CN101837129B - Medicament composition containing cMet inhibitor, HDAC (Histone Deacetylases) inhibitor and EGFR (Epidermal Growth Factor Receptor) tyrosine kinase inhibitor and application thereof - Google Patents
Medicament composition containing cMet inhibitor, HDAC (Histone Deacetylases) inhibitor and EGFR (Epidermal Growth Factor Receptor) tyrosine kinase inhibitor and application thereof Download PDFInfo
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Abstract
The invention relates to a medicament composition containing a histone deacetylases (HDAC) inhibitor, a hepatocyte growth factor receptor (cMet) inhibitor, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and application thereof in preparing the medicaments for treating liver cancer, lung cancer, colon cancer, kidney cancer, gastric cancer, brain tumor, sarcoma, pancreatic cancer, ovarian cancer, breast cancer or prostatic cancer. The medicament composition has the obvious synergistic effect, improves the curative efficiency of the medicaments, decreases the drug dosage and reduces the occurrence frequency of the side-effect.
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 the pharmaceutical composition and the application in the medicine of preparation treatment hepatocarcinoma, pulmonary carcinoma, colon cancer, renal carcinoma, gastric cancer, cerebroma, sarcoma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate thereof of C-MET HGFr (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor.
Background technology
World Health Organization's investigation report shows that global cancer condition is serious day by day, 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 of the number that cancer is dead also will be by increasing to 1,000 ten thousand 6,000,000 of every year.Wherein primary hepatocarcinoma is one of human modal malignant tumor for occurring in the epithelial canceration of hepatocyte and stones in intrahepatic bile duct; Pulmonary carcinoma is common malignancy, comes from bronchiolar epitheliums at different levels, is divided into cell lung cancer and nonsmall-cell lung cancer; Along with growth in the living standard, the change of dietary structure, the sickness rate of colon cancer is ascendant trend year by year.
The antitumor drug that has gone on the market at present is more, and like alkylating agent medicine, antimetabolite, AGPM, immunomodulator etc., but medicine is because toxicity is bigger mostly, and patient does not tolerate.Along with the Study on Molecular Mechanism to the incidence and development of tumor is more and more clearer, the multiple malignant tumor of molecular targeted treatment has received to be paid close attention to widely and pays much attention to.The molecular targeted agents selectivity is high, wide spectrum is effective, and its safety is superior to the cytotoxicity chemotherapeutics, is the new direction of present oncotherapy field development.
Hepatocyte growth factor (Hepatocyte growth factor, HGF) through with its target cell on special receptor (C-MET HGFr cMet) have the ability that promotes cell division, motion and shaping after combining.CMet is a proto-oncogene cMet encoded protein, is one type of transmembrane receptor with autonomy phosphorylation activity.HGF and cMet induce cMet receptor tyrosine phosphorylation on the after birth after combining, and the biological effect through signal transduction pathway performance HGF in the various kinds of cell, the generation of tumor cell, migrate and transfer process in brought into play important effect.Therefore, the activity that suppresses cMet may play important intervention effect to generation, invasion and attack and the transfer of tumor cell.CMet inhibitor grinding or got into clinical research has PF-02341066, SGX523 or PHA665752 etc.
Antibiotic FR 901228 has the tumor cell proliferation of inhibition, cell cycle arrest, inducing cell differentiation and promotes apoptotic effect.Wherein SAHA goes on the market, and MS-275, LBH589, Trichostatin (TSA), FK228 and west reach multiple Antibiotic FR 901228 entering clinical researches such as aniline in addition.
(epidermal growth factor receptor's EGF-R ELISA EGFR) plays an important role in the incidence and development of tumor, after it combines with part, inspires cascade reaction and causes cell proliferation, angiogenesis, transfer and apoptosis to suppress.Comprise in the multiple solid tumor of nonsmall-cell lung cancer that normal mistake of EGFR gene expressed, the poor prognosis of this expression of gene and some tumor is relevant.The endocellular metabolism zone of epidermal growth factor recipient tyrosine kinase inhibitor and ATP reversibility competition EGFR-TK, the automatic phosphorylation of inhibitory enzyme and the transmission of downstream signal.The medicine that has gone on the market is just like gefitinib (Gefitinib; Iressa), erlotinib (Erlotinib; Taceva) be approved for the treatment of nonsmall-cell lung cancer in late period; Synergism does not appear in the therapeutic scheme that associating gefitinib or erlotinib and carboplatin+paclitaxel/cisplatin+gemcitabine is used for the nonsmall-cell lung cancer in late period, no significant difference on overall life span.
Along with the progress of oncomolecularbiology, the molecular targeted treatment of tumor has become the focus of tumor research, in the treatment of kinds of tumors, has brought into play important effect.Yet; The biological behaviour of most of tumor is not to be arranged by single signal transduction pathway; But a plurality of signal transduction pathway concur; Therefore drug combination carries out targeted therapy to many target spots and will not only be intended to reduce or delay chemical sproof appearance, reduce toxicity, and especially rational three coupling medicines will be obtained better therapeutic to the synergism that cancerous cell kills and wounds through multiple medicine.
Summary of the invention
To above technological deficiency; The present invention provides a kind of pharmaceutical composition and the application in the medicine of preparation treatment hepatocarcinoma, pulmonary carcinoma, colon cancer, pulmonary carcinoma, renal carcinoma, gastric cancer, cerebroma, sarcoma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate thereof, is specially the application of pharmaceutical composition in the medicine of preparation treatment hepatocarcinoma, pulmonary carcinoma, colon cancer, renal carcinoma, gastric cancer, cerebroma, sarcoma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate that contains C-MET HGFr (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor.
The present invention contains in the pharmaceutical composition of C-MET HGFr (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) inhibitor, and said hepatocyte growth factor receptor inhibitor is PF-02341066, SGX523 or PHA665752 and respective analogs, derivant etc.; Said Antibiotic FR 901228 can be the medicine of the Antibiotic FR 901228 of any structure type; Like hydroximic acid, cyclic peptide, benzamides, fatty acid etc.; Specifically can for but be not limited to as, suberoylanilidehydroxamic acid (SAHA), Trichostatin (TSA), LBH589, MS-275, depsipeptide (FK228), Aphacidin, depsipeptides, west reach aniline, sodium butyrate, phenylbutyrate sodium; Said epidermal growth factor recipient tyrosine kinase inhibitor is gefitinib, erlotinib, Canertinib or PKI166 and respective analogs, derivant etc.
Said C-MET HGFr (cMet) inhibitor in the pharmaceutical composition of the present invention can be the medicine of the cMet inhibitor of any structure type; Like PF-02341066, SGX523 or PHA665752; Wherein, SGX-523 has applied for that by the research and development of SGX Pharmaceuticals company the I phase is clinical; PHA-665752 is researched and developed by Sugen company.
C-MET HGFr in the pharmaceutical composition of the present invention (cMet) inhibitor is preferably: PF-02341066, its structural formula are I.
In the pharmaceutical composition of the present invention, said component is not limited to PF-02341066 medicine itself, can also be its pharmaceutically useful salt, the analog of the derivant of PF-02341066 or the various PF-02341066 disclosed in the WO2007066187 patent application.
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, and 1411-1413 and JMC, 48,15,2005, the chemical compound of the formula II that is put down in writing among the 5047-5051:
In the pharmaceutical composition of the present invention, said component is not limited to said medicine itself, can also be the salt of their hydrate, analog, derivant and other organic or inorganic.
Among the present invention; Said EGF-R ELISA (EGFR) tyrosine kinase inhibitor can be the medicine of the epidermal growth factor recipient tyrosine kinase inhibitor of any structure type; Like gefitinib, erlotinib, Canertinib or PKI166; Wherein, Canertinib is the EGFR tyrosine kinase inhibitor, is researched and developed by Pfizer company; PKI-166, the EGFR tyrosine kinase inhibitor is researched and developed by Pfizer company.
Pharmaceutical composition mesocuticle growth factor recipient tyrosine kinase inhibitor of the present invention is preferably gefitinib or erlotinib or its combination, and wherein erlotinib is the chemical compound of the formula III put down in writing among the US5747498;
In the pharmaceutical composition of the present invention, said component is not limited to said medicine itself, can also be the salt of their analog, derivant, free alkali and other organic or inorganic.
The present invention contains in the pharmaceutical composition of C-MET HGFr (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor, and the mol ratio of hepatocyte growth factor receptor inhibitor, Antibiotic FR 901228 and epidermal growth factor recipient tyrosine kinase inhibitor is 0.3-3.0: 0.5-4.0: 1.5-15; The present invention further mol ratio of preferred said hepatocyte growth factor receptor inhibitor, Antibiotic FR 901228 and epidermal growth factor recipient tyrosine kinase inhibitor is 0.75-1.5: 1.0-2.0: 3.0-7.5.
The pharmaceutical composition that the present invention contains hepatocyte growth factor receptor inhibitor, Antibiotic FR 901228 and epidermal growth factor recipient tyrosine kinase inhibitor can be used to prepare the medicine of treating various tumors, and said tumor includes but not limited to hepatocarcinoma, pulmonary carcinoma, colon cancer, renal carcinoma, gastric cancer, cerebroma, sarcoma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate.
The application that the pharmaceutical composition of the preferred C-MET HGFr of the present invention (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor is used for preparing the medicine of treating hepatocarcinoma, pulmonary carcinoma and colon cancer.
In the application of the present invention in the medicine of preparation treatment hepatocarcinoma, pulmonary carcinoma, colon cancer, said hepatocyte growth factor receptor inhibitor PF-02341066, Antibiotic FR 901228 SAHA and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib mol ratio are 0.75-1.5: 1.0-2.0: 3.0-7.5; The mol ratio that is preferably PF-02341066, SAHA and erlotinib is 1.0-1.5: 1.5-2.0: 5.0-7.5; Further being preferably PF-02341066, SAHA and erlotinib mol ratio is 1.5: 2.0: 7.5.
Contain C-MET HGFr (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor compositions in the application of the medicine of preparation treatment hepatocarcinoma, pulmonary carcinoma, colon cancer, renal carcinoma, gastric cancer, cerebroma, sarcoma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate; In the scheme of the medicament of the present composition being processed administration simultaneously; C-MET HGFr (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor can be contained in in a kind of pharmaceutical preparation such as tablet or the capsule; Also can C-MET HGFr (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor be made preparation respectively; As make tablet or capsule respectively; And adopting the conventional mode in this area with their packings or combine, the patient takes according to the indication of package insert then simultaneously; In the scheme of the medicament of the present composition being processed administration successively; Can C-MET HGFr (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor be made different preparations respectively; And adopt the conventional mode in this area with their packings or combine; The patient takes according to the sequencing of package insert indication then; Or three kinds of compositions in the above-mentioned composition are processed a kind of preparation of controlled release; A kind of composition of elder generation in the release composition, the another kind of composition in the release composition and then discharge the third composition again, the patient only need take this controlled release composition preparation; In the scheme of the medicament that the present composition is prepared into the intersection administration; Can C-MET HGFr (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor be made different preparations respectively; And adopt the conventional mode in this area with their packings or combine; The patient takes according to the chi sequence of package insert indication then, the controlled release preparation that perhaps becomes C-MET HGFr (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor intersection to discharge this preparation of pharmaceutical compositions.
Contain in the application in the medicine of preparation treatment hepatocarcinoma, pulmonary carcinoma, colon cancer, renal carcinoma, gastric cancer, cerebroma, sarcoma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate of C-MET HGFr (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor compositions; C-MET HGFr in the said compositions (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor can use or with the using in order of any priority, as can C-MET HGFr (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor being taken to the patient simultaneously simultaneously; Also can take wherein a kind of earlier, take simultaneously again or take two kinds of medicines in addition with the order of any priority.The interval of taking for the three does not have special demands, but the interval of preferably taking three kinds of medicines is no more than one day; Perhaps three kinds of medicines replace administration.
Among the present invention; Can adopt the conventional method in this area to be prepared into the pharmaceutical preparation that is suitable for gastrointestinal administration or parenteral administration the C-MET HGFr among the present invention (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor; The pharmaceutical preparation that the present invention preferably processes gastrointestinal administration with C-MET HGFr (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor, its dosage form can be conventional tablet or capsule or controlled release, slow releasing preparation.In the pharmaceutical preparation of C-MET HGFr of the present invention (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor compositions; According to different dosage forms and preparation specification; The content of said compositions in preparation can be counted 1-99% for quality, is preferably 10%-90%; The adjuvant that preparation uses can adopt the conventional adjuvant in this area, reacts or the curative effect that do not influence medicine of the present invention is a prerequisite with the discord present composition; The method for preparing of said preparation can adopt the conventional method for preparing in this area to prepare.
Among the present invention; The preparation of compositions method does not have any restriction; C-MET HGFr (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor three can directly mix and make preparation then; Or respectively and/or corresponding auxiliary material mix and to make preparation respectively, and then packaging together, or mix and then mix and make preparation with corresponding auxiliary material respectively according to the conventional mode in this area.
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 is prerequisite to guarantee that this pharmaceutical composition can reach effective blood drug level in mammalian body.
The present invention has carried out C-MET HGFr (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor respectively, and both make up the test of killing Hep3B (hepatoma cell strain), A549 (lung cancer cell line), HCT-116 (colon cancer cell line) with the three arbitrarily; Results suggest; Three joint groups of C-MET HGFr of the present invention (cMet) inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor close treatment hepatocarcinoma, pulmonary carcinoma and colon cancer and have significant cooperative effect; The one pack system medicine or two joint groups that obviously are superior in them close; Improved the curative effect of medicine greatly; Reduce dosage, reduced the generation of side effect.
The specific embodiment
In conjunction with following examples the present invention is done further elaboration, but the present invention is not limited to this.
Embodiment
Reagent and method:
Cell: Hep3B (hepatoma cell strain), A549 (lung cancer cell line), HCT-116 (colon cancer cell line) are all available from American Type Culture Collection (ATCC), Rockville, MD, USA.
Medicine: institute's pharmaceutical composition is all by following method 1 or 2 said preparations of method in following examples; C-MET HGFr (cMet) inhibitor PF-02341066 is synthesized into reference to patent WO2007066187; Antibiotic FR 901228 SAHA presses document J.Med.Chem., and 1995,38,1411-1413 is synthesized into; EGF-R ELISA (EGFR) tyrosine kinase inhibitor erlotinib is synthesized into reference to patent US5747498.
Method 1: each component of accurate weighing corresponding pharmaceutical compositions, dissolve respectively with dimethyl sulfoxide, be made into the stock solution of 10mM separately; Preserve down at-20 ℃; Be diluted to suitable concentration with fresh culture medium during use, the solution of each component of 1 microlitre of respectively asking for then mixes subsequent use.In all tests, the ultimate density of dimethyl sulfoxide is answered≤5g/L, so that do not influence cell activity.
With all cells in the RPMI1640 culture medium that contains 10% calf serum, 100kU/L penicillin, 100mg/L streptomycin, 37 ℃, 5%CO
2Damp condition cultivate down, in the previous day of dosing, on six orifice plates, carry out cell inoculation 2 * 10
5/ hole adds the pharmaceutical composition solution of preparation as stated above then in cell, make each component reach its working concentration, specifically sees 1-18 in the table.
After the drug treating, measure cell death through trypan blue (Trypan Blue), cell turns into 10 minutes through carrying out pancreatin at 37 ℃ with trypsin sodium/EDTA.Get into the culture medium because dead cell comes off from incubator,, and then, mix with the trypan blue dyestuff with culture medium suspended sediment again through all cells of centrifugal collection under 1200 rev/mins.After the dyeing, count with optical microscope and hematimeter.Dyed the blue dead cell of counting by dyestuff.500 cells of picked at random are counted, and dead cell is recently expressed with the percentage that accounts for the grand total cell.
Method 2: each component of accurate weighing corresponding pharmaceutical compositions, dissolve respectively with dimethyl sulfoxide, be made into the stock solution of 10mM separately, preserve down at-20 ℃.Be diluted to suitable concentration with fresh culture medium during use, the solution for standby of each component of 1 microlitre of respectively asking for then.In all tests, the ultimate density of dimethyl sulfoxide is answered≤5g/L, so that do not influence cell activity.
With all cells in the RPMI1640 culture medium that contains 10% calf serum, 100kU/L penicillin, 100mg/L streptomycin, 37 ℃, 5%CO
2Damp condition cultivate down, in the previous day of dosing, on six orifice plates, carry out cell inoculation 2 * 10
5/ hole adds each component solution of the pharmaceutical composition of preparation as stated above with any order then in cell, make each component reach its working concentration, specifically sees 19-36 in the table.
After the drug treating, measure cell death through trypan blue (Trypan Blue), cell turns into 10 minutes through carrying out pancreatin at 37 ℃ with trypsin sodium/EDTA.Get into the culture medium because dead cell comes off from incubator,, and then, mix with the trypan blue dyestuff with culture medium suspended sediment again through all cells of centrifugal collection under 1200 rev/mins.After the dyeing, count with optical microscope and hematimeter.Dyed the blue dead cell of counting by dyestuff.500 cells of picked at random are counted, and dead cell is recently expressed with the percentage that accounts for the grand total cell.
Tabulate down in the drug regimen shown in 1, the combination of 1-18 prepares by method 2 by the combination of method 1, the 19-36.
Table 1
| Sequence number | PF-02341066 (micromole) | SAHA (micromole) | Erlotinib (micromole) |
| 1 | 0.75 | 1.0 | |
| 2 | 0.75 | 3.0 | |
| 3 | 1.0 | 3.0 | |
| 4 | 0.75 | 1.0 | 3.0 |
| 5 | 1.0 | 1.5 | |
| 6 | 1.0 | 5.0 | |
| 7 | 1.5 | 5.0 | |
| 8 | 1.0 | 1.5 | 5.0 |
| 9 | 1.5 | 2.0 | |
| 10 | 1.5 | 7.5 | |
| 11 | 2.0 | 7.5 |
| 12 | 1.5 | 2.0 | 7.5 |
| 13 | 0.75 | 1.0 | |
| 14 | 0.75 | 3.0 | |
| 15 | 1.0 | 3.0 | |
| 16 | 0.75 | 1.0 | 3.0 |
| 17 | 1.0 | 1.5 | |
| 18 | 1.0 | 5.0 | |
| 19 | 1.5 | 5.0 | |
| 20 | 1.0 | 1.5 | 5.0 |
| 21 | 1.5 | 2.0 | |
| 22 | 1.5 | 7.5 | |
| 23 | 2.0 | 7.5 | |
| 24 | 1.5 | 2.0 | 7.5 |
| 25 | 0.75 | 1.0 | |
| 26 | 0.75 | 3.0 | |
| 27 | 1.0 | 3.0 | |
| 28 | 0.75 | 1.0 | 3.0 |
| 29 | 1.0 | 1.5 | |
| 30 | 1.0 | 5.0 | |
| 31 | 1.5 | 5.0 | |
| 32 | 1.0 | 1.5 | 5.0 |
| 33 | 1.5 | 2.0 | |
| 34 | 1.5 | 7.5 | |
| 35 | 2.0 | 7.5 | |
| 36 | 1.5 | 2.0 | 7.5 |
The combination Synergistic of PF-02341066, SAHA and the erlotinib of embodiment 1 different proportion promotes the test of Hep3B cell death, sees table 2.
Table 2
Cause in the test of hepatoma cell strain Hep 3B cell death at the investigation related compound; Find when use 1.0 μ M PF-02341066 separately, 2.0 μ MSAHA, 7.5 μ M erlotinibs or lower concentration; Almost acellular death; Even any two kinds when under low concentration, share of above-mentioned three kinds of medicines; Have only 1.0 μ M PF-02341066+1.5 μ MSAHA, 1.0 μ M PF-02341066+5.0 μ M erlotinibs to share and can cause about 15% cell death, and the i.e. almost acellular death of 1.5 μ MSAHA+5.0 μ M erlotinibs of another kind of combination; But (1.0 μ M PF-02341066+1.5 μ M SAHA+5.0 μ M erlotinib) then produces the obvious synergistic effect when these three kinds of medicines share under above-mentioned low concentration, causes 43% cancer cell death; When above-mentioned three kinds of medicines make up respectively under higher concentration in twos; Can cause 28% cancer cell death when also having only 1.5 μ M PF-02341066+2.0 μ MSAHA to share; All the other two kinds combinations are that 1.5 μ M PF-02341066+7.5 μ M erlotinibs and 2.0 μ MSAHA+7.5 μ M erlotinibs only cause about 15% cell death; (1.5 μ M PF-02341066+2.0 μ M SAHA+7.5 μ M erlotinib) then produces significant more synergism when the three share, and causes 93% cancer cell death.
The combination Synergistic of PF-02341066, SAHA and the erlotinib of embodiment 2 different proportions promotes the test of A549 cell death, sees table 3.
Table 3
Cause in the test of lung cancer cell line A549 cell death at the investigation related compound; Find when use 1.5 μ M PF-02341066 separately, 1.5 μ MSAHA, 5.0 μ M erlotinibs or lower concentration; Almost acellular death; Even any two kinds when under low concentration, closing week of above-mentioned three kinds of medicines also only are no more than 15% cell death; But (1.0 μ M PF-02341066+1.5 μ M SAHA+5.0 μ M erlotinib) then produces the obvious synergistic effect when these three kinds of medicines share under above-mentioned low concentration, causes 43% cancer cell death; When above-mentioned three kinds of medicines make up respectively in twos, has only the cancer cell death of 15-22% under higher concentration; (1.5 μ MPF-02341066+2.0 μ M SAHA+7.5 μ M erlotinib) then produces significant more synergism when the three share, and causes 87% cancer cell death.
The combination Synergistic of PF-02341066, SAHA and the erlotinib of embodiment 3 different proportions promotes the test of HCT116 cell death, sees table 4.
Table 4
Cause in the test of colon cancer cell line HCT116 cell death at the investigation related compound; Find when using 1.5 μ M PF-02341066,1.5 μ M SAHA or lower concentration separately; Almost acellular death; Even when increasing erlotinib list concentration and being 7.5 μ M, 15% the cell death of also only having an appointment; When above-mentioned three kinds of medicines any two kinds when under low concentration, share, also only be no more than 15% cell death; But (1.0 μ MPF-02341066+1.5 μ MSAHA+5.0 μ M erlotinib) then produces the obvious synergistic effect when these three kinds of medicines share under above-mentioned low concentration, causes about 43% cancer cell death; When above-mentioned three kinds of medicines make up respectively in twos, also only be no more than 20% cancer cell death under higher concentration; (1.5 μ MPF-02341066+2.0 μ MSAHA+7.5 μ M erlotinib) then produces significant more synergism when the three share, and causes about 90% cancer cell death.
Claims (6)
1. pharmaceutical composition; It is characterized in that; Said compositions contains hepatocyte growth factor receptor inhibitor PF-02341066, Antibiotic FR 901228 SAHA and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib, and the mol ratio of PF-02341066, SAHA and erlotinib is 0.75-1.5: 1.0-2.0: 3.0-7.5.
2. pharmaceutical composition according to claim 1; It is characterized in that the mol ratio of said hepatocyte growth factor receptor inhibitor PF-02341066, Antibiotic FR 901228 SAHA and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib is 1.0: 1.5: 5.0.
3. pharmaceutical composition according to claim 1; It is characterized in that the mol ratio of said hepatocyte growth factor receptor inhibitor PF-02341066, Antibiotic FR 901228 SAHA and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib is 1.5: 2.0: 7.5.
4. the application of the described pharmaceutical composition of claim 1 in the medicine of preparation treatment hepatocarcinoma, pulmonary carcinoma or colon cancer.
5. application according to claim 4; It is characterized in that; In the application in the medicine of preparation treatment hepatocarcinoma, pulmonary carcinoma, colon cancer, said hepatocyte growth factor receptor inhibitor PF-02341066, Antibiotic FR 901228 SAHA and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib mol ratio are 1.0-1.5: 1.5-2.0: 5.0-7.5.
6. application according to claim 4; It is characterized in that the hepatocyte growth factor receptor inhibitor PF-02341066 in the said pharmaceutical composition, Antibiotic FR 901228 SAHA and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib use or using in order with any priority simultaneously.
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| 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 |
| TWI741731B (en) * | 2019-08-15 | 2021-10-01 | 大陸商深圳微芯生物科技股份有限公司 | Antitumor pharmaceutical composition comprising chidamide and use thereof |
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| CN1780627A (en) * | 2003-04-29 | 2006-05-31 | 贝林格尔.英格海姆国际有限公司 | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis |
| CN101080227A (en) * | 2004-12-15 | 2007-11-28 | 诺瓦提斯公司 | Combinations of therapeutic agents for treating cancer |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10287353B2 (en) | 2016-05-11 | 2019-05-14 | Huya Bioscience International, Llc | Combination therapies of HDAC inhibitors and PD-1 inhibitors |
| RU2770754C1 (en) * | 2018-08-17 | 2022-04-21 | Шэньчжэнь Чипскрин Байосайенсиз Ко., Лтд. | Combination of a histone deacetylase inhibitor and a protein kinase inhibitor and pharmaceutical application thereof |
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| CN101837129A (en) | 2010-09-22 |
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