CN101920015A - Pharmaceutical composition for cancer treatment - Google Patents
Pharmaceutical composition for cancer treatment Download PDFInfo
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- CN101920015A CN101920015A CN 201010257127 CN201010257127A CN101920015A CN 101920015 A CN101920015 A CN 101920015A CN 201010257127 CN201010257127 CN 201010257127 CN 201010257127 A CN201010257127 A CN 201010257127A CN 101920015 A CN101920015 A CN 101920015A
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Abstract
The invention relates to the field of medical technology, in particular to a pharmaceutical composition for cancer treatment, which consists of anti-angiogenesis drug Avastin and autophagy inhibitor chloroquine. When in use, Avastin and chloroquine are mixed according to respective dose, wherein the doses of Avastin and chloroquine are respectively 7.6mg/kg and 60mg/kg calculated according to weight. Animal experimental results show that the pharmaceutical composition can obviously inhibit the growth of skin cancer and liver cancer cells in mice, and the effect of inhabiting tumors is obviously higher than that of solely using Avastin or chloroquine, thus illustrating that the Avastin and the chloroquine have the function of synergistic inhibition on tumor growth, therefore, the pharmaceutical composition can be used for treating tumors.
Description
Technical field
The present invention relates to medical technical field, is a kind of pharmaceutical composition for the treatment of cancer.
Background technology
Malignant tumor is the No.1 killer of human life's health.Tumor needs functional blood vessel network oxygen, nutriment to be provided and to remove metabolite.Tumor also must make up the vascular system of oneself by formation new vessels net, so constantly advolution except obtaining the part blood vessel by merging with host blood vessel.If there is not vascular system that oxygen and nutriment are provided, the growth of solid tumor can not surpass 1mm
3In view of it takes place in tumor, developing important function, tumor vessel has become an important target spot of antineoplaston.
(fvascular endothelial growth fact or VEGF) can directly act on vascular endothelial cell to VEGF, stimulates it that mitosis takes place.It is relevant with the progress of tumor that the overexpression of VEGF has been proved, and in different types of tumors, as in nasopharyngeal carcinoma and the multiple myeloma all being the correlation molecule index of prognosis mala.In addition, in colorectal cancer, gastric cancer, cancer of pancreas, breast carcinoma, carcinoma of prostate, pulmonary carcinoma and melanoma, also play an important role.VEGF be at present known to the strongest angiogenic growth factor of effect, the factor of still the strongest increase vascular permeability, it mainly combines the effect of division growth, migration and the reconstructing blood vessel of performance promotion endotheliocyte with two kinds of receptor Fh-1, Flk-2 on the endotheliocyte.Because VEGF bring into play the effect of dominance in angiogenesis, therefore most researchs with VEGF or its receptor as the target spot for the treatment of.
Although anti-angiogenic medicaments has been obtained certain success, but still face many problems.The same with other most therapeutic schemes, anti-angiogenic medicaments seldom reaches and continues curative effect completely in clinical trial and animal tumor model, nearly all the drug resistance phenomenon can occur, especially the situation that the initial stage is effective, the later stage is invalid appears in anti-VEGFR therapeutic scheme in animal tumor model.The concrete mechanism of anti-angiogenic medicaments generation drug resistance it be unclear that, may make tumor generation persistence hypoxia relevant with the continuous action of anti-angiogenic medicaments with malnutrition, hypoxia and nutritional deficiency all can stimulate autophagy to start, make tumor cell by degraded and recycling the change metabolism of autophagy, thereby survived making adaptation response to intracellular organic matter.Studies confirm that suppressing autophagy can improve the apoptosis that malnutrition and weary oxygen cause.Therefore the activation of autophagy is that the adaptive change (as producing various angiogenesis factors again, promoting angiogenesis) that tumor is made under hypoxia and nutritional deficiency situation has won the time.Avastin (Avastin) is a kind of recombinant monoclonal VEGF antibody, research and develop by Switzerland pharmaceutical manufacturer Roche Holding Ag (ROCHE), obtained U.S. F DA approval listing in March, 2004, can combine with the various hypotypes of VEGF, the tumor-blood-vessel growth that can suppress the VEGF mediation is so be a kind of anti-angiogenic medicaments.Chloroquine is a kind of antimalarial drug, is proved to be a kind of autophagy inhibitor at present.But do not see so far Avastin and chloroquine are formed the report that pharmaceutical composition is used for the treatment of cancer.
Summary of the invention
The invention provides a kind of pharmaceutical composition for the treatment of cancer, be made up of anti-angiogenic medicaments and autophagy inhibitor, said anti-angiogenic medicaments is an Avastin; The autophagy inhibitor is a chloroquine.Pharmaceutical composition is to face the time spent to mix by Avastin and chloroquine dosage separately, and their dosages are respectively according to the weight:
Avastin 7.6mg/kg
Chloroquine 60mg/kg
During use Avastin and chloroquine are pressed the dosage mixing, be diluted to 200 μ l, then routinely by the peritoneal injection administration with normal saline.
Zoopery is the result show, pharmaceutical composition of the present invention can obviously suppress skin carcinoma, hepatoma carcinoma cell in the intravital growth of mice, and plantation tumor volume and weight reduce significantly, suppresses tumor effect apparently higher than independent use Avastin or chloroquine.
Preparation of pharmaceutical compositions method of the present invention is simple, easy to use, treats the effective of tumor.
Description of drawings
Fig. 1. pharmaceutical composition of the present invention is to the comparison diagram that influences of skin cancer cell plantation tumor mice body weight.
Fig. 2. pharmaceutical composition of the present invention suppresses the growth comparison diagram of mouse skin cancerous cell plantation tumor.
Fig. 3. pharmaceutical composition of the present invention suppresses the propagation comparison diagram of mouse skin cancerous cell plantation tumor.
Fig. 4. pharmaceutical composition of the present invention is to the comparison diagram that influences of hepatoma carcinoma cell plantation tumor mice body weight.
Fig. 5. pharmaceutical composition of the present invention suppresses rat liver cancer cell seeding tumor growth comparison diagram.
Fig. 6. pharmaceutical composition of the present invention suppresses rat liver cancer cell seeding tumor propagation comparison diagram.
The specific embodiment
Now with accompanying drawing the present invention is described in detail in conjunction with the embodiments.
Avastin (Roche company, lot number S20100023) is mixed with certain density Avastin solution with normal saline;
Chloroquine (SIGMA company. lot number C6628-25G), be mixed with certain density chloroquine solution with normal saline;
According to body weight by dosage Avastin 7.6mg/kg+ chloroquine 60mg/kg with Avastin solution and chloroquine solution in facing with preceding mixing.
Zoopery
60 C57 mices provide (down together) by The 2nd Army Medical College zoopery center, and male, average weight 20g is divided into six groups at random, and 10 every group, mouse melanin tumor cell B16, inoculum concentration 2X10 are inoculated in the oxter routinely
6Individual/200 μ l, to inoculate after 9 days, the plantation tumor is grown to about 150 cubic millimeters, and beginning administration in the 10th day is handled.
The blank group: after the plantation tumor became tumor, mice was not accepted any administration and handles.
The normal saline group: peritoneal injection normal saline 200 μ l, once a day, injected 10 days continuously;
The Avastin group: by the administration of mice body weight, the Avastin dosage is 7.6mg/kg, and required Avastin is diluted to 200 μ l with normal saline, peritoneal injection, once a day, successive administration 10 days.
The chloroquine group: by the administration of mice body weight, the chloroquine dosage is 60mg/kg, and required chloroquine is diluted to 200 μ l with normal saline, once a day, and successive administration 10 days.
Pharmaceutical composition group of the present invention: by the administration of mice body weight, Avastin dosage is 7.6mg/kg, and chloroquine dosage is 60mg/kg, and required pharmaceutical composition is diluted to 200 μ l with normal saline, once a day, by body weight, successive administration 10 days.
During each administration, measure the volume size (V=1/2a * b of mouse tumor body
2Wherein V is a gross tumor volume, and a is the minor axis length of tumor, and b is the major diameter length of tumor), administration was put to death the C57 mice on the 11st day after 10 days, the difference of mice body weight, plantation tumor weight and volume between each group of observation.Experimental result is shown in Fig. 1～3.
As seen from Figure 1, each organizes mice body weight change no significant difference, illustrates that mice has good tolerability to the different dosing regimes of this experiment.
As seen from Figure 2, present composition group can significantly suppress the increase of mouse skin cancer cell transplantation tumor weight, compare with blank group and normal saline group that there were significant differences (P＜0.01), the tumor weight of blank group and normal saline group is about 5 grams, and the tumor weight of present composition group is about 2 grams; Present composition group is compared with independent use chloroquine group or Avastin group, the effect that suppressing tumor weight increases has significant difference (P＜0.05), the weight of chloroquine group or Avastin group tumor is respectively about 3.9 grams and 3.8 grams, and the tumor weight of present composition group only is about 2, significant difference.This explanation chloroquine and Avastin have the collaborative effect that suppresses tumor growth.
As seen from Figure 3, in treatment cycle, be accompanied by the passing of time, the present composition can significantly slow down the growth of mouse skin cancer cell transplantation tumor volume, with blank group and normal saline group than there were significant differences (P＜0.01); When treatment finished, the gross tumor volume of blank group and normal saline group was about 5000 cubic millimeters, and the gross tumor volume of present composition group is about 2000 cubic millimeters; And present composition group compares with chloroquine group or Avastin group, has significant difference (P＜0.05) equally; Chloroquine group or Avastin group tumor size are about 4000 cubic millimeters, and the gross tumor volume of present composition group only is 2000 cubic millimeters, significant difference.Chloroquine and Avastin have the collaborative effect that suppresses tumor growth in this explanation present composition.
60 C57 mices, male, average weight 20g is divided into six groups at random, and 10 every group, rat liver cancer cell Hep1-6, inoculum concentration 5X10 are inoculated in the oxter routinely
6Individual/300 μ l, to inoculate after 10 days, the plantation tumor is grown to about 150 cubic millimeters, and beginning administration in the 11st day is handled.
Grouping and administration experiment 1 together, successive administration 12 days.
During each administration, measure tumor body volume size (V=1/2a * b
2Wherein V is a gross tumor volume, and a is a tumor minor axis length, and b is a tumor major diameter length), administration 12 days was put to death the C57 mice on the 13rd day, and the body weight of mice, the difference of tumor body volume and weight are respectively organized in observation.
Experimental result is shown in Fig. 4～6.
As seen from Figure 4, each organizes mice body weight change no significant difference, illustrates that mice has good tolerability to the different dosing regimes of this experiment.
As seen from Figure 5, the present composition can significantly suppress the increase of rat liver cancer cell transplantation tumor weight, with blank group and normal saline group than there were significant differences (P＜0.05), the tumor weight of blank group and normal saline group is about 1.5 grams, and the tumor weight of present composition group is about 0.5 gram; The present composition is compared with chloroquine group or Avastin group has significant difference (P＜0.05) equally, the weight of chloroquine group or Avastin group tumor is respectively about 1.3 grams and 1.2 grams, and the tumor weight of present composition group only is about 0.5 gram, significant difference.This explanation chloroquine and Avastin have the collaborative effect that suppresses tumor growth.
As seen from Figure 6, in treatment cycle, be accompanied by the passing of time, the present composition can significantly slow down the growth of rat liver cancer cell transplantation tumor volume, with blank group and normal saline group than there were significant differences (P＜0.01), when treatment finished, the gross tumor volume of blank group and normal saline group was respectively about 1100 and 1000 cubic millimeters, and the gross tumor volume of present composition group is about 500 cubic millimeters; Present composition group is compared with the Avastin group with the chloroquine group, suppress the same significant difference of effect (P＜0.05) that gross tumor volume increases, after treatment finishes, chloroquine group and Avastin group tumor size are respectively about 800 and 750 cubic millimeters, and the gross tumor volume of present composition group only is about 500 cubic millimeters.Chloroquine and Avastin have the collaborative effect that suppresses tumor growth in this explanation present composition.
Claims (2)
1. a pharmaceutical composition for the treatment of cancer is made up of anti-angiogenic medicaments and autophagy inhibitor, and said anti-angiogenic medicaments is an Avastin; The autophagy inhibitor is a chloroquine, faces the time spent Avastin and chloroquine are mixed by separately dosage.
2. by the described a kind of pharmaceutical composition for the treatment of cancer of claim 1, it is characterized in that the dosage of each component is respectively according to the weight:
Avastin 7.6mg/kg
Chloroquine 60mg/kg.
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| CN 201010257127 CN101920015A (en) | 2010-05-25 | 2010-08-13 | Pharmaceutical composition for cancer treatment |
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| CN201010185153.X | 2010-05-25 | ||
| CN201010185153 | 2010-05-25 | ||
| CN 201010257127 CN101920015A (en) | 2010-05-25 | 2010-08-13 | Pharmaceutical composition for cancer treatment |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2313095A2 (en) * | 2008-07-14 | 2011-04-27 | The Regents of the University of Colorado | Methods and products for treating proliferative diseases |
| WO2014018801A1 (en) * | 2012-07-25 | 2014-01-30 | The Texas A&M University System | Diagnosis and treatment of cancer using differentially expressed starvation markers |
| CN104971348A (en) * | 2014-04-03 | 2015-10-14 | 复旦大学 | Autophagy inhibitor and asparaginase composition and application thereof in preparation of tumor synergistic medicaments |
| CN106420744A (en) * | 2016-08-26 | 2017-02-22 | 宁国市厚普生物科技有限公司 | Composition for treating cancers and preparations and application thereof |
| CN110290787A (en) * | 2017-02-07 | 2019-09-27 | 昂科克罗斯株式会社 | For inhibiting the transfer of cancer and treating the composition of cancer |
| CN115624625A (en) * | 2022-07-04 | 2023-01-20 | 苏州大学 | Application of mitophagy inhibitor in preparation of medicine for treating arsenic-caused cell malignant transformation diseases |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101428025A (en) * | 2008-10-24 | 2009-05-13 | 中国人民解放军第四军医大学 | New use of anti-impaludism medicament hydroxyl chloroquine |
-
2010
- 2010-08-13 CN CN 201010257127 patent/CN101920015A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101428025A (en) * | 2008-10-24 | 2009-05-13 | 中国人民解放军第四军医大学 | New use of anti-impaludism medicament hydroxyl chloroquine |
Non-Patent Citations (3)
| Title |
|---|
| 《Clinical Investigation》 20070228 Ravi. K Amaravadi，et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma 326-336 1-2 第117卷, 第2期 2 * |
| 《基础医学与临床》 20080331 薛惠文 编译 抗疟药氯喹可能抑制某些癌症的发生 293页 1-2 第28卷, 第3期 2 * |
| 《癌症》 20090430 李国东 等 细胞自噬在肿瘤中作用的研究进展 445-448 1-2 第28卷, 第4期 2 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2313095A2 (en) * | 2008-07-14 | 2011-04-27 | The Regents of the University of Colorado | Methods and products for treating proliferative diseases |
| EP2313095A4 (en) * | 2008-07-14 | 2013-04-17 | Univ Colorado | Methods and products for treating proliferative diseases |
| US9073985B2 (en) | 2008-07-14 | 2015-07-07 | The Regents Of The University Of Colorado, A Body Corporate | Methods and products for treating proliferative diseases |
| WO2014018801A1 (en) * | 2012-07-25 | 2014-01-30 | The Texas A&M University System | Diagnosis and treatment of cancer using differentially expressed starvation markers |
| CN104971348A (en) * | 2014-04-03 | 2015-10-14 | 复旦大学 | Autophagy inhibitor and asparaginase composition and application thereof in preparation of tumor synergistic medicaments |
| CN106420744A (en) * | 2016-08-26 | 2017-02-22 | 宁国市厚普生物科技有限公司 | Composition for treating cancers and preparations and application thereof |
| CN106420744B (en) * | 2016-08-26 | 2019-06-07 | 宁国市厚普生物科技有限公司 | The compound and its preparation and purposes of a kind for the treatment of cancer |
| CN110290787A (en) * | 2017-02-07 | 2019-09-27 | 昂科克罗斯株式会社 | For inhibiting the transfer of cancer and treating the composition of cancer |
| CN110290787B (en) * | 2017-02-07 | 2022-11-18 | 昂科克罗斯株式会社 | Composition for inhibiting metastasis of cancer and treating cancer |
| CN115624625A (en) * | 2022-07-04 | 2023-01-20 | 苏州大学 | Application of mitophagy inhibitor in preparation of medicine for treating arsenic-caused cell malignant transformation diseases |
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Application publication date: 20101222 |