CN108514639A - It is a kind of to be used for antitumor combination medicine and its preparation and application - Google Patents
It is a kind of to be used for antitumor combination medicine and its preparation and application Download PDFInfo
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- CN108514639A CN108514639A CN201810387270.0A CN201810387270A CN108514639A CN 108514639 A CN108514639 A CN 108514639A CN 201810387270 A CN201810387270 A CN 201810387270A CN 108514639 A CN108514639 A CN 108514639A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
It being used for antitumor combination medicine and its preparation and application the present invention relates to a kind of, the combination medicine to include angiogenesis inhibitor class compound and disulfiram, and the weight proportion of the angiogenesis inhibitor class compound and disulfiram is：(1‑15):(1‑20).When angiogenesis inhibitor class compound is combined disulfiram medication by the present invention, compared with its any type independent medication, have the function of significantly improving anticancer effect.And tumour inhibiting rate improves 20% or more, which belongs to great progress in the research for the treatment of cancer.The applicant studies for the first time is found that angiogenesis inhibitor is significant synergistic with the use of having the function of under specific proportioning with disulfiram, and potential applicability in clinical practice is good.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of novel to be used for antitumor combination medicine and the joint
The application of drug.
Background technology
Studies have shown that there are two types of the supply blood vessel generation mechanisms that tumour growth is relied on：1, tumour is by secreted by itself
Cell factor, the normal blood vessels closed on can be stimulated to generate branch vessel, supplied to itself；2, tumor tissues are first at itself
Inside generates blood vessel sample as a result, then " grafting " on the normal blood vessels closed on.The two mechanism is essentially different, simply
For, the sequencing of inside and outside vascularization is different.The similar part of the two is then to be required for generating capillary structure, this
The main reason that the speciality of DIY, exactly anti-angiogenic medicaments can act.
Although anti-cell proliferation agents can kill tumour cell, due to the support of peripheral vessels, residual tumor cell
It still can get blood supply and be able to continued growth.Meanwhile abnormal tumor vessel makes drug be reduced to tumor tissues internal delivery, most
The effect of causing suppressing cell reproduction to be treated eventually, is limited.In recent years, researcher proposes new tumor pharmacother strategy, not only needle
To tumour cell, it to be more directed to tumor microenvironment, especially Tumor Angiongesis, hits tumour in all directions.With act only on
The chemotherapeutics of tumor cell proliferation is different, by being specifically bound with VEGF, prevents itself and acceptor interaction, plays to swollen
A variety of effects of tumor blood vessel：Existing tumor vessel is set to degenerate, to cut off oxygen needed for growth of tumour cell and other nutrition
Substance；Make the tumor vessel normalization of survival, pressed between reduction tumor tissues, improves transmission of the chemotherapeutics into tumor tissues,
Improve chemotherapy effect；Inhibit tumor angiogenesis, to persistently inhibit the growth and transfer of tumour cell.
However, Antineoplastic angiogenesis treatment result in the clinical research of other tumours is splendid, but in Treatment for Glioma
The effect of aspect is not satisfied；Including bevacizumab blocking VEGF, cilengitide inhibits integrin, Sutent or Si Dinibu
Inhibit vegf receptor, Imatinib or Dasatinib inhibit PDGFR, Enzastaurin (Enzastaurin) inhibit protein kinase C and
Rapamycin, everolimus or tesirolimus inhibit mTOR, cannot explain well this phenomenon at present.
Last century mid-term, the Erik Jacobsen of University of Copenhagen have found that disulfiram inhibits when studying disulfiram
Particularly important acetaldehyde dehydrogenase during alcohol metabolism causes the acetaldehyde that alcohol metabolism generates largely to be accumulated in human body,
Then there is the reaction of similar alcoholism.Under the effort of Jacobsen, disulfiram has been developed to a Temperance medicine.Closely
Since 20 years, the counteroffensive again of antialcoholic disulfiram is multiple the study found that disulfiram has antitumaous effect unexpectedly, can kill
The kinds of tumor cells such as breast cancer, prostate cancer.And up to more than 60 years " antialcoholic history ", it was demonstrated that disulfiram is fool proof,
Its side effect is much smaller compared to for the chemotherapeutics of most of tumours.
Angiogenesis inhibitor combination disulfiram application is effectively increased combination medicine anti-by the present invention significantly
Therapeutic effect in tumour medicine expands therapeutic domain of the combination medicine in antitumor, can substantially reduce controlling for patient
Treatment expense, with market potential value and far-reaching social effect.
Invention content
The object of the present invention is to provide a kind of for antitumor combination medicine and its preparation and application, existing to overcome
The deficiency mentioned in technology.The purpose of the present invention is be achieved through the following technical solutions：
It is a kind of be used for antitumor combination medicine, the combination medicine include angiogenesis inhibitor class compound and
The weight proportion of disulfiram, the angiogenesis inhibitor class compound and disulfiram is：(1-15):(1-20).
Further, the weight proportion of the angiogenesis inhibitor class compound and disulfiram is：1:(4-10).
Further, the angiogenesis inhibitor class compound include but not limited to Sutent, Si Dinibu,
Sorafenib, Tivozanib (replace Wo Zhani), cilengitide, Imatinib, Dasatinib, Enzastaurin, rapamycin, according to
At least one of Wei Mosi and tesirolimus.
Further, the combination medicine further includes at least one pharmaceutically acceptable carrier.
Further, the pharmaceutically acceptable carrier includes but not limited to liposome, polymer nanoparticle and magnetism
At least one of nanoparticle, dosage are 5~50 times of combination medicine weight.
Further, the angiogenesis inhibitor class compound includes Si Dinibu, Sorafenib, is pricked for fertile
It is one or two kinds of in Buddhist nun, cilengitide, Dasatinib, Enzastaurin and everolimus.
A kind of to be used for antitumor combination medicine as the preparation of active ingredient using described, the preparation includes solid pharmaceutical preparation
And injection.The solid pharmaceutical preparation includes but not limited to tablet, capsule, pill, micropill preparation.
Application of the combination medicine in the drug for preparing treating cancer described in a kind of, the cancer includes but not limited to liver
Cancer, kidney, breast cancer, colon cancer, nasopharyngeal carcinoma, carcinoma of urinary bladder, gastric cancer, cancer of the esophagus, prostate cancer, leukaemia, malignant mela noma
And lymthoma.
Beneficial effects of the present invention are：
It being used for antitumor combination medicine and its preparation and application the present invention provides a kind of, the present invention to be by tumor vessel
It is anti-with significantly improving compared with its any type independent medication when formation inhibitor class compound combines disulfiram medication
The effect of cancer effect.And tumour inhibiting rate improves 20% or more, which belongs to great progress in the research for the treatment of cancer.
The applicant studies for the first time is found that angiogenesis inhibitor is notable with the use of having under specific proportioning with disulfiram
Synergistic effect, potential applicability in clinical practice is good.In addition, applicant have also found that, 2 kinds of certain Tumor Angiongesis are pressed down
When preparation is used in combination with disulfiram, moreover it is possible to further increase tumor killing effect, therefore there is extremely important potential applicability in clinical practice.
Specific implementation mode
Illustrate specific implementation mode by taking specific experiment case as an example below, it should be understood that specific reality described herein
It applies example to be only used to explain the present invention, be not intended to limit the present invention.
Embodiment 1
It is a kind of be used for antitumor combination medicine, the combination medicine include angiogenesis inhibitor class compound and
The weight proportion of disulfiram, the angiogenesis inhibitor class compound and disulfiram is：(1-15):(1-20), such as 1:1、
1:5、1:7.5、1:10、1:15、1:20、5:1、10:1 or 15:1 etc.；It is preferred that 1:(4-10).
The angiogenesis inhibitor class compound include but not limited to Sutent, Si Dinibu, Sorafenib,
Tivozanib (replace Wo Zhani), cilengitide, Imatinib, Dasatinib, Enzastaurin, rapamycin, everolimus and
At least one of tesirolimus.
As further preferred embodiment, the combination medicine further includes at least one pharmaceutically acceptable load
Body.The pharmaceutically acceptable carrier includes but not limited at least one in liposome, polymer nanoparticle and magnetic nano particle
Kind, dosage is 5~50 times of combination medicine weight, such as 10 times or 20 times.
Drug in the present embodiment by two class drug synergisms, can effectively treat liver cancer, kidney, breast cancer,
Colon cancer, nasopharyngeal carcinoma, carcinoma of urinary bladder, gastric cancer, cancer of the esophagus, prostate cancer, leukaemia, malignant mela noma and lymthoma etc..
Embodiment 2
The preparation method for antitumor combination medicine in embodiment 1 is：Disulfiram powder and tumor vessel are given birth to
It is mixed in proportion at inhibitor type compound powder.
The combination medicine can be made into solid pharmaceutical preparation or injection, but active ingredient is consistent described in embodiment 1, is
Including angiogenesis inhibitor class compound and disulfiram, carrier can also be added；Solid pharmaceutical preparation includes tablet, capsule, ball
Agent, micropill preparation etc., specific preparation method referring to corresponding dosage form in the prior art preparation method.
Embodiment 3
Angiogenesis inhibitor class compound and disulfiram are pressed 1:7 be used as experimental group, using common pure water as
Contrast groups.
Experimental subjects：Healthy mice 10, every group 5,19 ± 1g of average weight, animal subject is through medical fitness.
Contrast groups are gavaged into pure water, the combination medicine in experimental group is pressed into each 3mL respectively, gavages mouse 3 times a day,
It is observed continuously 10 days, claims its weight, observation vigor situation, as a result, it has been found that, the weight of all mouse in experimental group and contrast groups
It is substantially unchanged with vigor, therefore the toxic side effect of the drug combination in the present invention is smaller or does not have.
Embodiment 4
1 experiment material
1.1 experimental animals and observation
Balb/c mouse, 10~12 week old, 21~23g of weight, half male and half female, by the limited public affairs of Wuhan Hua Lian section biotechnology
Department provides.Hubei University Of Technology's bioengineering and Foodstuffs Academy animal observation ward.
1.2 tumor tissues
Mouse Renca renal cancer tumor tissues, are provided by Biochemical Lab of Hubei University Of Technology.
1.3 experimental drug
1. angiogenesis inhibitor：It is provided, is set by Wuhan Mai Desen medical sci-teches limited liability company for Wo Zhani
It is preserved in -20 DEG C of refrigerators；Other angiogenesis inhibitors are provided by hospital of Tongji University of the Central China University of Science and Technology, and -10 DEG C of refrigerators are protected
It deposits.2. disulfiram：The Suzhou bio tech ltd Fu Lu, room temperature preserve.
1.4 laboratory apparatus
A ten thousandth assay balance, Beijing Sai Duolisi instrument systems Co., Ltd；The phases such as operating scissors, surgical clamp, tweezers
Surgical instrument is closed, (120 DEG C, 20min) are sterilized through excessively high Warm using preceding.
2 experimental methods
It is prepared by 2.1 lotus knurl kind mouse
Renca renal carcinoma tissues are taken out from liquid nitrogen, 37 DEG C of rapid defrostings adjust concentration to 1 × 108A/ml for
Injection.10 Balb/c mouse are taken, by 5 × 106A (0.2ml) Renca kidney cancer cells are inoculated in every mouse and cover lower skin, make
It is spare for kind of mouse.
It is prepared by 2.2Renca renal carcinoma models
Renca cells are with 5 × 108A/L is suspended in serum-free RPMI 1640 culture mediums, through the right lateral side of femur skin of mouse
Balb/c tumor-bearing mices are put to death after lower injection 0.1ml, inoculated tumour cell 5d, tumor tissue are stripped under aseptic condition, by tumour
Matter (g) is with physiological saline (ml) according to 1:Prepared by the homogenate of 3 ratios become suspension, and every mouse is inoculated in left armpit according to 0.2ml
Lower skin.
2.3 animal packets and administration
Next day is randomly divided into 4 groups according to weight after mouse inoculation tumour cell, every group 10 i.e. model group (0.5%CMC-
Na solution), angiogenesis inhibitor group, disulfiram group, combination medicine group.Dosage and mode are shown in Table 1.
1 experimental drug dosage regimen of table
Note：Ig indicates gastric infusion；Q.d. it indicates once a day.
The measurement of 2.4 tumour inhibiting rates
By Dosage Regimens Dosage.15d puts to death mouse, and tumor tissues is taken to claim knurl weight, calculates tumour inhibiting rate.
Average knurl weight × 100% of tumour inhibiting rate (%)=(average knurl weight of model group-treatment group's average knurl weight)/model group
2.5 statistical method
Data are indicated using " mean+standard deviation " (X ± SD), are analyzed using SPSS19.0 statistical softwares, variance is neat
It is examined using T, those who do not meet are analyzed using non-parametric test method.
3 experimental results
3.1 tumour inhibiting rate measurement results
When angiogenesis inhibitor is for Wo Zhani, tumour inhibiting rate measurement result is as shown in table 2.
Influence of the table 2 to Balb/c kidney tumor-bearing mice tumour inhibiting rates
Note：Compared with model control group：*P<0.05, * * P<0.01.
3.2 tumour inhibiting rate measurement results
When angiogenesis inhibitor is Si Dinibu, tumour inhibiting rate measurement result is as shown in table 3.
Influence of the table 3 to Balb/c kidney tumor-bearing mice tumour inhibiting rates
Note：Compared with model control group：*P<0.05, * * P<0.01.
3.3 tumour inhibiting rate measurement results
When angiogenesis inhibitor is Sutent, tumour inhibiting rate measurement result is as shown in table 4.
Influence of the table 4 to Balb/c kidney tumor-bearing mice tumour inhibiting rates
Note：Compared with model control group：*P<0.05, * * P<0.01.
3.4 tumour inhibiting rate measurement results
When angiogenesis inhibitor is everolimus, tumour inhibiting rate measurement result is as shown in table 5.
Influence of the table 5 to Balb/c kidney tumor-bearing mice tumour inhibiting rates
Note：Compared with model control group：*P<0.05, * * P<0.01.
3.5 tumour inhibiting rate measurement results
When angiogenesis inhibitor is tesirolimus, tumour inhibiting rate measurement result is as shown in table 6.
Influence of the table 6 to Balb/c kidney tumor-bearing mice tumour inhibiting rates
Note：Compared with model control group：*P<0.05, * * P<0.01.
From 3.1-3.5：For Wo Zhani, Si Dinibu, Sutent, everolimus or tesirolimus (2mg/kg)
It, can substantially reduced knurl weight (p after 10d is administered in continuous gavage<0.05), tumour inhibiting rate shows 2mg/kg agent between 36-39.2%
Amount has preferable inhibition Renca tumours life for Wo Zhani, Si Dinibu, Sutent, everolimus or tesirolimus
Long effect.
After 10d is administered in disulfiram (250mg/kg) continuous gavage, there is apparent tumor-inhibiting action (P<0.05), tumour inhibiting rate is
29.39%, show that the disulfiram of 15mg/kg dosage has the function of preferably inhibiting Renca tumour growths.
(combine when Wo Zhani, Si Dinibu, Sutent, everolimus or tesirolimus joint disulfiram will be replaced
Drug, wherein angiogenesis inhibitor 2mg/kg and disulfiram 15mg/kg) continuous gavage administration 10d after, can show very much
It writes and mitigates knurl weight (p<0.01), inhibitory rate has arrived 56-58%, and tumour inhibiting rate is used alone apparent than angiogenesis inhibitor
20% or so is improved, increase rate is high；The tumour inhibiting rate of combination medicine improves 26-30% than disulfiram exclusive use, improves
Rate is high.It follows that when angiogenesis inhibitor combines disulfiram medication, there is extraordinary inhibition Renca tumours
The effect of growth.
The above result shows that：For Wo Zhani, Si Dinibu, Sutent, everolimus or tesirolimus and disulfiram
Have the effect for the treatment of tumour when exclusive use, illustrates that there is synergy after the two is used cooperatively under the specific proportioning of the present invention
Effect, potential applicability in clinical practice is good.
3.6 tumour inhibiting rate measurement results
When angiogenesis inhibitor is other one or more, tumour inhibiting rate measurement result is as shown in table 7.
Influence of the table 7 to Balb/c kidney tumor-bearing mice tumour inhibiting rates
Note：Compared with model control group：*P<0.05, * * P<0.01.
The applicant is used cooperatively by using angiogenesis inhibitor of more than two kinds with disulfiram, as above
Shown in table 7, as a result, it has been found that, combine cilengitide in use, its tumor suppression using two kinds of angiogenesis inhibitor Enzastaurins
It is slightly improved when rate is used alone than a kind of angiogenesis inhibitor, has reached 41.33%, increase rate unobvious；However
(Enzastaurin 1mg/kg, cilengitide 1mg/kg, disulfiram is used in combination with disulfiram in Enzastaurin and cilengitide
15mg/kg), it is used in combination with disulfiram than a kind of angiogenesis inhibitor or two kinds of angiogenesis inhibitors
It is used in combination, tumour inhibiting rate all greatly improves, and has reached 66.63%, and the applicant is in order to verify whether it is that rear period error is led
It causes, has also further done multiple repetitions and tested, as a result, it has been found that, each result uses other kinds of 2 65% or more
Kind or more angiogenesis inhibitor and disulfiram be used cooperatively (some, which are combined, is not embodied in table 7), result
It is a kind of almost the same with only using.And Enzastaurin and cilengitide are used in combination the applicant, as a result, it has been found that its tumour inhibiting rate
Than floating there is no apparent.Thus it can further illustrate, by Enzastaurin and cilengitide and disulfiram use in conjunction, have bright
Aobvious synergistic function.
The present invention is not limited to above-mentioned preferred forms, anyone can show that other are various under the inspiration of the present invention
The product of form, however, make any variation in its shape or structure, it is every that there is skill identical or similar to the present application
Art scheme, is within the scope of the present invention.
Claims (10)
1. a kind of being used for antitumor combination medicine, it is characterised in that：The combination medicine includes angiogenesis inhibitor
The weight proportion of class compound and disulfiram, the angiogenesis inhibitor class compound and disulfiram is：(1-15):(1-
20)。
2. according to claim 1 be used for antitumor combination medicine, it is characterised in that：The Tumor Angiongesis inhibits
The weight proportion of agent class compound and disulfiram is：1:(4-10).
3. according to claim 2 be used for antitumor combination medicine, it is characterised in that：The Tumor Angiongesis inhibits
Agent class compound include but not limited to Sutent, Si Dinibu, Sorafenib, for Wo Zhani, cilengitide, Imatinib,
At least one of Dasatinib, Enzastaurin, rapamycin, everolimus and tesirolimus.
4. according to claim 3 be used for antitumor combination medicine, it is characterised in that：The combination medicine further include to
A kind of few pharmaceutically acceptable carrier.
5. according to claim 4 be used for antitumor combination medicine, it is characterised in that：The pharmaceutically acceptable load
The dosage of body is 5~50 times of combination medicine weight.
6. according to claim 5 be used for antitumor combination medicine, it is characterised in that：The pharmaceutically acceptable load
Body includes but not limited at least one of liposome, polymer nanoparticle and magnetic nano particle.
7. according to claim 4 be used for antitumor combination medicine, it is characterised in that：The Tumor Angiongesis inhibits
Agent class compound includes Si Dinibu, Sorafenib, replaces Wo Zhani, cilengitide, Dasatinib, Enzastaurin and everolimus
Middle one or two.
8. it is a kind of using described in any one of claim 1-7 for antitumor combination medicine as the preparation of active ingredient,
It is characterized in that：The preparation includes solid pharmaceutical preparation and injection.
9. the preparation according to claim 8 for antitumor combination medicine, it is characterised in that：The solid pharmaceutical preparation packet
Include but be not limited to tablet, capsule, pill, micropill preparation.
10. a kind of application of claim 1-7 any one of them combination medicines in the drug for being used to prepare treating cancer,
It is characterized in that, the cancer includes but not limited to liver cancer, kidney, breast cancer, colon cancer, nasopharyngeal carcinoma, carcinoma of urinary bladder, gastric cancer, esophagus
Cancer, prostate cancer, leukaemia, malignant mela noma and lymthoma.
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| CN201810387270.0A CN108514639A (en) | 2018-04-26 | 2018-04-26 | It is a kind of to be used for antitumor combination medicine and its preparation and application |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111803477A (en) * | 2020-08-11 | 2020-10-23 | 上海交通大学 | Application of abstinence sulfur in preparation of anti-head and neck cancer and anti-fibrosis drugs |
| CN114146073A (en) * | 2020-09-07 | 2022-03-08 | 上海交通大学医学院 | Application of disulfiram in enhancing immune response |
| CN114366749A (en) * | 2020-10-15 | 2022-04-19 | 中国人民解放军海军军医大学 | Application of integrin inhibitor in preparation of medicine for treating kidney cancer |
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| US20100099757A1 (en) * | 2006-12-04 | 2010-04-22 | Yossef Israeli-Shalev | Disulfiram doses and treatment regimen suitable for treatment of angiogenesis-dependent disorders |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111803477A (en) * | 2020-08-11 | 2020-10-23 | 上海交通大学 | Application of abstinence sulfur in preparation of anti-head and neck cancer and anti-fibrosis drugs |
| CN114146073A (en) * | 2020-09-07 | 2022-03-08 | 上海交通大学医学院 | Application of disulfiram in enhancing immune response |
| CN114146073B (en) * | 2020-09-07 | 2023-08-11 | 上海交通大学医学院 | Use of disulfiram to enhance immune responses |
| CN114366749A (en) * | 2020-10-15 | 2022-04-19 | 中国人民解放军海军军医大学 | Application of integrin inhibitor in preparation of medicine for treating kidney cancer |
| CN114366749B (en) * | 2020-10-15 | 2023-06-30 | 中国人民解放军海军军医大学 | Use of integrin inhibitors in the preparation of medicaments for the treatment of renal cancer |
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Application publication date: 20180911 |
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