CN101836989B - Medicament composition containing tetrandrine, tetrandrine derivatives and histone deacetylase inhibitor and application thereof - Google Patents
Medicament composition containing tetrandrine, tetrandrine derivatives and histone deacetylase inhibitor and application thereof Download PDFInfo
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Abstract
The invention relates to a medicament composition containing tetrandrine, tetrandrine derivatives and a histone deacetylase (HDAC) inhibitor and application thereof in preparing medicaments for treating colon cancer, liver cancer, lung cancer, stomach cancer, encephaloma, sarcoma, pancreatic cancer, ovarian cancer, breast cancer, prostatic cancer or glioma. The medicament composition has remarkable synergistic effect, improves the curative effect of the medicament, decreases the administration dosage and reduces the occurrence of side effects.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and the application in the medicine of preparation treatment cancer thereof, be specifically related to contain pharmaceutical composition and the application in preparation treatment colon cancer, hepatocarcinoma, pulmonary carcinoma, renal carcinoma, gastric cancer, cerebroma, sarcoma, cancer of pancreas, ovarian cancer, breast carcinoma, carcinoma of prostate or gliomatous medicine thereof of tetrandrine and tetrandrine analog derivative and Antibiotic FR 901228.
Background technology
World Health Organization's investigation report shows that global cancer condition is day by day serious, and 20 years from now on new patients' number will be increased to 1,500 ten thousand by present every year 1000 ten thousand, because the number that cancer is dead also will be by increasing to 1,000 ten thousand 6,000,000 of every year.Wherein pulmonary carcinoma is one of common malignant tumor, comes from bronchiolar epitheliums at different levels, is divided into cell lung cancer and nonsmall-cell lung cancer; Primary hepatocarcinoma is the canceration that occurs in hepatocyte and intrahepatic biliary epithelium cell, is one of human modal malignant tumor; The morbidity of colon cancer and environment, living habit, especially diet style is relevant.It is generally acknowledged that high fat diet and cellulose deficiency are main pathogenic factors.Along with growth in the living standard, the change of dietary structure, the sickness rate of colon cancer is year by year ascendant trend; Glioma is to betide neuroectodermal tumor, and it originates from neural Interstitial cell, is the intracranial common cancer, accounts for the 35-60% of intracranial tumor.
The antitumor drug that has gone on the market at present is more, and such as alkylating agent medicine, antimetabolite, antitumor antibiotics, immunomodulator etc., but medicine is because toxicity is larger mostly, and patient does not tolerate.Along with the Study on Molecular Mechanism to the genesis of tumor is more and more clearer, the molecular targeted therapy Several Kinds of Malignancy has been subject to paying close attention to widely and paying much attention to.The molecular targeted agents selectivity is high, wide spectrum is effective, and its safety is better than the cytotoxicity chemotherapeutics, is the new direction of present therapeutic field of tumor development.
Tetrandrine claims again tetrandrine (Tetrandrine), is the bisbenzylisoquinoline alkaloid that extracts from the root piece of Chinese herbal medicine Radix stephaniae tetrandrae, is the main effective ingredient of Radix stephaniae tetrandrae.Studies show that in early days tetrandrine has the widely pharmacological actions such as antiinflammatory, analgesia, blood pressure lowering, fibrosis.The clinical diseases such as hypertension, pneumosilicosis, hepatic fibrosis that are used for the treatment of have obtained good therapeutic effect.Studies confirm that in recent years, tetrandrine can not only directly suppress tumor growth, and the effect that has radiotherapy sensitization, reversing drug resistance, alleviates the chemicotherapy toxicity, demonstrates good potential applicability in clinical practice in antineoplaston.
Antibiotic FR 901228 has inhibition tumor cell propagation, cell cycle arrest, Cell differentiation inducing activity and promotes apoptotic effect.Wherein SAHA goes on the market, and MS-275, LBH589, Trichostatin (TSA), FK228 and west reach the multiple Antibiotic FR 901228s such as aniline and enter clinical research in addition.
Along with the progress of oncomolecularbiology, the tumor molecular targeted therapy has become the focus of tumor research, has brought into play important effect in the treatment of kinds of tumors.Yet, the biological behaviour of most of tumor is arranged by the single signal pathway, but a plurality of signal transduction pathway concur, therefore rational drug combination, the incomparable superiority of alone medicine is arranged, drug combination carries out targeted therapy for many target spots will not only be intended to minimizing or delay chemical sproof appearance, reduction toxicity, and obtain better curative effect by the synergism that multi-medicament kills and wounds cancerous cell.
Summary of the invention
For above technological deficiency; the invention provides a kind of pharmaceutical composition and the application in preparation treatment colon cancer, hepatocarcinoma, pulmonary carcinoma, renal carcinoma, gastric cancer, cerebroma, sarcoma, cancer of pancreas, ovarian cancer, breast carcinoma, carcinoma of prostate or gliomatous medicine thereof, be specially the pharmaceutical composition and the application in preparation treatment colon cancer, hepatocarcinoma, pulmonary carcinoma, renal carcinoma, gastric cancer, cerebroma, sarcoma, cancer of pancreas, ovarian cancer, breast carcinoma, carcinoma of prostate or gliomatous medicine thereof that contain tetrandrine and tetrandrine analog derivative and Antibiotic FR 901228.
The present invention contains in the pharmaceutical composition of tetrandrine and tetrandrine analog derivative and Antibiotic FR 901228, and described tetrandrine and tetrandrine analog derivative can be tetrandrine, its derivant and analog thereof.
Tetrandrine in the pharmaceutical composition of the present invention and tetrandrine analog derivative are preferably: tetrandrine, its corresponding structural formula is suc as formula shown in the I.
In the pharmaceutical composition of the present invention, described component includes but not limited to tetrandrine medicine itself, can also be its pharmaceutically useful salt, hydrate or derivant etc.
Among the present invention; described Antibiotic FR 901228 can be the medicine of the Antibiotic FR 901228 of any structure type; such as hydroximic acid, cyclic peptide, benzamides, fatty acid etc.; be specifically as follows but be not limited to as, suberoylanilide hydroxamicacid (SAHA), Trichostatin (TSA), LBH589, MS-275, depsipeptide (FK228), apicidin, west reach aniline, sodium butyrate, phenylbutyrate sodium.
Antibiotic FR 901228 is preferably SAHA, Trichostatin (TSA), LBH589 and MS-275 in the pharmaceutical composition of the present invention.
Wherein SAHA is JMC, 38,8,1995,1411-1413 and JMC, and the chemical compound of the formula II that puts down in writing among 48,15,2005, the 5047-5051:
Wherein LBH-589 is by the research and development of Novartis company, and commodity are called panobinstat, and it is clinical to be in the II phase, and its structural formula is shown in the formula III:
In the pharmaceutical composition of the present invention, described component is not limited to said medicine itself, can also be the salt of their hydrate, analog, derivant and other organic or inorganic.
The present invention contains in the pharmaceutical composition of tetrandrine and tetrandrine analog derivative and Antibiotic FR 901228, and the mol ratio of tetrandrine and tetrandrine analog derivative and Antibiotic FR 901228 is 1.0-20.0: 0.001-5.0; Further the mol ratio of preferred powder menispermine and tetrandrine analog derivative and Antibiotic FR 901228 is 2.5-10.0: 0.005-2.0.
The present invention contain tetrandrine and tetrandrine analog derivative and Antibiotic FR 901228 pharmaceutical composition can for the preparation of the treatment various tumors medicine, described tumor includes but not limited to colon cancer, hepatocarcinoma, pulmonary carcinoma, renal carcinoma, gastric cancer, cerebroma, sarcoma, cancer of pancreas, ovarian cancer, breast carcinoma, carcinoma of prostate or glioma.
The pharmaceutical composition of preferred powder menispermine of the present invention and tetrandrine analog derivative and Antibiotic FR 901228 is preferred for preparing the application in Hepatoma therapy, colon cancer, pulmonary carcinoma and the gliomatous medicine.
In the application of pharmaceutical composition of the present invention in the medicine of preparation Hepatoma therapy, the mol ratio of tetrandrine and Antibiotic FR 901228 is 2.5-10.0: 0.01-2.0.
In the application of pharmaceutical composition of the present invention in the medicine of preparation Hepatoma therapy, the mol ratio of described tetrandrine and SAHA is 2.5-10.0: 1.0-2.0; Further the mol ratio of preferred described tetrandrine and SAHA is 5.0-10.0: 1.5-2.0; Best mol ratio for described tetrandrine and SAHA is 10.0: 2.0.
In the application of pharmaceutical composition of the present invention in the medicine of preparation Hepatoma therapy, the mol ratio of described tetrandrine and LBH589 is 2.5-10.0: 0.01-0.025; Further the mol ratio of preferred described tetrandrine and LBH589 is 5.0-10.0: 0.015-0.025: best mol ratio for described tetrandrine and LBH589 is 7.5: 0.025 or 10.0: 0.025.
In the application of pharmaceutical composition of the present invention in the medicine of preparation treatment colon cancer, the mol ratio of described tetrandrine and LBH589 is 2.5-10.0: 0.01-0.03; Further the mol ratio of preferred described tetrandrine and LBH589 is 5.0-10.0: 0.02-0.03; The mol ratio of best preferred described tetrandrine and LBH589 is 10.0: 0.03.
In the application of pharmaceutical composition of the present invention in the medicine of preparation treatment pulmonary carcinoma, the mol ratio of described tetrandrine and LBH589 is 2.5-10.0: 0.01-0.03; Further the mol ratio of preferred described tetrandrine and LBH589 is 5.0-10.0: 0.02-0.03; The mol ratio of best preferred described tetrandrine and LBH589 is 10.0: 0.03.
In the application of pharmaceutical composition of the present invention in the gliomatous medicine of preparation treatment, the mol ratio of described tetrandrine and Antibiotic FR 901228 is 2.5-7.5: 0.005-1.0.
In the application of pharmaceutical composition of the present invention in the gliomatous medicine of preparation treatment, the mol ratio of described tetrandrine and SAHA is 2.5-7.5: 0.25-1.0; Further the mol ratio of preferred described tetrandrine and SAHA is 5.0-7.5: 0.5-1.0: best mol ratio for described tetrandrine and SAHA is 7.5: 1.0.
In the application of pharmaceutical composition of the present invention in the gliomatous medicine of preparation treatment, the mol ratio of described tetrandrine and LBH589 is 2.5-7.5: 0.005-0.015; Further the mol ratio of preferred described tetrandrine and LBH589 is 5.0-7.5: 0.01-0.015: best mol ratio for described tetrandrine and LBH589 is 7.5: 0.015.
Contain tetrandrine and tetrandrine analog derivative and Antibiotic FR 901228 compositions in preparation treatment colon cancer, hepatocarcinoma, pulmonary carcinoma, renal carcinoma, gastric cancer, cerebroma, sarcoma, cancer of pancreas, ovarian cancer, breast carcinoma, in the application of carcinoma of prostate or gliomatous medicine, in the scheme of the medicament of the present composition being made simultaneously administration, tetrandrine and tetrandrine analog derivative and Antibiotic FR 901228 can be contained in same pharmaceutical preparation such as tablet or the capsule, also tetrandrine and tetrandrine analog derivative and Antibiotic FR 901228 can be made respectively preparation, as making respectively tablet or capsule, and the mode that adopts this area routine is with their packings or combine, and then the patient takes simultaneously according to the indication of package insert; In the scheme of the medicament of the present composition being made successively administration, tetrandrine and tetrandrine analog derivative can be made respectively different preparations with Antibiotic FR 901228, and the mode that adopts this area routine is with their packings or combine, then the patient takes according to the sequencing of package insert indication, or two kinds of compositions in the above-mentioned composition are made a kind of preparation of controlled release, a kind of composition in elder generation's release composition and then the another kind of composition in the release composition, the patient only need to take this controlled release composition preparation; In the scheme of the medicament that the present composition is prepared into the intersection administration; tetrandrine and tetrandrine analog derivative can be made respectively different preparations with Antibiotic FR 901228; and the mode that adopts this area routine is with their packings or combine; then the patient takes according to the chi sequence of package insert indication, perhaps this pharmaceutical composition is prepared into the controlled release preparation that tetrandrine and tetrandrine analog derivative and Antibiotic FR 901228 intersection discharges.
In the application in preparation treatment colon cancer, hepatocarcinoma, pulmonary carcinoma, renal carcinoma, gastric cancer, cerebroma, sarcoma, cancer of pancreas, ovarian cancer, breast carcinoma, carcinoma of prostate or gliomatous medicine of tetrandrine and tetrandrine analog derivative and Antibiotic FR 901228 compositions, tetrandrine in the described compositions and tetrandrine analog derivative and Antibiotic FR 901228 can be used or simultaneously with the using in order of any priority, as tetrandrine and tetrandrine analog derivative and Antibiotic FR 901228 being taken to the patient simultaneously; Also can first Antibiotic FR 901228 be taken, then be taken to tetrandrine and tetrandrine analog derivative medicine to the patient, or take first Antibiotic FR 901228, then take tetrandrine and tetrandrine analog derivative medicine, the interval of taking for both does not have special requirement, but the interval of preferably taking two kinds of medicines is no more than one day; Perhaps two kinds of medicines replace administration.
Among the present invention; the method of tetrandrine of the present invention and tetrandrine analog derivative and Antibiotic FR 901228 employing this area routine can be prepared into the pharmaceutical preparation that is suitable for gastrointestinal administration or parenteral administration; the pharmaceutical preparation that the present invention preferably makes gastrointestinal administration with tetrandrine and tetrandrine analog derivative and Antibiotic FR 901228, its dosage form can be conventional tablet or capsule or controlled release, slow releasing preparation.In the pharmaceutical preparation of tetrandrine of the present invention and tetrandrine analog derivative and Antibiotic FR 901228 compositions, according to different dosage forms and preparation specification, the content of described compositions in preparation can be counted 1-99% for quality, is preferably 10%-90%; The adjuvant that preparation uses can adopt the adjuvant of this area routine, take the discord present composition react or the curative effect that do not affect medicine of the present invention as prerequisite; The preparation method of described preparation can adopt the preparation method of this area routine to be prepared.
Among the present invention; the preparation method of compositions does not have any restriction; tetrandrine and tetrandrine analog derivative and Antibiotic FR 901228 can directly be mixed and then made preparation; or respectively and/or corresponding adjuvant mix and make respectively preparation; and then be packaging together according to the mode of this area routine, or mix and then mix and make preparation with corresponding adjuvant respectively.
The dosage of the pharmaceutical composition among the present invention can carry out suitable variation according to the dosage form difference of administration object, route of administration or medicine, but to guarantee that this pharmaceutical composition can reach effective blood drug level as prerequisite in mammalian body.
The present invention has carried out respectively tetrandrine and tetrandrine analog derivative and Antibiotic FR 901228 combination and has killed HepG2; PLC/PRF/5 (hepatoma cell strain); A549 (lung cancer cell line); DLD1 (colon cancer cell line); the test of D37 (neuroglial cytoma strain); results suggest; tetrandrine of the present invention and tetrandrine analog derivative and Antibiotic FR 901228 combined therapy hepatocarcinoma; colon cancer; pulmonary carcinoma and glioma have significant cooperative effect; improved the curative effect of medicine; reduce dosage, reduced the generation of side effect.
The specific embodiment
The invention will be further elaborated with the following Examples, but the present invention is not limited to this.
Embodiment
Reagent and method:
Cell: HepG2, PLC/PRF/5 (hepatoma cell strain), A549 (lung cancer cell line), DLD1 (colon cancer cell line), D37 (neuroglial cytoma strain), all available from American TypeCulture Collection (ATCC), Rockville, MD, USA.
Medicine: institute's pharmaceutical composition is all by following method 1 or 2 described preparations of method in following examples; Tetrandrine is available from Sigma; Antibiotic FR 901228 all is synthesized into by document, and the synthesized reference document of SAHA is: J.Med.Chem., 1995,38,1411-1413; The synthesized reference document of LBH-589 is: WO2002022577.
Method 1: each component of the accurate corresponding pharmaceutical composition of weighing, dissolve respectively with dimethyl sulfoxide, be made into separately the stock solution of 10mM,-20 ℃ of lower preservations, be diluted to suitable concentration with fresh culture medium during use, the solution of each component of 1 microlitre of then respectively asking for mixes for subsequent use.In all tests, the ultimate density of dimethyl sulfoxide is answered≤5g/L, in order to do not affect the activity of cell.
With all cells in RPMI 1640 culture medium that contain 10% calf serum, 100kU/L penicillin, 100mg/L streptomycin, 37 ℃, 5%CO
2Damp condition under cultivate, in the previous day of dosing, carry out cell inoculation 2 * 10 at six orifice plates
5Then/hole adds the as stated above medicinal composition solution of preparation in cell, make each component reach its working concentration, specifically sees Table 1-27 in 1.
After the drug treating, measure cell death by trypan blue (Trypan Blue), cell turns into 10 minutes by carrying out pancreatin at 37 ℃ with trypsin sodium/EDTA.Because dead cell comes off from incubator enter the culture medium, by all cells of centrifugal collection under 1200 rev/mins, and then with culture medium Eddy diffusion precipitate, mix with the trypan blue dyestuff.After the dyeing, count with optical microscope and hematimeter.By the dead cell of counting of dyes au bleu.Choose at random 500 cells and count, dead cell is recently expressed with the percentage that accounts for the grand total cell.
Method 2: each component of the accurate corresponding pharmaceutical composition of weighing, dissolve respectively with dimethyl sulfoxide, be made into separately the stock solution of 10mM ,-20 ℃ of lower preservations.Be diluted to suitable concentration with fresh culture medium during use, the solution for standby of each component of 1 microlitre of then respectively asking for.In all tests, the ultimate density of dimethyl sulfoxide is answered≤5g/L, in order to do not affect the activity of cell.
With all cells in RPMI 1640 culture medium that contain 10% calf serum, 100kU/L penicillin, 100mg/L streptomycin, 37 ℃, 5%CO
2Damp condition under cultivate, in the previous day of dosing, carry out cell inoculation 2 * 10 at six orifice plates
5Then/hole adds as stated above each component solution of the pharmaceutical composition of preparation with any order in cell, make each component reach its working concentration, specifically sees Table 28-51 in 1.
After the drug treating, measure cell death by trypan blue (Trypan Blue), cell turns into 10 minutes by carrying out pancreatin at 37 ℃ with trypsin sodium/EDTA.Because dead cell comes off from incubator enter the culture medium, by all cells of centrifugal collection under 1200 rev/mins, and then with culture medium Eddy diffusion precipitate, mix with the trypan blue dyestuff.After the dyeing, count with optical microscope and hematimeter.By the dead cell of counting of dyes au bleu.Choose at random 500 cells and count, dead cell is recently expressed with the percentage that accounts for the grand total cell.
In the drug regimen shown in the lower tabulation 1, the combination of 1-12 prepares by method 2 by the combination of method 1, the 13-21.
Table 1
The tetrandrine (Tetrandrine) of embodiment 1 different proportion promotes the test of HepG2 cell death with the combination Synergistic of SAHA, sees Table 2.
Table 2
Cause in the test of hepatoma cell strain HepG2 cell death at the investigation related compound, find when using 5.0 μ M tetrandrine or lower concentration, 1.5 μ M SAHA or lower concentration separately, to only have the seldom cell death of amount; Even when increasing concentration to 10.0 μ M tetrandrine, the 2.0 μ M SAHA of single medicine, the 10-20% cell death of also only having an appointment; (5.0 μ M tetrandrine+1.5 μ M SAHA) then produce obvious synergism when both share under low concentration, cause about 32% cancer cell death; When both share with the ratio of 10.0 μ M tetrandrine+2.0 μ M SAHA, then produce more significant synergism, cause about 85% cancer cell death.
The tetrandrine of embodiment 2 different proportions and the combination Synergistic of LBH589 promote the test of HepG2 cell death, see Table 3.
Table 3
Cause in the test of hepatoma cell strain HepG2 cell death at the investigation related compound, find when using 5.0 μ M tetrandrine, 0.015 μ M LBH589 or lower concentration separately, to only have the seldom cell death of amount; Even when increasing concentration to 10.0 μ M tetrandrine, the 0.025 μ M LBH589 of single medicine, 20% cell death of also only having an appointment; (5.0 μ M tetrandrine+0.015 μ M LBH589) then produce obvious synergism when both share under low concentration, cause about 20% cancer cell death; When both share with the ratio of 10.0 μ M tetrandrine+0.025 μ M LBH589, then produce more significant synergism, cause 91% cancer cell death.
The tetrandrine of embodiment 3 different proportions and the combination Synergistic of LBH589 promote the test of PLC/PRF/5 cell death, see Table 4.
Table 4
Cause in the test of hepatoma cell strain PLC/PRF/5 cell death 15% the cell death of finding when independent use 5.0 μ M tetrandrine, 0.015 μ M LBH589 or lower concentration, only to have an appointment investigating related compound; Even when increasing concentration to 7.5 μ M tetrandrine, the 0.025 μ MLBH589 of single medicine, the 20-25% cell death of also only having an appointment; (5.0 μ M tetrandrine+0.015 μ M LBH589) then produce obvious synergism when both share under low concentration, cause about 34% cancer cell death; When both share with the ratio of 7.5 μ M tetrandrine+0.025 μ M LBH589, then produce more significant synergism, cause 95% cancer cell death.
The tetrandrine of embodiment 4 different proportions and the combination Synergistic of LBH589 promote the test of DLD1 cell death, see Table 5.
Table 5
Cause in the test of colon cancer cell line DLD1 cell death 10% the cell death of finding when independent use 5.0 μ M tetrandrine, 0.02 μ M LBH589 or lower concentration, only to have an appointment investigating related compound; Even when increasing concentration to 10.0 μ M tetrandrine, the 0.03 μ M LBH589 of single medicine, 20% cell death of also only having an appointment; (5.0 μ M tetrandrine+0.02 μ M LBH589) then produce obvious synergism when both share under low concentration, cause about 23% cancer cell death; When both share with the ratio of 10.0 μ M tetrandrine+0.03 μ M LBH589, then produce more significant synergism, cause 82% cancer cell death.
The tetrandrine of embodiment 5 different proportions and the combination Synergistic of LBH589 promote the test of A549 cell death, see Table 6.
Table 6
Cause in the test of lung cancer cell line A549 cell death 15% the cell death of finding when independent use 5.0 μ M tetrandrine, 0.02 μ M LBH589 or lower concentration, only to have an appointment investigating related compound; Even when increasing concentration to 10.0 μ M tetrandrine, the 0.03 μ M LBH589 of single medicine, 20% cell death of also only having an appointment; (5.0 μ M tetrandrine+0.02 μ M LBH589) then produce obvious synergism when both share under low concentration, cause about 30% cancer cell death; When both share with the ratio of 10.0 μ M tetrandrine+0.03 μ M LBH589, then produce more significant synergism, cause 76% cancer cell death.
The tetrandrine of embodiment 6 different proportions and the combination Synergistic of SAHA promote the test of D37 cell death, see Table 7.
Table 7
Cause in the test of neuroglial cytoma strain D37 cell death at the investigation related compound, find when using 5.0 μ M tetrandrine, 0.5 μ M SAHA or lower concentration separately, to only have the seldom cell death of amount; Even when increasing concentration to 7.5 μ M tetrandrine, the 1.0 μ M SAHA of single medicine, 20% cell death of also only having an appointment; (5.0 μ M tetrandrine+0.5 μ M SAHA) then produce obvious synergism when both share under low concentration, cause about 21% cancer cell death; When both share with the ratio of 7.5 μ M tetrandrine+1.0 μ M SAHA, then produce more significant synergism, cause 99% cancer cell death.
The tetrandrine of embodiment 7 different proportions and the combination Synergistic of LBH589 promote the test of D37 cell death, see Table 8.
Table 8
Cause in the test of neuroglial cytoma strain D37 cell death at the investigation related compound, find when using 5.0 μ M tetrandrine, 0.01 μ M LBH589 or lower concentration separately, to only have the seldom cell death of amount; Even when increasing concentration to 7.5 μ M tetrandrine, the 0.015 μ MLBH589 of single medicine, 20% cancer cell death of also only having an appointment; (5.0 μ M tetrandrine+0.01 μ M LBH589) then produce obvious synergism when both share under low concentration, cause about 26% cancer cell death; When both share with the ratio of 7.5 μ M tetrandrine+0.015 μ M LBH589, then produce more significant synergism, cause 99% cancer cell death.
Claims (17)
1. a pharmaceutical composition is characterized in that, described pharmaceutical composition contains tetrandrine and Antibiotic FR 901228.
2. pharmaceutical composition according to claim 1 is characterized in that, the mol ratio of described tetrandrine and Antibiotic FR 901228 is 1.0-20.0: 0.001-5.0.
3. pharmaceutical composition according to claim 2 is characterized in that, the mol ratio of described tetrandrine and Antibiotic FR 901228 is 2.5-10.0: 0.005-2.0.
4. pharmaceutical composition according to claim 3 is characterized in that, described Antibiotic FR 901228 is that SAHA, MS275, LBH589, TSA or west reach aniline.
5. the application of the arbitrary described pharmaceutical composition of claim 1-4 in preparation treatment gastric cancer, cerebroma, ovarian cancer, breast carcinoma, colon cancer, hepatocarcinoma, pulmonary carcinoma, renal carcinoma, sarcoma, cancer of pancreas, carcinoma of prostate or gliomatous medicine.
6. application according to claim 5 is characterized in that, in the application in the medicine of preparation Hepatoma therapy, the mol ratio of tetrandrine and Antibiotic FR 901228 is 2.5-10.0: 0.01-2.0.
7. application according to claim 6 is characterized in that, in the application in the medicine of preparation Hepatoma therapy, described Antibiotic FR 901228 is SAHA or LBH589, and the mol ratio of described tetrandrine and SAHA is 2.5-10.0: 1.0-2.0; Or the mol ratio of described tetrandrine and LBH589 is 2.5-10.0: 0.01-0.025.
8. application according to claim 7 is characterized in that, in the application in the medicine of preparation Hepatoma therapy, the mol ratio of described tetrandrine and SAHA is 5.0-10.0: 1.5-2.0; Or the mol ratio of described tetrandrine and LBH589 is 5.0-10.0: 0.015-0.025.
9. application according to claim 8 is characterized in that, in the application in the medicine of preparation Hepatoma therapy, the mol ratio of described tetrandrine and SAHA is 10.0: 2.0; Or the mol ratio of described tetrandrine and LBH589 is 7.5: 0.025 or 10.0: 0.025.
10. application according to claim 5; it is characterized in that; in the application in the medicine of preparation treatment colon cancer, pulmonary carcinoma, described Antibiotic FR 901228 is LBH589, and the mol ratio of described tetrandrine and LBH589 is 2.5-10.0: 0.01-0.03.
11. application according to claim 10 is characterized in that, in the application in the medicine of preparation treatment colon cancer, pulmonary carcinoma, the mol ratio of described tetrandrine and LBH589 is 5.0-10.0: 0.02-0.03.
12. application according to claim 11 is characterized in that, in the application in the medicine of preparation treatment colon cancer, pulmonary carcinoma, the mol ratio of described tetrandrine and LBH589 is 10: 0.03.
13. application according to claim 5 is characterized in that, in the application of the gliomatous medicine of preparation treatment, the mol ratio of described tetrandrine and Antibiotic FR 901228 is 2.5-7.5: 0.005-1.0.
14. application according to claim 13, it is characterized in that, in the application of the gliomatous medicine of preparation treatment, described Antibiotic FR 901228 is SAHA or LBH589, and the mol ratio of described tetrandrine and SAHA is 2.5-7.5: 0.25-1.0; Or the mol ratio of described tetrandrine and LBH589 is 2.5-7.5: 0.005-0.015.
15. application according to claim 14 is characterized in that, in the application of the gliomatous medicine of preparation treatment, the mol ratio of described tetrandrine and SAHA is 5.0-7.5: 0.5-1.0; Or the mol ratio of described tetrandrine and LBH589 is 5.0-7.5: 0.01-0.015.
16. application according to claim 15 is characterized in that, in the application of the gliomatous medicine of preparation treatment, the mol ratio of described tetrandrine and SAHA is 7.5: 1.0; Or the mol ratio of described tetrandrine and LBH589 is 7.5: 0.015.
17. application according to claim 5 is characterized in that, the tetrandrine in the described pharmaceutical composition and Antibiotic FR 901228 are used or using in order with any priority simultaneously.
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| CN104873512A (en) * | 2015-05-21 | 2015-09-02 | 魏华 | Pharmaceutical composition with synergistic effect and myofibroblast capable of resisting organ fibrosis and tumor stroma and application |
| TWI794171B (en) | 2016-05-11 | 2023-03-01 | 美商滬亞生物國際有限公司 | Combination therapies of hdac inhibitors and pd-l1 inhibitors |
| CN112439070A (en) * | 2019-08-28 | 2021-03-05 | 深圳微芯生物科技股份有限公司 | Sidapamide pharmaceutical composition and application thereof |
| CN113679755A (en) * | 2021-08-18 | 2021-11-23 | 西南民族大学 | Anticancer use of compounds |
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| US10287353B2 (en) | 2016-05-11 | 2019-05-14 | Huya Bioscience International, Llc | Combination therapies of HDAC inhibitors and PD-1 inhibitors |
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