every 5000 cells in hole.
With 200 μm of ol/L, 100 μm of ol/L, 50 μm of ol/L, 25 μm of ol/L, 12.5 μm of ol/L, 6.25 μ after culture 12 hours
Mol/L, dihydroartemisinine (DHA) solution of 3.125 μm of ol/L, 20 μm of ol/L, 10 μm of ol/L, 5 μm of ol/L, 2.5 μm of ol/L,
1.25 μm of ol/L, 0.63 μm of ol/L, 0.31 μm of ol/L fludarabine (4F) solution be respectively acting on culture after cell, be used in combination
Above-mentioned dihydroartemisinine (DHA) solution and fludarabine (4F) cooperate with the cell after culture respectively with molar ratio 10:1.
Using the DMSO of same volume score step by step doubling dilution as control.
After acting on 48h, the CCK8 detection reagent of 10 μ L is added in every hole, continues to cultivate 2h.It is detected with all-wave length microplate reader
Light absorption value at OD450nm, then calculates inhibiting rate according to the following formula:
Inhibiting rate (GI)=(C-T)/C*100%, wherein C is control group activity of tumor cells, and T is medication therapy groups tumour
Cell activity.
Drug combination index (Combination Index, CI) is calculated using Calcusyn software, according to Chou-
Talaly definition, CI < 1 indicate that two medicines (component) is synergistic, and CI=1 indicates that two medicines (component) has synergistic effect, CI > 1
Indicate that two medicines (component) has antagonism.
It is CI=(D) that two medicines, which are combined Chou-Talaly formula,1/(Dx)1+(D)2/(Dx)2(meaning of formula and each parameter can
Bibliography: Chou T C.Theoretical basis, experimental design, and computerized
simulation of synergism and antagonism in drug combination studies[J]
.Pharmacological Reviews, 2006,58 (3): 621-681.).
As a result as shown in table 2 and Fig. 4.
Table 2 acts on the test result of breast cancer cell
| Types of medicines | Concentration (μM) | Inhibiting rate (%) | CI |
| DHA | 12.5 | 6.76 | - |
| 4F | 1.25 | 60.69 | - |
| DHA+4F | 12.5+1.25 | 60.8 | 0.723 |
| DHA | 25 | 13.12 | - |
| 4F | 2.5 | 76.61 | - |
| DHA+4F | 25+2.5 | 75.6 | 0.461 |
By table 2 and Fig. 4 it is found that fludarabine (4F) has apparent synergistic function within the scope of debita spissitudo with DHA.
(3) test of colon cancer cell is acted on
Take the Human colorectal carcinoma HT29 cells DF-12 training of the mycillin of FBS, 100U/mL containing 10% (mass fraction)
Base is supported at a temperature of 37 DEG C, the CO of 5% (percent by volume)2It is cultivated in incubator, grows to logarithmic growth phase to cell, used
0.25% pancreatin digestive juice digestion prepares single cell suspension, is inoculated in 96 orifice plates with the concentration of every 5000 cells in hole.
With 100 μm of ol/L, 50 μm of ol/L, 25 μm of ol/L, 12.5 μm of ol/L, 6.25 μm of ol/L, 3.125 after culture 12 hours
Dihydroartemisinine (DHA) solution and 10 μm of ol/L, 5 μm of ol/L, 2.5 μm of ol/L, 1.25 μ of μm ol/L, 1.563 μm of ol/L
Mol/L, 0.63 μm of ol/L, 0.31 μm of ol/L, 0.156 μm of ol/L fludarabine (4F) solution be respectively acting on culture after it is thin
Born of the same parents, and after cooperating with culture respectively with above-mentioned dihydroartemisinine (DHA) solution and fludarabine (4F) with molar ratio 10:1
Cell.Using the DMSO of same volume score step by step doubling dilution as control.
After acting on 48h, the CCK8 detection reagent of 10 μ L is added in every hole, continues to cultivate 2h.It is detected with all-wave length microplate reader
Light absorption value at OD450nm, then calculates inhibiting rate according to the following formula:
Inhibiting rate (GI)=(C-T)/C*100%, wherein C is control group activity of tumor cells, and T is medication therapy groups tumour
Cell activity.
Drug combination index (Combination Index, CI) is calculated using Calcusyn software, according to Chou-
Talaly definition, CI < 1 indicate that two medicines (component) is synergistic, and CI=1 indicates that two medicines (component) has synergistic effect, CI > 1
Indicate that two medicines (component) has antagonism.
It is CI=(D) that two medicines, which are combined Chou-Talaly formula,1/(Dx)1+(D)2/(Dx)2(meaning of formula and each parameter can
Bibliography: Chou T C.Theoretical basis, experimental design, and computerized
simulation of synergism and antagonism in drug combination studies[J]
.Pharmacological Reviews, 2006,58 (3): 621-681.).
As a result as shown in table 3 and Fig. 5.
Table 3 acts on the test result of colon cancer cell
| Types of medicines | Concentration (μM) | Inhibiting rate (%) | CI |
| DHA | 6.25 | 1.97 | - |
| 4F | 0.625 | 32.31 | - |
| DHA+4F | 6.25+0.625 | 36.43 | 0.465 |
| DHA | 12.5 | 1.17 | - |
| 4F | 1.25 | 45.31 | - |
| DHA+4F | 12.5+1.25 | 47.36 | 0.57 |
By table 3 and Fig. 5 it is found that fludarabine (4F) has apparent synergistic function within the scope of debita spissitudo with DHA.
(4) test of liver cancer cells is acted on
Human hepatoma HepG2 cell is taken to use the RPMI1640 of the mycillin of FBS, 100U/mL containing 10% (mass fraction)
Culture medium is at a temperature of 37 DEG C, the CO of 5% (percent by volume)2It is cultivated in incubator, grows to logarithmic growth phase to cell, used
0.25% pancreatin digestive juice digestion prepares single cell suspension, is inoculated in 96 orifice plates with the concentration of every 5000 cells in hole.
With 200 μm of ol/L, 100 μm of ol/L, 50 μm of ol/L, 25 μm of ol/L, 12.5 μm of ol/L, 6.25 μ after culture 12 hours
Dihydroartemisinine (DHA) solution and 20 μm of ol/L, 10 μm of ol/L, 5 μm of ol/L, 2.5 μm of ol/ of mol/L, 3.125 μm of ol/L
L, 1.25 μm of ol/L, 0.63 μm of ol/L, 0.31 μm of ol/L fludarabine (4F) solution be respectively acting on culture after cell, and
After cooperating with culture respectively with above-mentioned dihydroartemisinine (DHA) solution, fludarabine (4F) solution with molar ratio 10:1
Cell.Using the DMSO of same volume score step by step doubling dilution as control.
After acting on 48h, the CCK8 detection reagent of 10 μ L is added in every hole, continues to cultivate 2h.It is detected with all-wave length microplate reader
Light absorption value at OD450nm, then calculates inhibiting rate according to the following formula:
Inhibiting rate (GI)=(C-T)/C*100%, wherein C is control group activity of tumor cells, and T is medication therapy groups tumour
Cell activity.
Drug combination index (Combination Index, CI) is calculated using Calcusyn software, according to Chou-
Talaly definition, CI < 1 indicate that two medicines (component) is synergistic, and CI=1 indicates that two medicines (component) has synergistic effect, CI > 1
Indicate that two medicines (component) has antagonism.
It is CI=(D) that two medicines, which are combined Chou-Talaly formula,1/(Dx)1+(D)2/(Dx)2(meaning of formula and each parameter can
Bibliography: Chou T C.Theoretical basis, experimental design, and computerized
simulation of synergism and antagonism in drug combination studies[J]
.Pharmacological Reviews, 2006,58 (3): 621-681.).
As a result as shown in table 4 and Fig. 6.
Table 4 acts on the test result of liver cancer cells
By table 4 and Fig. 6 it is found that fludarabine (4F) has apparent synergistic function within the scope of debita spissitudo with DHA.
When the second Studies on Anticancer Components be one of qinghaosu, Artesunate, Artemether, arteether when, due to its with it is double
The structural similarity of hydrogen arteannuin also has synergy with capecitabine, fludarabine, hydroxycarbamide within the scope of debita spissitudo
Effect.
Claims (10)
1. a kind of anti-tumor compositions, which is characterized in that including the first Studies on Anticancer Components and the second Studies on Anticancer Components, described first
Studies on Anticancer Components be one or more of capecitabine, fludarabine, hydroxycarbamide combination or capecitabine, fludarabine,
The salt of one or more of hydroxycarbamide；Second Studies on Anticancer Components be dihydroartemisinine, first Studies on Anticancer Components with
The molar ratio of dihydroartemisinine is 1-10:1-20；Or second Studies on Anticancer Components for qinghaosu or can be metabolized generation pair
The antitumoral compounds of hydrogen arteannuin, first Studies on Anticancer Components and qinghaosu or the metabolism of the second Studies on Anticancer Components generate double
The molar ratio of hydrogen arteannuin is 1-10:1-20, and the antitumoral compounds that can be metabolized generation dihydroartemisinine are sweet wormwood amber
The combination of one or more of ester, Artemether, arteether.
2. anti-tumor compositions according to claim 1, which is characterized in that first Studies on Anticancer Components is hydroxycarbamide,
Second Studies on Anticancer Components is dihydroartemisinine, and the molar ratio of hydroxycarbamide and dihydroartemisinine is 10:1.
3. anti-tumor compositions according to claim 1, which is characterized in that the first Studies on Anticancer Components be hydroxycarbamide, second
Studies on Anticancer Components is the combination of one or more of qinghaosu, Artesunate, Artemether, arteether, and hydroxycarbamide and second resist
The molar ratio for the dihydroartemisinine that the metabolism of tumour component generates is 10:1.
4. anti-tumor compositions according to claim 1, which is characterized in that first Studies on Anticancer Components is Ka Peita
Shore, the second Studies on Anticancer Components are dihydroartemisinine, and the molar ratio of capecitabine and dihydroartemisinine is 1:2.
5. anti-tumor compositions according to claim 1, which is characterized in that the first Studies on Anticancer Components is capecitabine, the
Secondary antibody tumor group is divided into the combination of one or more of qinghaosu, Artesunate, Artemether, arteether, capecitabine and blueness
The molar ratio for the dihydroartemisinine that artemisin or the metabolism of the second Studies on Anticancer Components generate is 1:2.
6. anti-tumor compositions according to claim 1, which is characterized in that first Studies on Anticancer Components is that fluorine reaches drawing
Shore, the second Studies on Anticancer Components are dihydroartemisinine, and the molar ratio of fludarabine and dihydroartemisinine is 1:10-20.
7. anti-tumor compositions according to claim 1, which is characterized in that the first Studies on Anticancer Components is fludarabine, the
Secondary antibody tumor group is divided into the combination of one or more of qinghaosu, Artesunate, Artemether, arteether, fludarabine and blueness
The molar ratio for the dihydroartemisinine that artemisin or the metabolism of the second Studies on Anticancer Components generate is 1:10-20.
8. a kind of application of anti-tumor compositions as described in claim 1 in terms of preparing anti-tumor drug.
9. a kind of application of anti-tumor compositions as described in claim 1 in terms of preparation inhibits cancer cell drug, feature
It is, the cancer cell is at least one of leukaemia, colon cancer, liver cancer, breast cancer cell.
10. a kind of anti-tumor drug, which is characterized in that including main ingredient and auxiliary material, the main ingredient include the first Studies on Anticancer Components and
Second Studies on Anticancer Components, first Studies on Anticancer Components are the group of one or more of capecitabine, fludarabine, hydroxycarbamide
It closes or the salt of one or more of capecitabine, fludarabine, hydroxycarbamide；Second Studies on Anticancer Components is double hydrogen sweet wormwoods
The molar ratio of element, first Studies on Anticancer Components and dihydroartemisinine is 1:1-20；Or second Studies on Anticancer Components is blueness
Artemisin can be metabolized the antitumoral compounds for generating dihydroartemisinine, and first Studies on Anticancer Components and qinghaosu or second are anti-
The molar ratio for the dihydroartemisinine that the metabolism of tumour component generates is 1:1-20, and described can be metabolized generates the anti-swollen of dihydroartemisinine
Tumor compound is the combination of one or more of Artesunate, Artemether, arteether.
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