CN104436194A - Anti-cancer composition with synergistic effect - Google Patents
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Abstract
The invention relates to an anti-cancer composition with synergistic effect, specifically a composition comprising an effective amount of at least one VEGF / VEGFR inhibitor and dopamine. The composition provided by the invention can obviously inhibit the growth of tumor cells, substantially reduce the use of anticancer drugs, and reduce the treatment risk and cost, and has broad application prospects.
Description
Technical field
The present invention relates to a kind of anti-cancer composition, the Preparation Method And The Use with synergistic function.
Background technology
Cancer, also known as malignant tumor, is a kind of by the not normal disease caused of control growth and proliferation of cell mechanism.Cancerous cell except grow out of control except, organize arround also locally invading and even transfer to other parts of health.The traditional method of current Therapeutic cancer comprises radiotherapy or chemotherapy, and can adopt the method for electrotherapy for some local entities's tumor, these traditional methods have certain curative effect, but secondary work of its poison quite greatly, in the process for the treatment of, brings great misery to patient.In tumor disease, entity tumor accounts for the overwhelming majority, and the generation of entity tumor, development and Preventive all depend on tumor neovasculature formation.Tumor-blood-vessel growth is the necessary requirement of implanted solid tumor growth and transfer.The tumor " starvation " of Tumor suppression vascularization, the blood supply of blocking-up tumor tissues, is considered to one of most promising new method for the treatment of solid tumor.
VEGF (Vascular Endothelial Growth Factor, vascular endothelial cell growth factor) be a kind of angiogenesis factor in tumor-blood-vessel growth process, it is the hormone regulator of endothelial cell differentiation, the development of solid tumor and the expression of VEGF are closely related, VEGF is as the key angiogenic growth factor in tumor angiogenesis, it is combined with the vegf receptor tyrosine kinase of specificity overexpression at neovascular endothelium cell surface, activates tyrosine kinase thus plays biological function.Thus be the new way that the tumor vascular targeted treatment (refer to use vegf receptor tyrosine kinase inhibitor) of target spot has become oncotherapy in recent years with vegf receptor tyrosine kinase.In addition, prior art has disclosed and has adopted antibody and VEGF sequester and the VEGF antagonism that produces can grow (Kim, 1993, Nature362,841-844) by Tumor suppression.Therefore, VEGF VEGF itself and receptor VEGFR (Vascular Endothelial Growth Factor Receptor) become the important target spot of cancer therapy drug antiangiogenic therapy already, such medicine comprises the monoclonal antibody of multiple micromolecule VEGFR inhibitor and VEGF, the former comprises Sutent (Sunitinib, SN), Sorafenib (Sorafenib), pazopanib (Pazopanib) and Axitinib (Axitinib) etc.The latter comprises bevacizumab (Bevacizumab) and ranibizumab (Ranibizumab) etc.These medicines can be referred to as VEGF/VEGFR inhibitor by us.
Endogenous dopamine (Dopamine, DA) be central nervous system (central nervous system, CNS) most important Catecholamines Neurotransmitters in Blood, its receptor is dopamine receptor (Dopamine Receptor, DR).DR is mainly distributed in central nervous system, which control many CNS functions such as motion, cognition, emotion, endocrine regulation; DR is also distributed in the peripheral tissues such as cardiovascular, kidney, pancreas, adrenal gland, research increasing in recent years shows also there is DR signal path in peripheral tissues, can regulate the secretion etc. of myocardium output, blood pressure, renal function, insulin and hormone, this is the periphery function of DR.But DA to the effect of tumor and DR always very limited for a long time in the research of tumor cells expression situation.
Hematopoietic Malignancies originates from stem cell-like cell, and the foundation of this theory changes people for tumorigenicity and chemotherapeutical conventional wisdom.Subsequently, in the entity tumor of breast carcinoma, nervous system neoplasms and other non-hemopoietic systems, also confirm successively, also exist and there is the pluripotent stem cell that self-renewal capacity energy specific differentiation becomes the various constituent of organ, impel people more in depth to carry out the biological study of tumor stem cell.These have the stem cell-like cell with normal stem cell similar characteristic, or are called the existence of tumor stem cell colony, have implied the real source of tumor.
Although the chemotherapy of tumor successfully can reduce the load of many entity tumors now, eliminate the cell of fast breeding, but the root being difficult to reach its failure of radical cure may be exactly have ignored the removing for tumor proliferation pond, for recurrence in the future and transfer hide some dangers for.Tumor is for chemotherapeutics
drug resistance is relevant to the characteristic of tumor stem cell.The mechanism of the opposing medicine of tumor stem cell uniqueness and poisonous substance infringement, may become the intractable basis of tumor, makes the biggest obstacle that the drug resistance of tumor is regarded as in chemotherapy.For the research of drug resistance of tumor, especially analyze tumor stem cell and the relation between it, significant for the development promoting tumor chemical therapy.Generally believe,
drug resistance and the tumor stem cell of tumor have close relationship.
Summary of the invention
The present inventor is in the process of research treatment of cancer, beat all discovery, the inhibitor (also can be described as in this article " VEGF/VEGFR inhibitor ") of VEGF VEGF or its receptor VEGFR and dopamine conbined usage can demonstrate fabulous tumor inhibitory effect.After both discoveries coupling that we are surprised, its active anticancer strengthens greatly.
Therefore, an object of the present invention is to provide a kind of anti-cancer composition with synergistic function, include at least one cancer therapy drug of effective amount and a kind of non-cancer therapy drug of effective dose, described cancer therapy drug is VEGF/VEGFR inhibitor; Described non-cancer therapy drug is dopamine; Described dopamine can make to produce synergistic function with the therapeutic effect of VEGF VEGF or its receptor cancer therapy drug that is target spot.
According to an aspect of the present invention, described VEGF/VEGFR inhibitor, be preferably the monoclonal antibody of micromolecular VEGFR inhibitor and VEGF, wherein, micromolecular VEGFR inhibitor is preferably Sorafenib (Sorafenib, Bayer/Onyx, 2005), Sutent (Sunitinib, pFizer, 2006), pazopanib (Pazopanib, GSK, 2009), Axitinib (Axitinib, pFizer, 2012) one or more and pharmaceutically in acceptable salt, most preferably be Sutent (Sunitinib, SN) and pharmaceutically acceptable salt.The monoclonal antibody of VEGF is preferably bevacizumab (Bevacizumab, Genentech, 2004), ranibizumab (Ranibizumab, Genentech, 2006).
Described pharmaceutically acceptable salt is synthesized from parent compound by the chemical method of routine, and described parent compound comprises part that is alkaline or acidity.Usually, described salt is as by the free acid of these compounds or alkali form and stoichiometric suitable alkali or acid reaction and preparation in water or in organic solvent or the mixture at water and organic solvent.Usually, non-aqueous media such as ether, ethyl acetate, ethanol, isopropyl alcohol or acetonitrile is preferred.The example of acid-addition salts comprises inorganic acid addition salt example hydrochloric acid salt, hydrobromate, hydriodate, sulfate, nitrate, phosphate, and organic acid addition salt is as acetate, trifluoroacetate, maleate, fumarate, citrate, oxalates, succinate, tartrate, malate, mandelate, dipyrone and tosilate.The example of base addition salts comprises inorganic salt as sodium, potassium, calcium and ammonium salt, and organically alkali metal salt as the amino acid salts of ethylenediamine, ethanolamine, N, N-bis-alkylene ethanolamine, triethanolamine and alkalescence.
According to an aspect of the present invention, described cancer mean comprise tumor, neoplasia and any other malignant tissue or cell.Specifically comprise colon cancer or rectal cancer, metastatic colorectal cancer, pulmonary carcinoma, non-squamous nonsmall-cell lung cancer, breast carcinoma, metastatic breast cancer, transitivity HER2 negative breast cancer, the brain cancer, adult's glioblastoma, child's glioblastoma, child's repellence glioblastoma, glioma, ependymoma, astrocytoma, medulloblastoma, child's medulloblastoma, glioma, oligodendroglioma or meningioma, renal carcinoma is as advanced renal cell carcinoma, bladder cancer, cervical cancer, colon cancer (comprising colorectal carcinoma), the esophageal carcinoma, gastric cancer, incidence cancer, hepatocarcinoma, pulmonary carcinoma (small cell lung cancer and nonsmall-cell lung cancer), squamous nonsmall-cell lung cancer, melanoma, myeloma, neuroblastoma, ovarian cancer, cancer of pancreas, carcinoma of prostate, sarcoma (comprising osteosarcoma), skin carcinoma (comprising squamous cell carcinoma), gastric cancer, carcinoma of testis, thyroid carcinoma, uterus carcinoma, mesothelioma, cancer of biliary duct, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, salivary-gland carcinoma, or carcinoma sarcomatodes.
According to an aspect of the present invention, at least one cancer therapy drug of described effective dose and the non-cancer therapy drug of effective dose are used at same time or different time.When same time is used, each component in described compositions is with same or independently dosage form use.When different time uses, each component of described compositions can use identical or different dosage form.
According to an aspect of the present invention, the term " associating " that uses in the whole text of description or " coupling " or " administering drug combinations " or " drug combination " refer to and are included in the use of identical or independently in pharmaceutical preparation therapeutic agent at same time or different time.
Another object of the present invention is to provide a kind of anticancer preparation, and it comprises the described anti-cancer composition with synergistic function and customary adjuvant pharmaceutically.Described customary adjuvant comprises lubricant, filler, surfactant, solubilizing agent, cosolvent etc.
According to an aspect of the present invention, often kind of medicine in described anticancer preparation can be tablet, capsule, suspensoid, solution, injection etc. separately or jointly.
Present invention achieves following beneficial effect:
(1) treatment for certain tumor is combined by one or more anticarcinogens (VEGF/VEGFR inhibitor) and dopamine, external can the growth of remarkable inhibition tumor cell, in body can significantly Tumor suppression volume increase and obviously extend by the life cycle investigating object, it is alone that its Be very effective is better than anticarcinogen.
(2) drug combination of the present invention can greatly reduce the use of anticarcinogen under the basis ensureing identical active anticancer, decreases the Operative risk under larger dose caused by cancer therapy drug and toxic and side effects (toxic and side effects of usual alone anticarcinogen is all larger).
(3) use of non-anticarcinogen makes the treatment cost of patient greatly reduce.Because usual cancer therapy drug is all somewhat expensive, consumption required when reaching identical drug effect after coupling is significantly less than dosage during alone anticarcinogen, and therefore patient spends the expense in Drug therapy therefore greatly to reduce.
(4) growth of anti-cancer composition to tumor stem cell (closely related with drug resistance of tumor) with synergistic function of the present invention has obvious inhibitory action, illustrates that the present invention can be used as good solution solution field of cancer and makes us thorny tumor drug resistance sex chromosome mosaicism.
Accompanying drawing explanation
Fig. 1 be Sutent (A, B, C) and dopamine (D, E, F) respectively to human breast cancer cell (MCF-7), the inhibitory action of the human breast cancer cell (MCF-7/Adr) of adriamycin-resistant and breast carcinoma stem cell propagation.Medicine is to the half-inhibition concentration (IC of cell
50) from A to F, be respectively 8.27,8.97,9.41,17.69, > 100,12.59 μMs.
Fig. 2 is Sutent and the human breast cancer cell (MCF-7/Adr) of dopamine administering drug combinations to adriamycin-resistant and the synergism of breast carcinoma stem cell Proliferation Ability.In figure, A and B represents the inhibitory action that two prescriptions are used and different coupling mode is bred MCF-7/Adr and breast carcinoma stem cell respectively, and numerical value is less than the killing effect of 0 expression to cell.C and D then represents the index of cooperation of different coupling modes in two kinds of cells respectively, and index of cooperation is less than 1 and represents two kinds of medicines and have synergism.
Fig. 3 is the growth (n=3) that Sutent and dopamine coupling suppress female tumor bearing nude mice tumor.A, the growth curve of gross tumor volume when human breast cancer cell (MCF-7/Adr) tumor bearing nude mice of adriamycin-resistant gives blank, Sutent (in gavage dosage), dopamine (lumbar injection) and two kinds of Drug combinations respectively; B, each group tumor photo; C, each group nude mice life cycle; D, each group nude mice weight curve over time.
Fig. 4 is the tumor growth delay (n=5) that various dose Sutent and dopamine coupling suppress human breast cancer cell (MCF-7/Adr) mice with tumor of adriamycin-resistant.A, the tumor volume growth curve of tumor bearing nude mice under 9 kinds of administering modes; B, the time graph of each group nude mice weight; C, the tumor real shooting photo of each group tumor administration after 21 days.
Detailed description of the invention
For a better understanding of the present invention, current inventor provides following embodiment, but, these embodiments only illustratively object and providing, and be not interpreted as limitation of the present invention, because wherein many changes are possible, and do not depart from the spirit and scope of the invention.Although the compositions and methods of the invention are described in particular, person of ordinary skill in the field is apparent, described compositions can be made or/and the step of method or step occur in sequence change, but do not depart from concept of the present invention and category.More particularly, the apparent medicine similar in other pharmacology processes of chemically and being biologically correlated with can replace medicine as herein described, reaches same or analogous effect simultaneously.Described those skilled in the art are apparent all should be considered in category of the present invention and concept all this similar replacements or modification.
The present invention have studied VEGFR inhibitor Sutent (SN) and dopamine (DA) is alone and both share the inhibitory action of Cells Proliferation of Human Breast Cancer and the inhibitory action to the nude mouse tumor growth that human breast cancer cell is inoculated.
Embodiment 1
the alone inhibitory action to Cells Proliferation of Human Breast Cancer of SN and DA.
To take the logarithm trophophase cell, with 0.25% pancreatin-0.53mmol/L EDTA solution digestion, counting.By MCF-7 (human breast cancer cell), MCF-7/Adr (the MCF-7 cell to Adriamycin resistant), breast carcinoma stem cell by 1 × 10
4individual/hole is inoculated in 96 porocyte culture plates.After cultivating 24h, carry out administration, the final concentration of SN mono-medicine administration group is 0,0.01,0.1,1,2,5,10,100 μM; The final concentration of DA mono-medicine administration group is 0,0.01,0.1,1,10,20,50,100 μM, often group establish 6 parallel, continue to hatch 48h.When investigating administering drug combinations, for 4 parallel 96 orifice plates, it is 0,2,20,100 μM that the concentration of DA sets gradually, and in every 1 96 orifice plate, the concentration of SN is all set to 0,1,2,5,10 μM, often group establish 6 parallel.Continue to hatch 48h.Discard culture medium after hatching end, every hole adds 10% trichloroacetic acid (TCA, w/v) solution of 100 μ l pre-coolings in advance, 4 DEG C of fixing 1h; Discard TCA solution, tap water 5 times, dries naturally; Every hole adds 100 μ l0.4% Sulforhodamine B (SRB) dyestuffs, and dye under room temperature 30min; Discard SRB dyestuff, wash 5 times with 1% acetum, naturally dry; Every hole adds 200 μ l10mmol/LTris solution (pH10.5), and on agitator, jolting 10min makes the SRB be combined with tumor cell alkaline amino acid residue dissolve, and microplate reader measures 540nm wavelength place absorbance.The absorbance of blank group and drug treating group is expressed as OD
control, 540and OD
sample, 540.Wherein one piece of 96 porocyte culture plate not administration process, by above-mentioned steps process after other Tissue Culture Plates give SN, its mean light absorbency is set to OD
0h, 540.Cell survival rate is pressed formula 1-1 and is calculated:
If the OD of drug treating group
sample, 540be less than OD
0h, 540, namely cell survival rate is less than 0, illustrates that medicine not only can the propagation of inhibition tumor cell, and can kill tumor cell.Cell lethality is pressed formula 1-2 and is calculated.
The IC of result display (see Fig. 1): SN in MCF-7, MCF-7/Adr and breast carcinoma stem cell three cell strains
50(suppressing the drug level needed for 50% cell proliferation) is respectively 8.27,8.97,9.41 μMs (Figure 1A), the IC50 of DA is respectively: 17.69, > 100,12.59 μMs (Figure 1B), used without significant difference to the suppression of three kinds of cells in vitro when visible SN is alone, when DA is alone, other two kinds of cells are significantly less than to the inhibitory action of MCF-7/Adr cell.
Embodiment 2
the inhibitory action that SN and DA coupling is bred MCF-7/Adr cell and tumor stem cell.
By the inhibitory action of on cell proliferation after SRB method investigation variable concentrations SN and variable concentrations DA coupling, and analyze the size of index of cooperation (combination index, CI).Adopt the method for bibliographical information to calculate index of cooperation, calculate the theoretical absorbance of administering drug combinations group according to formula 1-3, the absorbance of actual measurement and the ratio of theoretical value are index of cooperation (formula 1-4).CI value is less than, is equal to and greater than 1, show respectively SN and DA have collaborative, add and and antagonism.
Result display (see Fig. 2), no matter to MCF-7/Adr cell or tumor stem cell, DA coupling enhances the inhibitory action of SN to cancerous cell significantly, and strengthen (Fig. 2 A) with the rising of DA concentration, after two medicine couplings simultaneously, index of cooperation (CI) is all less than 1, illustrate that two medicine couplings do not have antagonism (CI > 1), neither simple addition (CI=1), but synergistic function.
Embodiment 3
sN and DA coupling is to the inhibitory action (single dose) of tumor in breast carcinoma resistance Transplanted tumor model in body
BALB/c nude mice raises inoculation MCF-7/Adr cell after a week.Take the logarithm the MCF-7/Adr cell of trophophase, be prepared into single cell suspension, the centrifugal 5min of 1,000rpm through 0.25% pancreatin-0.53mmol/L EDTA solution digestion, cell PBS washes twice, and adjusting cell density with PBS is 1 × 10
7individual/ml.Aseptically second pair of mammary subcutaneous fat pad subcutaneous injection 0.2ml cell suspension (about 2 × 10 on the left of nude mice
6individual cell).With the major diameter (D of vernier caliper measurement tumor
max) and minor axis (D
min), calculate gross tumor volume V (V=D
max× D
min 2/ 2).
MCF-7/Adr cell in-situ is inoculated into 12 BALB/c nude mice mammary gland positions, obtains heteroplastic breast cancer tumour model, when the mean tumour volume of nude mice is about 100mm
3time, be divided into 4 groups at random, often organize 3.SN administering mode is oral administration gavage, and drug solvent is 1,2-PD; DA administering mode is lumbar injection, and drug solvent is normal saline, and dosage regimen is as follows: (1) blank group: every day lumbar injection 0.1ml normal saline, gavage 0,2ml1,2-propylene glycol solution; (2) SN group: every day lumbar injection 0,1ml normal saline, the 1,2-PD solution of gavage 0.2ml SN, dosage is 40mg/kg; (3) DA group, every day lumbar injection 0.1ml DA normal saline solution, gavage 0,2ml1,2-propylene glycol solution, dosage is 50mg/kg; (4) administering drug combinations group, every day lumbar injection 0.1ml DA normal saline solution, the 1,2-PD solution of gavage 0.2ml SN, the dosage of DA is the dosage of 50mg/kg, SN is 40mg/kg.Each group of equal every day is administered once, and measures gross tumor volume and weigh nude mice body weight before administration, until nude mice is dead, and record life span.
Result display (see Fig. 3) DA is alone to gross tumor volume not significant inhibitory action, but the coupling of DA and SN significantly can reduce the size (Fig. 3 A and Fig. 3 B) of tumor, extend nude mice life cycle (Fig. 3 C), and (Fig. 3 D) is had no significant effect to nude mice weight, toxic and side effects lower after describing two medicine couplings.
Embodiment 4
sN and DA coupling is to the inhibitory action (multiple dose) of tumor in breast carcinoma resistance Transplanted tumor model in body.
It is more than pharmacodynamic results (n=3) in primary body, in order to ensure the verity of result, we have carried out the larger experiment of sample size again, often group inoculation has the quantity of the tumor bearing nude mice of drug resistance MCF-7/Adr cell to be at least 5, and add the SN of 20mg/Kg and 80mg/Kg two dosage in addition, respectively alone and with 50mg/kg DA coupling (in whole test, DA dosage remains unchanged), altogether increase by 4 experimental grouies (totally 8 groups).
Result as shown in Figure 4.Can find out with DA coupling after, gross tumor volume is all more alone has significance to decline, the effect that 20mg/kg SN and DA share is better than or close to the alone effect of 40mg/kg SN, the effect that 40mg/kg SN and DA share is better than the alone effect of 80mg/kg SN, after 80mg/kg SN and DA coupling, the result of gross tumor volume is astonishing, tumor growth has been totally constrained, and nude mice weight does not have significant change simultaneously, illustrates that the general toxicity of this drug combination is less.
The coupling can finding out SN and DA from above inside and outside result in vitro or in vivo to the suppression of tumor growth all significantly better than the effect of alone SN, especially result highly significant in body; Describe
this coupling scheme is not only to Common tumors effectively, also there is good result to resistant tumors, be conducive to the drug resistance of tumor and the tumor that solve extensively existence clinically at present branch problem (all closely related with tumor stem cell).
According to the knowledge of prior art, Sutent produces anticancer effect by the signal path of the VEGFR on inhibition tumor cell.Confirm that VEGF/VEGFR inhibitor Sutent and dopamine conbined usage can produce unforeseeable anticancer effect by experiment of the present invention.Due to the generation of VEGF/VEGFR inhibitor equal energy Tumor suppression new vessels mechanism, block the nutrition supply carrying out autoblood needed for tumor cell proliferation, and this kind of medicine that current each major company has gone on the market all demonstrates obvious anti-tumor activity, therefore those skilled in the art easily predict other VEGF/VEGFR inhibitor identical with Sutent antitumaous effect mechanism thus (as Sorafenib, pazopanib, Axitinib and bevacizumab, ranibizumab), after dopamine conbined usage, also will produce according to the unforeseeable anticancer effect of prior art, (such as adopting the method in above-described embodiment) that this effect can be carried out verifying by those skilled in the art by experiment.
Situation occurred based on current cancer is known, and the present invention has broad application prospects.
Claims (10)
1. have an anti-cancer composition for synergistic function, it is characterized in that, said composition includes at least one VEGF/VEGFR inhibitor and the dopamine of effective amount.
2. the anti-cancer composition with synergistic function according to claim 1, is characterized in that, described VEGF/VEGFR inhibitor is VEGFR micromolecular inhibitor or VEGF monoclonal antibody.
3. the anti-cancer composition with synergistic function according to claim 2, it is characterized in that, described VEGFR micromolecular inhibitor is selected from Sutent, pazopanib, Axitinib, Sorafenib and one or more pharmaceutically in acceptable salt thereof.
4. the anti-cancer composition with synergistic function according to claim 1, is characterized in that, described VEGF monoclonal antibody be selected from bevacizumab or ranibizumab one or both.
5. the anti-cancer composition with synergistic function according to claim 1, is characterized in that, described VEGF/VEGFR inhibitor is Sutent or its pharmaceutically acceptable salt.
6. the anti-cancer composition with synergistic function according to claim 1, is characterized in that, described cancer is solid carcinoma.Be preferably breast carcinoma, bladder cancer, cervical cancer, colon cancer, the esophageal carcinoma, incidence cancer, hepatocarcinoma, pulmonary carcinoma (small cell lung cancer and nonsmall-cell lung cancer), non-squamous nonsmall-cell lung cancer, melanoma, myeloma, neuroblastoma, ovarian cancer, cancer of pancreas, carcinoma of prostate, renal carcinoma, advanced renal cell carcinoma, sarcoma (comprising osteosarcoma), skin carcinoma (comprising squamous cell carcinoma), gastric cancer, carcinoma of testis, thyroid carcinoma, uterus carcinoma, mesothelioma, cholangiocellular carcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, renal carcinoma, salivary-gland carcinoma, small cell lung cancer, or carcinoma sarcomatodes.
7. the anti-cancer composition with synergistic function according to claim 6, is characterized in that, described cancer is breast carcinoma.
8. the anti-cancer composition with synergistic function according to claim 1, is characterized in that, described anti-cancer composition has prevention for Common tumors or drug resistant cancer or therapeutic activity.
9. there is a pharmaceutical preparation for antitumaous effect, comprise the anti-cancer composition of claim 1 and the customary adjuvant of pharmaceutics.The dosage form of this pharmaceutical preparation is the regular dosage form of art of pharmacy, and wherein different types of medicine is packed separately or jointly packed, and different types of medicine is same one dosage type low temperature or different dosage form.
10. the anti-cancer composition with synergistic function according to any one of claim 1-10 is preparing the application in cancer therapy drug.
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| CN106963948A (en) * | 2017-05-12 | 2017-07-21 | 顾艳宏 | A Pa is combined the application in colon cancer drug is prepared for Buddhist nun with the antibody of Anti PD 1 |
| CN107261145A (en) * | 2017-08-08 | 2017-10-20 | 四川九章生物科技有限公司 | A kind of antineoplastic combination medicine and its purposes in cancer therapy drug is prepared |
| CN107261145B (en) * | 2017-08-08 | 2021-03-09 | 四川九章生物科技有限公司 | Anti-tumor combined medicine and application thereof in preparing anti-cancer medicine |
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| CN108187055A (en) * | 2018-03-06 | 2018-06-22 | 北京大学 | A kind of anti-cancer composition with synergistic function |
| CN111166758A (en) * | 2019-12-10 | 2020-05-19 | 安徽瀚海博兴生物技术有限公司 | A combined anticancer medicine prepared from ouabain |
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