CN103656615B - A kind of HM-3 and platinum class, taxanes or his shore class medicine purposes in preparing solid tumor drugs - Google Patents
A kind of HM-3 and platinum class, taxanes or his shore class medicine purposes in preparing solid tumor drugs Download PDFInfo
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Abstract
The invention discloses a kind of HM 3 and platinum class, taxanes or his shore class medicine are used in the purposes preparing in solid tumor drugs, belong to the drug world for the treatment of tumor.Platinum class, taxanes or his shore class antimetabolite are as active component, and are aided with acceptable pharmaceutical carrier and make various pharmaceutically acceptable preparation.Know that Disintegrin HM 3 target spot is clear and definite, in conjunction with platinum class, taxanes or his shore class reasonable employment through great many of experiments, it is possible to effectively suppress pulmonary carcinoma, hepatocarcinoma, gastric cancer, breast carcinoma, cervical cancer, ovarian cancer, intestinal cancer etc. to increase in interior tumor.Drug combination of the present invention can effectively treat tumor as drug use, and its drug combination is scientific, rational, feasible and effective, is greatly enlarged the treatment spectrum of oncotherapy, reduces toxic and side effects, has notable social value and market value.
Description
Technical field
The present invention relates to the purposes of a kind of Drug therapy tumor, be a kind of HM-3 and platinum class, taxanes or his shore class medicine purposes in preparing solid tumor drugs in particular..
Background technology
Tumor is the disease of a kind of complexity, is used alone a kind of medicine and is extremely difficult to preferable therapeutic effect, the most often uses the mode of drug combination to treat.In oncotherapy, the advantage of drug combination is to heighten the effect of a treatment, and reduces the generation of untoward reaction, prevents tumor from producing drug resistance.Mechanism of action according to antineoplastic agent carries out reasonable drug combination, is one of impressive progress in chemotherapy drug treatment tumor in recent years.The antitumor drug of different mechanism of action share, and tends to heighten the effect of a treatment.As share destroying the DNA structure alkylating agent (such as cyclophosphamide or BCNU) with function with the MTX stoping DNA to repair, synergism often can be produced.Additionally from reducing drug toxicity consideration: bone marrow depression is the toxicity that most antineoplastic agent is total.Can some antineoplastic agents little to bone marrow inhibition of use in conjunction, such as tumor-targeting drug, reduce cytotoxic drug using dosage, while therapeutic effect can be improved, be substantially reduced the misery of patient.
Although patent ZL200510040378.5 previously discloses the inhibitor RGD-ED having therapeutic effect to melanotic tumor, but and undisclosed other tumors there is therapeutic effect.Patent application 200610039484.6 blood vessel formation inhibitor IIM 3-3 and its preparation method and application discloses the high effect blood vessel production inhibitor HM-3 with integrin affinity, this inhibitor contains the Agiogenesis inhibition whole aminoacid sequence of albumen Endostatin, connect the polypeptide containing arginine-glycine-aspartic acid sequence at its c-terminus, be made up of 18 aminoacid.Early-stage Study shows that HM-3 can effectively suppress endothelial cell migration and angiogenesis, thus suppresses tumor growth.Molecular mechanism research shows further, and its action target spot is the integrin receptor α v β 3 that tumor crosses high expressed, and acts on, by α v β 3, the signal path that intracellular is different, and HM-3 can also directly suppress vegf expression.HM-3 target spot and the mechanism of action are clear and definite, and pharmacodynamic study shows that it can effectively suppress the growth of the entity tumor including including pulmonary carcinoma, gastric cancer, hepatocarcinoma, breast carcinoma etc., has one-tenth one class anti-cancer agent to be developed.Patent 201110122070.0HM-3 polypeptide lyophilized powder preparation and preparation method thereof discloses HM-3 polypeptide lyophilized powder preparation, this product has the highest activity and purity and a good medical effect, but single preparation for complicated different tumours co-exist specific aim the strongest.
Defect existing for single drug, increasing researcher pays close attention to drug combination.Even substantial amounts of research domestic and international for drug combination shows the tumor that same organization type, differentiation degree are identical, the sensitivity of same medicine is also possible to difference, therefore, different oncotherapys needs to carry out the screening of medicine.Because some medicine is only effective to specific tumors cell, it is invalid or poor efficiency to other tumors, it is therefore desirable to experiment goes to grope and verify its therapeutic effect.Drug combination is also such, is not that at will several chemicalses are put together all can be effective to some tumor.Because between medicine, combination is on the one hand because mechanism is different, it is not necessary to can produce good effect;It addition, between medicine exist interact, some drug combinations not only will not potentiation, also can produce opposite effect, such as antagonism.
In the last few years, angiogenesis inhibitor class medicine and chemotherapy drugs in combination were applied and were extensively applied in cancer clinical treatment, and the use in conjunction of medicine is the most increasingly paid attention to by pharmacologist.In practice, the merging of medicine for treatment often can reduce dosage, heighten the effect of a treatment, reduces toxicity, and this phenomenon is in medical science or does not only has the biggest practical value, and provides the most significant information for exploration to the mechanism of action and effect link in theory.But for concrete medicine, due to the complexity of the character of medicine, always those skilled in the art insoluble problem how is used in combination.
For the medicine for the treatment of tumor, because it is the most complicated that tumor cell has the strongest drug resistance, pathogenesis, being used alone a certain chemotherapeutic agent and be extremely difficult to effectively suppress the effect of tumor, the Drug combination needing mechanism different can be only achieved effective therapeutic effect.But existing between medicine and interact, need to carry out verifying whether it can reach optimum therapeuticing effect by test during the Drug combination of different mechanism, if using improper, not only action effect is the best but also can produce bigger toxic and side effects.It addition, different tumors are the most different to the sensitivity of a certain medicine, it is also desirable to through the drug combination kind that substantial amounts of experiment sieving is suitable for.Drug combination needs to have carried out lot of experiments and carrys out screening of medicaments combination, because Drug combination needs to detect whether action effect has potentiation or synergism;Using dosage, order of administration, dosage period, different tumor indication are required for being verified by test and finding simultaneously.To those skilled in the art, obtain only by experiment effectively time that have the specifically chosen of drug combination of very good effect for treating certain class disease be extremely difficult.
Summary of the invention
1, goal of the invention
For the shortage of combination medicine in existing treatment of solid tumors, it is an object of the present invention to provide a kind of HM-3 and platinum class, taxanes or his shore class medicine purposes in preparing solid tumor drugs, HM-3 associating platinum class, taxanes, the mode of his shore class medicine is used to be applied to treat in the medicine of the entity tumor of high expressed integrin receptor, by this medicine being used in combination, common effect can be played.
2, technical scheme
Solution principle:
AP25 is used in combination with platinum class, taxanes, antimetabolitas, is, according to these three medicine, there is the most different mechanism of action, reach preferable antitumous effect (booster action ++), reduce toxicity.
First, be HM-3 be a kind of target polypeptide, there is integrin inhibitory action and angiogenesis suppression action.Tumor-blood-vessel growth is the basis of reproduction, growth promoter and reparation, and most malignant entity tumor such as pulmonary carcinoma, hepatocarcinoma, ovarian cancer, cervical cancer and breast carcinoma etc. are all blood vessel dependent tumors.On the one hand new vessels provides nutrition and oxygen, another aspect or the important channel of neoplasm metastasis for tumor growth.Therefore, suppression tumor neogenetic blood vessels can effectively suppress the generation of tumor, develops and shift.Tumor neogenetic blood vessels is by many cytokine modulatings, and one of wherein relevant to tumor-blood-vessel growth important tumor vascular endothelial cell molecule is the few members of integrin family.Integrin is the receptor of various kinds of cell epimatrix composition, is widely present in cell surface, is a sizable receptor family.This receptoroid is made up of a α chain and a β chain, is all working in the combination of part, and different α chains and the combination of β chain determine the specificity of part.Up to the present, it has been found that 15 kinds of α chains and 9 kinds of β chains.In tumor cell, the component of integrin there occurs the change of complexity, and roughlly speaking, the integrin quantity participating in organizational structure declines, and the integrin quantity relevant with cell migration rises.Integrin α5 β1, α v β 5, α v β 3 etc. are relevant with angiogenesis and cell migration, and wherein α v β 3 can affect the several very important process in canceration.It can be with the Glycoprotein binding of various kinds of cell epimatrix, and α v β 3 can also be combined with metalloproteases, degradation of cell epimatrix, thus is more beneficial for invading;Two other is apoptosis and angiogenesis by the process that α v β 3 affects, and on the capillary endothelial cell participating in angiogenesis, the expression of α v β 3 also raises.In tumor vascular endothelial cell, angiogenesis factor class has close relationship, as VEGF, FGF can raise the expression of α v β 3 with the expression of integrin.α v β 3 monoclonal antibody can suppress its function, therefore, it is possible to promote apoptosis and angiogenesis inhibiting.HM-3 can target integrin alpha v beta 3, suppresses vegf expression, thus reaches antineoplastic effect.
Platinum antineoplastic chemotherapeutic agent action target spot is the DNA of proliferative cell, has the effect of the difunctional group of similar alkylating agent, can combine with intracellular base, makes DNA molecular chain interior and interchain intersection binding, thus loses function not reproducible.Also the synthesis of RNA and protein is suppressed during high concentration.Including cisplatin (DDP), carboplatin (CBP), JM-216 (oxaliplatin, L-OHP) etc..This type of medicine antitumor spectra is wide, it is adaptable to most solid tumors, such as breast carcinoma, ovarian cancer, hepatocarcinoma etc.;Can be using drug combination as the choice drug such as nonsmall-cell lung cancer, hepatocarcinoma.Cisplatin (DDP) main adverse reaction is serious digestive tract reaction, Toxicity of Kidney, secondly also has bone marrow transplantation, acoustic nerve toxicity, all relevant with using dosage.
Taxanes medicine includes that the mechanism of action of docetaxel is to strengthen tubulin polymerization effect and suppression microtubule depolymerization effect, results in stable non-functional vascular bundle, thus tumoricidal mitosis.Micro-pipe is a kind of constituent of eukaryotic cell, and it is that the micro-pipe dimer being made up of two similar polypeptide (a and p) subunits is formed.Under normal circumstances, there is dynamic equilibrium between micro-pipe and tubulin dimer.Paclitaxel can make to lose therebetween this dynamic equilibrium, induces and promotes tubulin polymerization, preventing depolymerization, stablizes micro-pipe.These effects cause cell can not form spindle and spindle fiber when carrying out mitosis, it is suppressed that cell division and propagation, thus play antitumor action.
His shore class antimetabolite such as gemcitabine etc. is a kind of Difluoronucleosides class antimetabolite anticarcinogen destroying cellular replication, it it is the water-soluble analogues of cytosine deoxyriboside, it it is the substitute of the substrate of a kind of inhibition to ribonucleotide reductase, this enzyme in DNA synthesis and repair process, to the generation of required Deoxydization nucleotide it is critical that.This product can mix nucleotide triphosphoric acid, and the DNA end in elongation enters DNA, then in conjunction with another Deoxydization nucleotide, produces the chain termination of a kind of sheltering so that DNA can not occur polyreaction.The cell death that this effect produces has the cell death of predetermined programmed or the morphology of apoptosis (apoptosis) and physiologic character.
A kind of HM-3 and platinum class, taxanes or his shore class medicine purposes in preparing solid tumor drugs.
Using described platinum class, taxanes or his shore class medicine as active component, and it is aided with acceptable pharmaceutical carrier and makes various pharmaceutically acceptable preparation.Described platinum class is cisplatin, stannum platinum, cisplatin, nedaplatin, eptalatin, carboplatin, NSC-241240, carboplatin, lobaplatin, oxaliplatin, promise shellfish platinum or Satraplatin JM216 BMS 182751;Taxanes medicine is paclitaxel, docetaxel, Paclitaxel liposome, Albumin binding paclitaxel;His shore class medicine is capecitabine, gemcitabine or decitabine.Described solid tumor is high expressed integrin receptor α v β 3, the solid tumor of α 5 β 1 is pulmonary carcinoma, hepatocarcinoma, breast carcinoma, cervical cancer, ovarian cancer, gastric cancer or intestinal cancer.Under HM-3 effective dose, and other chemotherapeutic agents halve or reduce to clinical speculate dosage 1/4 in the case of be used in combination.
Use the not same tumor of nude inoculation people, set up tumor model, be grouped when gross tumor volume reaches about 100mm3: be divided into negative control group, positive controls, independent medication group and drug combination group, be administered;Often group mice number is more than 6, and coincidence statistics requested number, after treating 14-21 days, dissect mice, calculate tumor weight, often organize the tumor control rate after treatment according to tumor re-computation, employing Jin's formula is tested, and reaches in the oncotherapy group write present invention of booster action.
3, beneficial effect
The invention discloses a kind of HM-3 and platinum class, taxanes or his shore class medicine purposes in preparing solid tumor drugs, after HM-3 and oxaliplatin and docetaxel or xeloda being used in combination, pulmonary carcinoma, hepatocarcinoma, gastric cancer, breast carcinoma, cervical cancer, ovarian cancer, intestinal cancer treatment are served potentiation.
Know that Disintegrin HM-3 target spot is clear and definite through great many of experiments, in conjunction with platinum class, taxanes or his shore class reasonable employment, can effectively suppress pulmonary carcinoma, hepatocarcinoma, gastric cancer, breast carcinoma, cervical cancer, ovarian cancer, intestinal cancer etc. to increase in interior tumor, concentrate drug combination can reach the effect of potentiation.Drug combination of the present invention treats tumor science, reasonable, feasible effectively energy treats the medicine of human solid cancers as preparation, be greatly enlarged the treatment spectrum of oncotherapy, reduce toxic and side effects, have notable social value and market value.
(1) in HM-3 associating oxaliplatin, the docetaxel application treatment to people's pulmonary carcinoma H460 transplanted tumor in nude mice, being used alone HM-3 tumour inhibiting rate is 49.11%, oxaliplatin, docetaxel combination (than clinical dosage speculate halve in the case of) be tumour inhibiting rate be 50.23%, three's combination has then reached collaborative effect, and tumour inhibiting rate is 86.11%.
(2) in HM-3 associating oxaliplatin, the xeloda treatment to people's hepatocarcinoma SMMC-7721 transplanted tumor in nude mice, being used alone HM-3 tumour inhibiting rate is 49.12%, oxaliplatin, xeloda combination (than clinical dosage speculate halve in the case of) be tumour inhibiting rate be 48.19%, three's combination has then reached collaborative effect, and tumour inhibiting rate is 86.89%.
(3) in HM-3 associating docetaxel, the oxaliplatin treatment to human breast carcinoma MDA-MB-231 transplanted tumor in nude mice, being used alone HM-3 tumour inhibiting rate is 50.38%, docetaxel and oxaliplatin combination (than clinical dosage speculate halve in the case of) be tumour inhibiting rate be 49.33%, three's combination has then reached the effect strengthened, and tumour inhibiting rate is 86.99%.
(4) in HM-3 associating docetaxel, the oxaliplatin treatment to cervical cancer Hela cells transplanted tumor in nude mice, being used alone HM-3 tumour inhibiting rate is 50.01%, docetaxel and oxaliplatin combination (than clinical dosage speculate halve in the case of) be tumour inhibiting rate be 47.11%, three's combination has then reached collaborative effect, and tumour inhibiting rate is 83.98%.
(5) in the oxaliplatin HM-3 treatment to human ovarian cancer A2780 transplanted tumor in nude mice, being used alone HM-3 tumour inhibiting rate is 50.11%, oxaliplatin (than clinical dosage speculate halve in the case of) be tumour inhibiting rate be 40.88%, the two combination has then reached collaborative effect, and tumour inhibiting rate is 82.79%.
(6) in HM-3 associating oxaliplatin, the xeloda treatment to people's Gastric Cancer MGC-803 transplanted tumor in nude mice, being used alone HM-3 tumour inhibiting rate is 46.11%, oxaliplatin, xeloda combination (than clinical dosage speculate halve in the case of) be tumour inhibiting rate be 40.79%, three's combination has then reached the effect strengthened, and tumour inhibiting rate is 84.12%.
(7) in HM-3 associating oxaliplatin (or xeloda) treatment to people's intestinal cancer HT29 transplanted tumor in nude mice, being used alone HM-3 tumour inhibiting rate is 46.34%, oxaliplatin, xeloda combination (than clinical dosage speculate halve in the case of) be tumour inhibiting rate be 41.87%, three's combination has then reached collaborative effect, and tumour inhibiting rate is 81.88%.
Accompanying drawing explanation
Fig. 1 is HM-3 associating oxaliplatin, the docetaxel application inhibitory action design sketch to people's pulmonary carcinoma H460 transplanted tumor in nude mice;
Fig. 2 is that HM-3 combines oxaliplatin, the xeloda inhibitory action design sketch to people's hepatocarcinoma SMMC-7721 transplanted tumor in nude mice;
Fig. 3 is that HM-3 combines docetaxel, the oxaliplatin inhibitory action design sketch to human breast carcinoma MDA-MB-231 transplanted tumor in nude mice;
Fig. 4 is that HM-3 combines docetaxel, the oxaliplatin internal inhibitory action design sketch to cervical cancer Hela cells transplanted tumor in nude mice;
Fig. 5 is the oxaliplatin HM-3 inhibitory action design sketch to human ovarian cancer A2780 transplanted tumor in nude mice;
Fig. 6 is that HM-3 combines oxaliplatin, the xeloda inhibitory action design sketch to people's Gastric Cancer MGC-803 transplanted tumor in nude mice;
Fig. 7 is HM-3 associating oxaliplatin (or xeloda) the inhibitory action design sketch to people's intestinal cancer HT29 transplanted tumor in nude mice;
Wherein, G2:HM-3(high dose);Dosage in G3:HM-3();G4: chemical medicine (high dose);G5: chemical medicine (middle dosage);G6: combine group 1;G7: combine group 2;Data above all by SPSS software T check analysis, represents each group of average tumor weight, tumour inhibiting rate=(negative group tumor weight-treatment group tumor weight)/negative group tumor weight × 100% with mean ± SD.
Detailed description of the invention
In the present invention, HM-3 is peptide molecule, and human body using dosage scope is 9-27 milligram/m2, using intravenous drip administering mode, once, dosage period is 14-21 days in intravenous drip every day;Advise 2-4 cycle.
Docetaxel, intravenous injection, single medicine injection amount is 75-100mg/m2, domestic use 75mg/m2, drug combination 60-75mg/m2, intravenous drip 1 hour, within every 3 weeks, it is repeated once.
Oxaliplatin is when medication alone or in combination, it is recommended that dosage is 130mg/m2, add infusion 2-6 hour in 250~500ml5% glucose solutions.When not having major toxicity to occur, within every 3 weeks, (21 days) are administered once.Adjustment dosage is with safety, and the most neurologic safety is foundation.
Xeloda recommended dose 2.5g/m every day2, it is used in conjunction 2 weeks, has a rest 1 week.Every TDD divides 2 to be swallowed inferior to use half an hour water after meal sooner or later.As treatment should be stopped when the state of an illness continues and deteriorates or produce intolerable toxicity.
In drug combination, one is to speculate mice consumption to halve dosage under with oxaliplatin, Taxotere, xeloda according to human dose with HM-3 effective dose to use, one is to halve dosage with HM-3 and speculate that other chemicals consumptions of mice reduce to use under 1/4 dosage according to human dose, under reducing drug use dose profile, each group drug combination has all reached reinforced effects.
After generally evaluating two kinds of drug combinations, whether action intensity strengthens and uses Jin's formula to test, and judges whether combination with medication group effect is better than alone by the significance of comparing difference between group.Data is used Jin's formula expression formula q=E (A+B) (actual measurement merges effect)/EA+EB-EA*EB (expection merges effect) and evaluates whether two medicines therapeutic effect after being used in combination is better than individually dosed by interpretation q value.If q between 0.85-1.15 be simple be added (+), for strengthening (++) between 1.15-2.0, q>2.0, for being obviously enhanced (+++), is antagonism (--) between 0.85-0.55, and q<0.55 is obvious antagonism (---).According to the error of biotic experiment about 15%, the q value that effect is added is expanded to 0.85-1.15.Q > 1.15 is synergism.
Use the not same tumor of nude inoculation people, set up tumor model, be grouped when gross tumor volume reaches about 100mm3: be divided into negative control group, positive controls, independent medication group and drug combination group, be administered;Often group mice number is more than 6, coincidence statistics requested number, after treating 14-21 days, dissects mice, calculates tumor weight, often organizes the tumor control rate after treatment according to tumor re-computation, uses Jin's formula to test, and reaches the oncotherapy group write of booster action.
Embodiment 1HM-3 associating oxaliplatin, the docetaxel inhibitory action to people's pulmonary carcinoma H460 transplanted tumor in nude mice
The cancerous lung tissue taking growth animated period is aseptically milled, and is prepared as 1 × 107/ mL born of the same parents' suspension, with 0.1mL kind in right side of mice oxter.Treat that gross tumor volume reaches 100mm3Left and right vernier caliper measurement transplanted tumor diameter, dynamically observes animal subject antineoplastic effect.With tail vein injection or subcutaneous administrations, dosage regimen is shown in Table 1.The pendulous frequency of diameter of tumor is for every other day to survey once.Being administered volume is 0.2ml/.Negative control tail vein injection normal saline.After 21 days, sacrifice, operation strips tumor mass and weighs.The computing formula of gross tumor volume (tumor volume, TV) is:
TV=1/2×a×b2
Wherein a, b represent length and width respectively.
Result according to measuring calculates relative tumour volume (relative tumor volume, RTV), and computing formula is: RTV=Vt/V0.Wherein V0For (d during sub-cage administration0) measure gained gross tumor volume, VtGross tumor volume during for measuring each time.The evaluation index of anti-tumor activity is Relative tumor rate of increase T/C(%), computing formula is as follows:
TRTV: treatment group RTV;CRTV: negative control group RTV.
Table 1 is administered and arranges
The tumour inhibiting rate such as table 2 recaptured according to tumor after treatment:
Table 2 tumor weight (g) and tumour inhibiting rate (%)
Data analysis software is SPSS, represents each group of average tumor weight with mean ± SD.Tumour inhibiting rate=(negative group tumor weight-treatment group tumor weight)/negative group tumor weight × 100%, according to T assay, * P < 0.05 is notable, and * * P < 0.01 is pole significant difference.
Test evaluation result:
Q height=E(A+B)/(EA+EB EA × EB)=86.11%/(49.11%+50.23%-49.11%*50.23%)=1.15
In Q=E(A+B)/(EA+EB EA × EB)=77.45%/(32.32%+39.22%-32.32%*39.22%)=1.31
According to calculating, this group HM-3 is enhancing (++) effect, i.e. synergism in drug combination high dose group (oxaliplatin and docetaxel halve with quantity ratio) and middle dosage group (with quantity than reducing to 1/4) evaluation result.According to the observation, after animal joint medication, body weight to reduce slowly with using chemical medicine ratio, and state is better than oxaliplatin and docetaxel combination group, illustrates that toxic and side effects reduces.
Embodiment 2HM-3 associating oxaliplatin, the xeloda inhibitory action to people's hepatocarcinoma SMMC-7721 transplanted tumor in nude mice
The liver cancer tissue taking growth animated period is aseptically milled, and is prepared as 1 × 107/ mL born of the same parents' suspension, with 0.1mL kind in right side of mice oxter.Other participate in embodiment 1.
Test is divided into 7 groups, and HM-3 group often organizes 8, and other treatment group often organizes 10, and matched group 13, concrete dosage regimen is shown in Table 3.
Table 3 is administered and arranges
Tumor weight (g) and tumour inhibiting rate (%) when table 4 treats the 21st day
Data analysis software is SPSS, represents each group of average tumor weight with mean ± SD.Check according to T, calculate tumour inhibiting rate=(negative group tumor weight-treatment group tumor weight)/negative group tumor weight × 100%, obtain result above.* P < 0.05 is notable, and * * P < 0.01 is pole significant difference.
Test evaluation result:
Q height=E(A+B)/(EA+EB EA × EB)=86.89%/(49.12%+48.19%-49.12%*48.19%)=1.18
In Q=E(A+B)/(EA+EB EA × EB)=80.30%/(43.23%+40.77%-43.23%*40.77%)=1.20 evaluation result: potentiation, removal error is synergism.According to calculating, this group HM-3 is enhancing (++) effect in drug combination high dose group (oxaliplatin and xeloda halve with quantity ratio) and middle dosage group (with quantity than reducing to 1/4) evaluation result, and removal error is synergism.According to the observation, after animal joint medication, body weight to reduce slowly with using chemical medicine ratio, and state is better than oxaliplatin and xeloda combination group, illustrates that toxic and side effects reduces.
Embodiment 3HM-3 associating docetaxel, the oxaliplatin inhibitory action to human breast carcinoma MDA-MB-231 transplanted tumor in nude mice
The breast cancer tissue taking growth animated period aseptically mills, and is prepared as 1 × 107/ mL born of the same parents' suspension, with 0.1mL kind in right side of mice oxter.Other model preparation methoies see embodiment 1.
Test is divided into 8 groups, and negative control group 12, HM-3 group 8, other treatment group often organizes 10.Concrete dosage regimen sees the table 1 in embodiment 1.Treat the 21st day after terminating, dissect nude mice, take tumor, measure tumour inhibiting rate.
Table 5 tumor weight (g) and tumour inhibiting rate (%)
Data analysis software is SPSS, represents each group of average tumor weight with mean ± SD.Tumour inhibiting rate=(negative group tumor weight-treatment group tumor weight)/negative group tumor weight × 100%, according to T assay, * P < 0.05 is notable, and * * P < 0.01 is pole significant difference.
Evaluation of test result:
Q height=E(A+B)/(EA+EB EA × EB)=86.99%/(50.38%+49.33%-50.38%*49.33%)=1.16
In Q=E(A+B)/(EA+EB EA × EB)=79.88%/(36.11%+43.11%-36.11%*43.11%)=1.25
Evaluation result: potentiation, removal error is synergism.According to calculating, this group HM-3 is enhancing (++) acts in drug combination treatment breast carcinoma high dose group (oxaliplatin and docetaxel halve with quantity ratio) and middle dosage group (HM-3 halves, oxaliplatin and docetaxel and quantity than reducing to 1/4) evaluation result.According to the observation, after animal joint medication, body weight to reduce slowly with using chemical medicine ratio, and state is better than oxaliplatin and docetaxel group, illustrates that toxic and side effects reduces.
Embodiment 4HM-3 associating docetaxel, the oxaliplatin internal inhibitory action to cervical cancer Hela cells transplanted tumor in nude mice
The cervical cancer Hela cells tissue of the people taking growth animated period is aseptically milled, and is prepared as 1 × 107/ mL born of the same parents' suspension, with 0.1mL kind in right side of mice oxter.Other test method operates with reference to embodiment 1.Administration arranges same table 1, the results are shown in Table 6.
Table 6 tumor weight (g) and tumour inhibiting rate (%)
Data analysis software is SPSS, represents each group of average tumor weight with mean ± SD.Tumour inhibiting rate=(negative group tumor weight-treatment group tumor weight)/negative group tumor weight × 100%, according to T assay, * P < 0.05 is notable, and * * P < 0.01 is pole significant difference.
Evaluation of test result:
Q height=E(A+B)/(EA+EB EA × EB)=88.98%/(50.01%+47.11%-50.01%*47.11%)=1.21
In Q=E(A+B)/(EA+EB EA × EB)=78.02%/(37.12%+40.99%-37.12%*40.99%)==1.24
Evaluation result: potentiation, removes error, for synergism.According to calculating, this group HM-3 is synergism at drug combination treatment cervical cancer high dose group (oxaliplatin and docetaxel halve with quantity ratio) and middle dosage group (HM-3 halves, and oxaliplatin and docetaxel reduce to 1/4 with quantity ratio) evaluation result.According to the observation, after animal joint medication, body weight to reduce slowly with using chemical medicine ratio, and state is better than oxaliplatin and docetaxel group, illustrates that side effect reduces.
The embodiment 5 oxaliplatin HM-3 inhibitory action to human ovarian cancer A2780 transplanted tumor in nude mice
The ovarian cancer A2780 tissue of the people taking growth animated period is aseptically milled, and is prepared as 1 × 107/ mL born of the same parents' suspension, with 0.1mL kind in right side of mice oxter.Other test method operates with reference to embodiment 1.Test administration is shown in Table 7.
Table 7 is administered and arranges
The results are shown in Table 8.
Table 8 tumor tumor weight (g) and tumour inhibiting rate (%)
Data analysis software is SPSS, represents each group of average tumor weight with mean ± SD.Tumour inhibiting rate=(negative group tumor weight-treatment group tumor weight)/negative group tumor weight × 100%, according to T assay, * P < 0.05 is notable, and * * P < 0.01 is pole significant difference.
Test evaluation result:
Q height=E(A+B)/(EA+EB EA × EB)=1.17
In Q=E(A+B)/(EA+EB EA × EB)=1.27
Evaluation result: collaborative.According to calculating, this group HM-3 is collaborative (++) effect at drug combination treatment ovarian cancer high dose group (oxaliplatin halves with quantity ratio) and middle dosage group (HM-3 halves, and oxaliplatin reduces to 1/4 with quantity ratio) evaluation result.According to the observation, after animal joint medication, body weight to reduce slowly with using chemical medicine ratio, and state is better than oxaliplatin group, illustrates that toxic and side effects reduces.
Embodiment 6HM-3 associating oxaliplatin, the xeloda inhibitory action to people's Gastric Cancer MGC-803 transplanted tumor in nude mice
The stomach organization taking growth animated period is aseptically milled, and is prepared as 1 × 107/ mL born of the same parents' suspension, with 0.1mL kind in right side of mice oxter.Other become tumor and evaluation methodology to see embodiment 1.
Test is divided into 7 groups, HM-3 group 8, and other treatment group often organizes 10, and matched group 12, concrete dosage regimen is shown in embodiment 2, table 3.Tumor weight and the tumour inhibiting rate calculated according to tumor restatement are shown in Table 9.
Table 9 tumor tumor weight (g) and tumour inhibiting rate (%)
Data analysis software is SPSS, represents each group of average tumor weight with mean ± SD.Tumour inhibiting rate=(negative group tumor weight-treatment group tumor weight)/negative group tumor weight × 100%, according to T assay, * P < 0.05 is notable, and * * P < 0.01 is pole significant difference.
Q height=E(A+B)/(EA+EB EA × EB)=1.23
In Q=E(A+B)/(EA+EB EA × EB)=1.18
Evaluation result: synergism, removal error is synergism.According to calculating, this group HM-3 is synergism at drug combination treatment gastric cancer high dose group (oxaliplatin and xeloda halve with quantity ratio) and middle dosage group (oxaliplatin and xeloda halve with quantity than minimizing to 1/4 with quantity ratio) evaluation result.According to the observation, after animal joint medication, body weight to reduce slowly with using chemical medicine ratio, and state is better than oxaliplatin and xeloda group, illustrates that toxic and side effects reduces.
Embodiment 7HM-3 associating oxaliplatin (or xeloda) inhibitory action to people's intestinal cancer HT29 transplanted tumor in nude mice
The intestinal cancer HT29 tissue of the people taking growth animated period is aseptically milled, and is prepared as 1 × 107/ mL born of the same parents' suspension, with 0.1mL kind in right side of mice oxter.Other test method operates with reference to embodiment 1.Dosage regimen is with reference to embodiment 5(table 7), the results are shown in Table 10.
Table 10 tumor tumor weight (g) and tumour inhibiting rate (%)
Data analysis software is SPSS, represents each group of average tumor weight with mean ± SD.Tumour inhibiting rate=(negative group tumor weight-treatment group tumor weight)/negative group tumor weight × 100%, according to T assay, * P < 0.05 is notable, and * * P < 0.01 is pole significant difference.
Q height=E(A+B)/(EA+EB EA × EB)=1.18
In Q=E(A+B)/(EA+EB EA × EB)=1.24
Evaluation result: synergism.According to calculating, this group HM-3 is synergism at drug combination treatment intestinal cancer high dose group (oxaliplatin or xeloda halve with quantity ratio) and middle dosage group (HM-3 halves, and oxaliplatin or xeloda reduce to 1/4 with quantity ratio) evaluation result.According to the observation, after animal joint medication, body weight to reduce slowly with using chemical medicine ratio, and state is better than oxaliplatin or xeloda group, illustrates that toxic and side effects reduces.
Claims (1)
1. HM-3 and platinum class, taxanes or his a shore class medicine purposes in preparing solid tumor drugs, wherein by described platinum class,
Taxanes or his shore class medicine are as active component, and are aided with acceptable pharmaceutical carrier and make various pharmaceutically acceptable
Preparation, wherein particularly as follows: HM-3 associating oxaliplatin, docetaxel are to people's pulmonary carcinoma;HM-3 associating oxaliplatin, card training
His shore is to people's hepatocarcinoma;HM-3 associating docetaxel, oxaliplatin are to human breast carcinoma;HM-3 combines docetaxel, Ao Shali
Platinum is to human cervical carcinoma;Oxaliplatin HM-3 is to human ovarian cancer;HM-3 associating oxaliplatin or capecitabine are to people's gastric cancer;
HM 3 combines oxaliplatin or capecitabine to people's intestinal cancer.
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