CN101653606B - Pharmaceutical composition containing protein kinase B inhibitor and epidermal growth factor recipient tyrosine kinase inhibitor and application thereof - Google Patents
Pharmaceutical composition containing protein kinase B inhibitor and epidermal growth factor recipient tyrosine kinase inhibitor and application thereof Download PDFInfo
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- CN101653606B CN101653606B CN 200810135514 CN200810135514A CN101653606B CN 101653606 B CN101653606 B CN 101653606B CN 200810135514 CN200810135514 CN 200810135514 CN 200810135514 A CN200810135514 A CN 200810135514A CN 101653606 B CN101653606 B CN 101653606B
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- URLYINUFLXOMHP-UHFFFAOYSA-N CN(c1c(c2c[n]3C(C4O)OC(COP(O)(O)=O)C4O)c3ncn1)N=C2N Chemical compound CN(c1c(c2c[n]3C(C4O)OC(COP(O)(O)=O)C4O)c3ncn1)N=C2N URLYINUFLXOMHP-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to a pharmaceutical composition containing a protein kinase B (Akt/PKB) inhibitor and an epidermal growth factor recipient (EGFR) tyrosine kinase inhibitor, and application of the pharmaceutical composition in the preparation of medicaments for treating colon cancer, liver cancer, lung cancer, stomach cancer, brain tumors, pancreatic cancer, ovarian cancer, mammary cancer or prostate cancer. The pharmaceutical composition has significant synergistic effect, improves the treatment effect of the medicaments, reduces the administration dose and reduces 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 the medicine of preparation treatment intestinal cancer, hepatocarcinoma, pulmonary carcinoma, gastric cancer, cerebroma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate thereof of protein kinase B (Akt/PKB) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor.
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.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; Cancer of pancreas is one of higher digestive system tumor of grade malignancy, and sickness rate is year by year ascendant trend.Because onset concealment lacks effective method of early diagnosis, often reach an advanced stage when making a definite diagnosis or shift, the patients with terminal median survival interval is no more than six months, and the treatment new method of therefore studying cancer of pancreas is extremely urgent.
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.
Akt/PKB is a kind of serine/threonine protein kitase, belong to protein kinase A, protein kinase G, Protein kinase C superfamily that cAMP relies on, it is the key molecule in the PI3K/Akt path, by multiple effect substrates such as phosphorylation mTOR, Bad, GSK3, mdm2, caspase families, at the growth, propagation, the inhibited apoptosis that promote tumor cell, impel cell invasion and transfer, promote angiogenesis, the aspects such as apoptosis of cell play an important role in the opposing chemotherapy and radiation.After being suppressed, Akt will suppress most of downstream molecules, control tumor development and transfer, and the Akt/PKB signal path is unusual and tumor development is in close relations, and Akt has become an important novel targets of antineoplaston.Piperazine Li Fuxin (perifosine) is lipid Akt inhibitor, to the clinical trial well afoot of the therapeutic effect such as carcinoma of prostate, cancer of pancreas, pulmonary carcinoma; TCN-p (Triciribinephosphate) was used for lymphadenomatous treatment in 2008 by the FDA approval.
EGF-R ELISA (epidermal growth factor receptor, EGFR) plays an important role in the genesis of tumor, behind it and the ligand binding, inspires cascade reaction and causes cell proliferation, angiogenesis, transfer and apoptosis to suppress.Comprise in the multiple entities tumor of nonsmall-cell lung cancer that normal mistake of EGFR gene expressed, the expression of this gene is relevant with the poor prognosis of some tumor.The endocellular metabolism zone of epidermal growth factor recipient tyrosine kinase inhibitor and ATP reversibility competition tyrosine kinase, the autophosphorylation 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 advanced Non-small cell lung, no significant difference on Overall survival synergism do not appear, in the therapeutic scheme that associating gefitinib or erlotinib and carboplatin+paclitaxel/cisplatin+gemcitabine is used for advanced Non-small cell lung.
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 drug combination carries out targeted therapy for many target spots and will not only be intended to reduce or delay chemical sproof appearance, reduce toxicity, and obtains 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 the medicine of preparation treatment intestinal cancer, hepatocarcinoma, pulmonary carcinoma, gastric cancer, cerebroma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate thereof, be specially the application of pharmaceutical composition in the medicine of preparation treatment intestinal cancer, hepatocarcinoma, pulmonary carcinoma, gastric cancer, cerebroma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate that contains protein kinase B (Akt/PKB) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor.
The present invention contains in the pharmaceutical composition of protein kinase B (Akt/PKB) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor, described protein kinase B (Akt/PKB) inhibitor can be for the medicine of protein kinase B (Akt/PKB) inhibitor of any structure type, such as Wortmannin, piperazine Li Fuxin or TCN-p.
Protein kinase B in the pharmaceutical composition of the present invention (Akt/PKB) inhibitor is preferably: TCN-p, its structural formula are formula I.
In the pharmaceutical composition of the present invention, described component is not limited to TCN-p medicine itself, can also be its pharmaceutically useful salt, the analog of the hydrate of TCN-p, derivant or the various TCN-p disclosed in the US4123524 patent application.
Among the present invention, described EGF-R ELISA (EGFR) tyrosine kinase inhibitor can be the medicine of EGF-R ELISA (EGFR) tyrosine kinase inhibitor of any structure type, such as gefitinib, erlotinib, Canertinib or PKI-166, wherein, Canertinib is researched and developed by Pfizer company; PKI-166 is researched and developed by Pfizer company.
Pharmaceutical composition epidermal growth factor receptor of the present invention (EGFR) tyrosine kinase inhibitor is preferably gefitinib or erlotinib or its combination, and wherein erlotinib is the chemical compound of the formula II that puts down in writing among the US5747498;
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, free alkali and other organic or inorganic.
The present invention contains in the pharmaceutical composition of protein kinase B (Akt/PKB) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor, and the mol ratio of protein kinase B (Akt/PKB) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor is 2.0-20:1.0-20; Preferred molar ratio is 5.0-10:2.5-10.
The present invention contain protein kinase B (Akt/PKB) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor pharmaceutical composition can for the preparation of the treatment various tumors medicine, described tumor includes but not limited to intestinal cancer, hepatocarcinoma, pulmonary carcinoma, gastric cancer, cerebroma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate.
The pharmaceutical composition of optimization protein kinase b (Akt/PKB) inhibitor of the present invention and EGF-R ELISA (EGFR) tyrosine kinase inhibitor is for the preparation of the application in the medicine for the treatment of pulmonary carcinoma, colon cancer and cancer of pancreas.
In the application of pharmaceutical composition of the present invention for the preparation of the medicine for the treatment of pulmonary carcinoma, colon cancer and cancer of pancreas, the mol ratio of described TCN-p and erlotinib is 5.0-10.0:2.5-10.0; The mol ratio that is preferably TCN-p and erlotinib is 7.5-10.0:5.0-10.0; Further the mol ratio of preferred TCN-p and erlotinib is 10.0:10.0.
Contain protein kinase B (Akt/PKB) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor compositions in preparation treatment intestinal cancer, hepatocarcinoma, pulmonary carcinoma, gastric cancer, cerebroma, cancer of pancreas, ovarian cancer, in the application of the medicine of breast carcinoma or carcinoma of prostate, in the scheme of the medicament of the present composition being made simultaneously administration, protein kinase B (Akt/PKB) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor can be contained in same pharmaceutical preparation such as tablet or the capsule, also protein kinase B (Akt/PKB) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor 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, protein kinase B (Akt/PKB) inhibitor can be made respectively different preparations with EGF-R ELISA (EGFR) tyrosine kinase inhibitor, 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, protein kinase B (Akt/PKB) inhibitor can be made respectively different preparations with EGF-R ELISA (EGFR) tyrosine kinase inhibitor, 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 protein kinase B (Akt/PKB) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor intersection discharges.
Protein kinase B (Akt/PKB) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor compositions are in preparation treatment intestinal cancer, hepatocarcinoma, pulmonary carcinoma, gastric cancer, cerebroma, cancer of pancreas, ovarian cancer, in the application in the medicine of breast carcinoma or carcinoma of prostate, protein kinase B in the described compositions (Akt/PKB) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor can use or simultaneously with the using in order of any priority, as protein kinase B (Akt/PKB) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor being taken to the patient simultaneously; Also can first EGF-R ELISA (EGFR) tyrosine kinase inhibitor be taken, then be taken to protein kinase B (Akt/PKB) inhibitor medicaments to the patient, or take first EGF-R ELISA (EGFR) tyrosine kinase inhibitor, then take protein kinase B (Akt/PKB) inhibitor medicaments, 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, can adopt the method for this area routine to be prepared into the pharmaceutical preparation that is suitable for gastrointestinal administration or parenteral administration protein kinase B of the present invention (Akt/PKB) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor, the pharmaceutical preparation that the present invention preferably makes gastrointestinal administration with protein kinase B (Akt/PKB) 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 protein kinase B of the present invention (Akt/PKB) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor 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, then protein kinase B (Akt/PKB) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor can directly mix makes 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 protein kinase B (Akt/PKB) inhibitor and NCI-H1650 (lung cancer cell line) is killed in the combination of EGF-R ELISA (EGFR) tyrosine kinase inhibitor, HCT-116 (colon cancer cell line), the test of Panc-10.05 (pancreas cancer cell strain), results suggest, protein kinase B of the present invention (Akt/PKB) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor combined therapy pulmonary carcinoma, colon cancer and cancer of pancreas 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: NCI-H1650 (lung cancer cell line), HCT-116 (colon cancer cell line), Panc-10.05 (pancreas cancer cell strain), all available from American Type Culture 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; Protein kinase B (Akt/PKB) inhibitor TCN-p is synthesized into reference to patent US4123524; EGF-R ELISA (EGFR) tyrosine kinase inhibitor erlotinib is synthesized into reference to patent US5747498.
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 the RPMI1640 culture medium that contains 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, 1-6 in specifically seeing Table.
After the dosing 5 days, 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 the RPMI1640 culture medium that contains 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, 7-9 in specifically seeing Table.
After the dosing 5 days, 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 1-6 prepares by method 2 by the combination of method 1, the 7-9.
Table 1
The TCN-p of embodiment 1 different proportion and the combination Synergistic of erlotinib promote the test of NCI-H1650 cell death, see Table 2.
Table 2
| Group | Use amount (μ M) | Cell mortality % |
| Matched group | 2.3±0.8 |
Cause in the test of lung cancer cell line NCI-H1650 cell death at the investigation related compound, find when using 7.5 μ MTCN-p or lower concentration, 5.0 μ M erlotinibs or lower concentration separately, to only have the seldom cell death of amount; Even when increasing concentration to the 10.0 μ MTCN-p of single medicine or 10.0 μ M erlotinib, 15% cell death of also only having an appointment; (7.5 μ MTCN-p+5.0 μ M erlotinib) then produces obvious synergism when both share under low concentration, causes 40% cancer cell death; When both share with the ratio of 10.0 μ MTCN-p+10.0 μ M erlotinibs, then produce more significantly synergism, cause about 85% cancer cell death.
The TCN-p of embodiment 2 different proportions and the combination Synergistic of erlotinib promote the test of HCT-116 cell death, see Table 3.
Table 3
Cause in the test of colon cancer cell line HCT-116 cell death at the investigation related compound, find when using 7.5 μ MTCN-p or lower concentration, 5.0 μ M erlotinibs or lower concentration separately, to only have the seldom cell death of amount; Even increase concentration to the 10.0 μ MTCN-p or 10.0 of single medicine
During μ M erlotinib, the 10-15% cell death of also only having an appointment; (7.5 μ MTCN-p+5.0 μ M erlotinib) then produces obvious synergism when both share under low concentration, causes about 40% cancer cell death; When both share with the ratio of 10.0 μ MTCN-p+10.0 μ M erlotinibs, then produce more significantly synergism, cause about 90% cancer cell death.
The TCN-p of embodiment 3 different proportions and the combination Synergistic of erlotinib promote the test of Panc-10.05 cell death, see Table 4.
Table 4
Cause in the test of pancreas cancer cell strain Panc-10.05 cell death at the investigation related compound, find when using 7.5 μ MTCN-p or lower concentration, 5.0 μ M erlotinibs or lower concentration separately, to only have the seldom cell death of amount; Even when increasing concentration to the 10.0 μ MTCN-p of single medicine or 10.0 μ M erlotinib, the 10-15% cell death of also only having an appointment; (7.5 μ M TCN-p+5.0 μ M erlotinib) then produces obvious synergism when both share under low concentration, causes about 60% cancer cell death; When both share with the ratio of 10.0 μ MTCN-p+10.0 μ M erlotinibs, then produce more significantly synergism, cause about 90% cancer cell death.
Claims (8)
1. a pharmaceutical composition is characterized in that containing protein kinase B inhibitor TCN-p and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib.
2. pharmaceutical composition according to claim 1 is characterized in that, the mol ratio of described protein kinase B inhibitor TCN-p and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib is 2.0-20:1.0-20.
3. pharmaceutical composition according to claim 2 is characterized in that, the mol ratio of described protein kinase B inhibitor TCN-p and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib is 5.0-10:2.5-10.
4. the application of the arbitrary described pharmaceutical composition of claim 1-3 in the medicine of preparation treatment intestinal cancer, hepatocarcinoma, pulmonary carcinoma, gastric cancer, cerebroma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate.
5. application according to claim 4 is characterized in that, in the application of the medicine for preparing treatment pulmonary carcinoma, colon cancer or cancer of pancreas, the mol ratio of described TCN-p and erlotinib is 5.0-10:2.5-10.
6. application according to claim 5 is characterized in that, in the application of the medicine for preparing treatment pulmonary carcinoma, colon cancer or cancer of pancreas, the mol ratio of described TCN-p and erlotinib is 7.5-10:5.0-10.
7. application according to claim 6 is characterized in that, in the application of the medicine for preparing treatment pulmonary carcinoma, colon cancer or cancer of pancreas, the mol ratio of described TCN-p and erlotinib is 10:10.
8. application according to claim 4 is characterized in that, the protein kinase B inhibitor TCN-p in the described pharmaceutical composition and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib use or using in order with any priority simultaneously.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200810135514 CN101653606B (en) | 2008-08-19 | 2008-08-19 | Pharmaceutical composition containing protein kinase B inhibitor and epidermal growth factor recipient tyrosine kinase inhibitor and application thereof |
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| CN 200810135514 CN101653606B (en) | 2008-08-19 | 2008-08-19 | Pharmaceutical composition containing protein kinase B inhibitor and epidermal growth factor recipient tyrosine kinase inhibitor and application thereof |
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| CN101653606B true CN101653606B (en) | 2013-02-13 |
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| CN107091930B (en) * | 2017-03-07 | 2020-09-15 | 杭州百凌生物科技有限公司 | Method for rapidly predicting and improving sensitivity of non-small cell lung cancer cells to epidermal growth factor receptor inhibitor |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5747498A (en) * | 1996-05-28 | 1998-05-05 | Pfizer Inc. | Alkynyl and azido-substituted 4-anilinoquinazolines |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5747498A (en) * | 1996-05-28 | 1998-05-05 | Pfizer Inc. | Alkynyl and azido-substituted 4-anilinoquinazolines |
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