CN101653607B - Pharmaceutical composition containing hepatocyte growth factor receptor inhibitor and mitogen extracellular kinase inhibitor and application thereof - Google Patents
Pharmaceutical composition containing hepatocyte growth factor receptor inhibitor and mitogen extracellular kinase inhibitor and application thereof Download PDFInfo
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- CN101653607B CN101653607B CN 200810135515 CN200810135515A CN101653607B CN 101653607 B CN101653607 B CN 101653607B CN 200810135515 CN200810135515 CN 200810135515 CN 200810135515 A CN200810135515 A CN 200810135515A CN 101653607 B CN101653607 B CN 101653607B
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- KTEIFNKAUNYNJU-GFCCVEGCSA-N C[C@H](c(c(Cl)ccc1F)c1Cl)Oc1c(N)ncc(-c2c[n](C3CCNCC3)nc2)c1 Chemical compound C[C@H](c(c(Cl)ccc1F)c1Cl)Oc1c(N)ncc(-c2c[n](C3CCNCC3)nc2)c1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
Abstract
The invention relates to a pharmaceutical composition containing a hepatocyte growth factor receptor (cMet) inhibitor and a mitogen extracellular kinase (MEK) inhibitor, and application of the pharmaceutical composition in the preparation of medicaments for treating liver cancer, lung cancer, stomach cancer, intestinal 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 Hepatoma therapy, pulmonary carcinoma, gastric cancer, intestinal cancer, cerebroma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate thereof of hepatocyte growth factor receptor inhibitor and mitogen extracellular kinase inhibitor.
Background technology
World Health Organization's investigation report shows, 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 primary hepatocarcinoma is the canceration that occurs in hepatocyte and intrahepatic biliary epithelium cell, is one of human modal malignant tumor; 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.
Hepatocyte growth factor (Hepatocyte growth factor, HGF) by with its target cell on special receptor (C-MET HGFr cMet) in conjunction with after have the ability that promotes cell division, motion and shaping.CMet is the albumen of proto-oncogene cMet coding, is the transmembrane receptor that a class has the autonomy phosphorylation activity.HGF and cMet in conjunction with after induce cMet receptor tyrosine phosphorylation on the after birth, and the biological effect by 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.At the hepatocyte growth factor receptor inhibitor that grinds or entered clinical research PF-02341066, SGX523 or PHA665752 etc. are arranged.
Mitogen activated protein kinase (mitogen-activated protein kinase, MAPK) cascade is the important channel of cell signalling, the various kinds of cell external signal (such as somatomedin, cytokine, the tumour promotion factor) of raising can be passed on to nucleus step by step by phosphoric acid activation, and activate multiple nuclear factor, such as C-myc, C-jun etc., participate in Growth of Cells, growth, division, and the various physiological processes such as differentiation, and in malignant transformation of cells and evolution, play an important role.As important ring---mitogen extracellular kinase (the mitogenextracellular kinase in the MAPK signal transduction pathway, MEK) can be by activation such as multiple somatomedin, inflammatory factor and environmental stress reactions, the propagation that causes cell, therefore, mek inhibitor becomes a new direction of antitumor drug research.
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 appearance, the reduction toxicity that targeted therapy will not only be intended to reduce or delay drug resistance for many target spots, 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 Hepatoma therapy, pulmonary carcinoma, gastric cancer, intestinal cancer, cerebroma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate thereof, be specially the pharmaceutical composition that contains C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor and in the application of the medicine for preparing Hepatoma therapy, pulmonary carcinoma, gastric cancer, intestinal cancer, cerebroma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate.
In the pharmaceutical composition that contains C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor of the present invention, described C-MET HGFr (cMet) inhibitor can be the medicine of the hepatocyte growth factor receptor inhibitor of any structure type, such as PF-02341066, SGX523 or PHA665752, wherein, SGX-523 has applied for that by the research and development of SGXPharmaceuticals company the I phase is clinical; PHA-665752 is researched and developed by Sugen company.
In the pharmaceutical composition of the present invention, described hepatocyte growth factor receptor inhibitor is preferably PF-02341066, and structural formula is formula I:
Described 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.
Among the present invention, described mitogen extracellular kinase inhibitor can be for the medicine of the mitogen extracellular kinase inhibitor of any structure type, such as U0126, ARRY-142886, CI-1040 or PD325901, wherein, PD-325901 is by Pfizer company research and development, carrying out at present the II phase clinical; CI-1040 is researched and developed by Pfizer company.
In the pharmaceutical composition of the present invention, described mitogen extracellular kinase inhibitor is preferably U0126 or ARRY-142886 or its combination, and wherein ARRY-142886 is the chemical compound of the formula II that puts down in writing among the WO03/077914;
In the pharmaceutical composition of the present invention, described component is not limited to said medicine itself, can also be the salt of their analog, derivant and organic or inorganic thereof.
The present invention contains in the pharmaceutical composition of C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor, and the mol ratio of described C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor is 0.1-5.0:0.05-2.0; The mol ratio of further preferred C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor is 0.5-2.0:0.15-1.0.
The present invention contain C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor pharmaceutical composition can for the preparation of the treatment various tumors medicine, described tumor includes but not limited to hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer, cerebroma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate.
The pharmaceutical composition of C-MET HGFr of the present invention (cMet) inhibitor and mitogen extracellular kinase inhibitor is preferred for preparing the application in the medicine of Hepatoma therapy or cancer of pancreas.
In the application of pharmaceutical composition of the present invention for the preparation of the medicine of Hepatoma therapy, C-MET HGFr (cMet) inhibitor is preferably PF-02341066, and mitogen extracellular kinase inhibitor is preferably ARRY-142886; Wherein, the mol ratio of described PF-02341066 and ARRY-142886 is 0.5-2.0:0.15-0.5, being preferably PF-02341066 and ARRY-142886 mol ratio is 1.0-2.0:0.25-0.5, and best is that PF-02341066 and ARRY-142886 mol ratio are 2.0:0.5.
The present composition is in the application of the medicine of preparation treatment cancer of pancreas, described C-MET HGFr (cMet) inhibitor is preferably PF-02341066, mitogen extracellular kinase inhibitor is preferably ARRY-142886, wherein, the mol ratio of described PF-02341066 and ARRY-142886 is 0.5-2.0:0.25-1.0.
Pharmaceutical composition of the present invention is in the application of the medicine of preparation treatment AsPC-1 type cancer of pancreas, and the mol ratio of described PF-02341066 and ARRY-142886 is 1.0-2.0:0.25-1.0; The mol ratio of preferred PF-02341066 and ARRY-142886 is 1.5-2.0:0.5-1.0; The mol ratio that the best is preferably PF-02341066 and ARRY-142886 is 2.0:1.0.
Wherein in the application of the medicine for preparing treatment Hs766T type cancer of pancreas, the mol ratio of described PF-02341066 and ARRY-142886 is 0.5-1.5:0.25-1.0; The mol ratio of preferred PF-02341066 and ARRY-142886 is 1.0-1.5:0.5-1.0; The mol ratio that the best is preferably PF-02341066 and ARRY-142886 is 1.5:1.0.
Contain C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor compositions at the preparation Hepatoma therapy, pulmonary carcinoma, gastric cancer, intestinal 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, C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor can be contained in same pharmaceutical preparation such as tablet or the capsule, also C-MET HGFr (cMet) inhibitor and mitogen extracellular 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, C-MET HGFr (cMet) inhibitor can be made respectively different preparations with mitogen extracellular 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, C-MET HGFr (cMet) inhibitor can be made respectively different preparations with mitogen extracellular 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 C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor intersection discharges.
C-MET HGFr of the present invention (cMet) inhibitor and mitogen extracellular kinase inhibitor compositions are at the preparation Hepatoma therapy, pulmonary carcinoma, gastric cancer, intestinal cancer, cerebroma, cancer of pancreas, ovarian cancer, in the application of the medicine of breast carcinoma or carcinoma of prostate, C-MET HGFr in the described compositions (cMet) inhibitor and mitogen extracellular kinase inhibitor can use or simultaneously with the using in order of any priority, as C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor being taken to the patient simultaneously; Also can first mitogen extracellular kinase inhibitor be taken, then be taken to C-MET HGFr (cMet) inhibitor medicaments to the patient, or take first mitogen extracellular kinase inhibitor, then take C-MET HGFr (cMet) 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 C-MET HGFr of the present invention (cMet) inhibitor and mitogen extracellular kinase inhibitor, the pharmaceutical preparation that the present invention preferably makes gastrointestinal administration with C-MET HGFr (cMet) inhibitor and mitogen extracellular 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 and mitogen extracellular kinase inhibitor compositions, according to different dosage forms and preparation specification, the content of described compositions in preparation can be 1-99% in mass, 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 C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor compositions does not have any restriction, then C-MET HGFr (cMet) inhibitor and mitogen extracellular 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 C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor makes up the test of killing HepG2 (hepatoma cell strain), AsPC-1, Hs766T (pancreas cancer cell strain), results suggest, C-MET HGFr of the present invention (cMet) inhibitor and mitogen extracellular kinase inhibitor combined therapy hepatocarcinoma, cancer of pancreas have significant cooperative effect, not only improved the curative effect of medicine, and reduced 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 (hepatoma cell strain), AsPC-1 (pancreas cancer cell strain), Hs766T (pancreas cancer cell strain) 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 described preparations of method in following examples; Mitogen extracellular kinase inhibitor ARRY-142886 is synthesized into reference to patent WO03/077914; C-MET HGFr (cMet) inhibitor PF-02341066 is synthesized into reference to patent WO2007066187.
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.Dead cell comes off from incubator and enters the culture medium, by all cells of centrifugal collection under 1200 rev/mins, and then with culture medium Eddy diffusion precipitate, mixes 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 is by method 1 preparation; 7-9 is by method 2 preparations.
Table 1
The PF-02341066 of embodiment 1 different proportion and the combination Synergistic of ARRY-142886 promote the test of HepG2 cell death, see Table 2.
Table 2
Cause in the test of hepatoma cell strain HepG2 cell death at the investigation related compound, find when using 2.0 μ M PF-02341066 or lower concentration, 0.25 μ M ARRY-142886 or lower concentration separately, to only have the seldom cell death of amount; Even when increasing concentration to the 0.5 μ MARRY-142886 of single medicine, 20% cell death of also only having an appointment; (1.0 μ M PF-02341066+0.25 μ M ARRY-142886) then produces obvious synergism when both share under low concentration, causes approximately 60% cancer cell death; When both share with the ratio of 2.0 μ MPF-02341066+0.5 μ MARRY-142886, then produce more significantly synergism, cause approximately 100% cancer cell death.
The PF-02341066 of embodiment 2 different proportions and ARRY-142886 combination Synergistic promote the AsPC-1 cell death, see Table 3.
Table 3
Cause in the test of pancreas cancer cell strain AsPC-1 cell death at the investigation related compound, find when using 1.5 μ M PF-02341066 or lower concentration, 0.5 μ MARRY-142886 or lower concentration separately, to only have the seldom cell death of amount; Even only have an appointment the 15-20% cell death when increasing concentration to the 2.0 μ MPF-02341066 of single medicine or 1.0 μ MARRY-142886; (1.5 μ M PF-02341066+0.5 μ M ARRY-142886) then produces obvious synergism when both share under low concentration, causes approximately 60% cancer cell death; When both share with the ratio of 2.0 μ MPF-02341066+1.0 μ MARRY-142886, then produce more significantly synergism, cause approximately 90% cancer cell death.
The PF-02341066 of embodiment 3 different proportions and ARRY-142886 combination Synergistic promote the Hs766T cell death, see Table 4.
Table 4
Cause in the test of pancreas cancer cell strain Hs766T cell death at the investigation related compound, find when using 1.5 μ MPF-02341066 or lower concentration, 1.0 μ MARRY-142886 or lower concentration separately, to only have the seldom cell death of amount; And when both share with the ratio of 1.5 μ M PF-02341066+1.0 μ MARRY-142886, then produce obvious synergism, cause approximately 85% cancer cell death.
Claims (15)
1. a pharmaceutical composition is characterized in that containing hepatocyte growth factor receptor inhibitor PF-02341066 and mitogen extracellular kinase inhibitor ARRY-142886.
2. pharmaceutical composition according to claim 1 is characterized in that, the mol ratio of described hepatocyte growth factor receptor inhibitor PF-02341066 and mitogen extracellular kinase inhibitor ARRY-142886 is 0.1-5.0:0.05-2.0.
3. pharmaceutical composition according to claim 2 is characterized in that, the mol ratio of described hepatocyte growth factor receptor inhibitor PF-02341066 and mitogen extracellular kinase inhibitor ARRY-142886 is 0.5-2.0:0.15-1.0.
4. the application of the arbitrary described pharmaceutical composition of claim 1-3 in the medicine of preparation Hepatoma therapy, pulmonary carcinoma, gastric cancer, intestinal 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 Hepatoma therapy, described PF-02341066 and ARRY-142886 mol ratio are 0.5-2.0:0.15-0.5.
6. application according to claim 5 is characterized in that, in the application of the medicine for preparing Hepatoma therapy, described PF-02341066 and ARRY-142886 mol ratio are 1.0-2.0:0.25-0.5.
7. application according to claim 6 is characterized in that, in the application of the medicine for preparing Hepatoma therapy, described PF-02341066 and ARRY-142886 mol ratio are 2.0:0.5.
8. application according to claim 4 is characterized in that, in the application of the medicine for preparing the treatment cancer of pancreas, described PF-02341066 and ARRY-142886 mol ratio are 0.5-2.0:0.25-1.0.
9. application according to claim 8 is characterized in that, in the application of the medicine for preparing treatment AsPC-1 type cancer of pancreas, described PF-02341066 and ARRY-142886 mol ratio are 1.0-2.0:0.25-1.0.
10. application according to claim 9 is characterized in that, in the application of the medicine for preparing treatment AsPC-1 type cancer of pancreas, described PF-02341066 and ARRY-142886 mol ratio are 1.5-2.0:0.5-1.0.
11. application according to claim 10 is characterized in that, in the application of the medicine for preparing treatment As PC-1 type cancer of pancreas, described PF-02341066 and ARRY-142886 mol ratio are 2.0:1.0.
12. application according to claim 8 is characterized in that, in the application of the medicine for preparing treatment Hs 766T type cancer of pancreas, described PF-02341066 and ARRY-142886 mol ratio are 0.5-1.5:0.25-1.0.
13. application according to claim 12 is characterized in that, in the application of the medicine for preparing treatment Hs 766T type cancer of pancreas, described PF-02341066 and ARRY-142886 mol ratio are 1.0-1.5:0.5-1.0.
14. application according to claim 13 is characterized in that, in the application of the medicine for preparing treatment Hs 766T type cancer of pancreas, described PF-02341066 and ARRY-142886 mol ratio are 1.5:1.0.
15. application according to claim 4 is characterized in that, the hepatocyte growth factor receptor inhibitor PF-02341066 in the described pharmaceutical composition and mitogen extracellular kinase inhibitor ARRY-142886 use or using in order with any priority simultaneously.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1482932A1 (en) * | 2002-03-13 | 2004-12-08 | Array Biopharma, Inc. | N3 alkylated benzimidazole derivatives as mek inhibitors |
| WO2007066187A2 (en) * | 2005-12-05 | 2007-06-14 | Pfizer Products Inc. | Method of treating abnormal cell growth |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1482932A1 (en) * | 2002-03-13 | 2004-12-08 | Array Biopharma, Inc. | N3 alkylated benzimidazole derivatives as mek inhibitors |
| WO2007066187A2 (en) * | 2005-12-05 | 2007-06-14 | Pfizer Products Inc. | Method of treating abnormal cell growth |
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