Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Flavopiridol (L86-8275) is a synthetic flavone currently undergoing Phase I clinical trials. It is active against a series of human cancer cell lines and has been shown to inhibit a broad range of protein kinases, including cyclin-dependent kinases and protein kinase C (PKC). Previous studies have shown that the PKC-specific inhibitor safingol significantly enhances the induction of apoptosis by mitomycin-C (MMC) in gastric cancer cells. Because flavopiridol can potentially inhibit PKC, we elected to determine the extent to which flavopiridol would promote MMC-induced apoptosis in both gastric and breast cancer cells. For these studies, MKN-74 gastric cancer cells and MDA-MB-468 breast cancer cells were exposed to either no drug, 1 microgram/ml MMC alone, 300 nM flavopiridol alone, or a combination of chemotherapy with flavopiridol for 24 h. Sequence specificity was also examined by first exposing cells to MMC for 24 h followed by flavopiridol for 24 h or to the same drugs in the reverse order. Apoptosis was measured by quantitative fluorescence microscopy of nuclear chromatin condensation in cells stained with the dye, bisbenzimide trihydrochloride. Exposure of MKN-74 cells to flavopiridol alone induced apoptosis in 12 +/- 1% of the cells, and exposure to MMC alone induced apoptosis in 10 +/- 1%. However, the combination of flavopiridol and MMC increased the induction of apoptosis to 55 +/- 3% of the cells (P < 0.005 for the drug combination versus flavopiridol alone). Pretreatment with the PKC activator 3-phorbol 12-myristate 13-acetate only partially reversed this effect (43 +/- 1%; P < 0.025). In MDA-MB-468 cells, flavopiridol alone induced apoptosis in 17 +/- 1% of the cells, and MMC alone induced apoptosis in 10 +/- 1% of the cells. The combination of flavopiridol and MMC increased the percentage of MDA-MB-468 cells undergoing apoptosis to 58 +/- 4% (P < 0.005 for the drug combination versus flavopiridol alone). Sequential treatment with MMC followed by flavopiridol induced apoptosis in 63 +/- 2% of the MKN-74 cells (P < 0.05 versus the concomitant drug combination) and in 76 +/- 2% of the MDA-MB-468 cells (P < 0.025 versus the concomitant drug combination), whereas flavopiridol followed by MMC did not increase the induction of apoptosis in either cell line. As determined by the terminal deoxynucleotidyl transferase labeling of the 3' ends of DNA fragments produced in apoptotic cells, the induction of apoptosis with the combination of flavopiridol and MMC occurred to MKN-74 cells in all phases of the cell cycle (i.e., G0-G1, S, and G2-M). These results indicate that flavopiridol potentiates the cytotoxic effect of the chemotherapeutic agent MMC by promoting drug-induced apoptosis in tumor cells. Sequencing studies suggest that MMC followed by flavopiridol or simultaneous treatment is superior to flavopiridol followed by MMC. The enhancement of MMC-induced apoptosis by flavopiridol may be partially PKC dependent and is not associated with one specific region of the cell cycle.
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PMID:Potentiation of apoptosis by flavopiridol in mitomycin-C-treated gastric and breast cancer cells. 981 32

Flavopiridol is a synthetic flavonoid inhibitor of cyclin-dependent kinases, which is under development by Aventis Pharma (formerly Hoechst Marion Roussel) and the National Cancer Institute (NCI) for the potential treatment of cancer and proliferative disorders. By May 2001, the product was in phase IIa trials and had achieved proof-of-concept in phase I/IIa trials as a monotherapy. At this time, Aventis expected a global submission to take place in 2003 [409257]. By July 1999, the compound had entered phase II trials for gastric cancer and leukemia, and phase I/II trials for esophageal tumor and non-small cell lung cancer (NSCLC) [277372], [325929], [331850]. Phase II trials for colon and renal cancer [411684], [411769] and phase I trials for prostate cancer [279466] have also been reported. Analysts Merrill Lynch predicted in September and November 2000 that the product would be launched by 2003, with sales of EUR 50 million in that year, rising to EUR 100 million in 2004 [383742], [391426]. In April 1999, ABN Amro predicted annual sales of DM 100 million in 2002 [328676].
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PMID:Flavopiridol. National Cancer Institute. 1189 28

Gastric cancer is one of the leading causes of cancer death throughout the world. It is a disease in desperate need of new therapeutic approaches. Docetaxel, a semisynthetic taxane, has shown potent activity against a broad range of solid tumors. However, in gastric cancer, response rates to docetaxel remain only approximately 20%. In these studies we show that flavopiridol, a cyclin-dependent kinase inhibitor, potentiates docetaxel-induced apoptosis 3-fold in MKN-74 human gastric cells. This effect is sequence dependent, such that flavopiridol must follow docetaxel to induce this effect. Docetaxel induces transient arrest in the M phase of the cell cycle. Cells exit mitosis in a specific time window without cytokinesis with a decrease in cyclin B1/cdc-2 kinase activity and MPM-2 labeling. Flavopiridol treatment of docetaxel-treated cells enhances the exit from mitosis with a more rapid decrease in mitotic markers including MPM-2 labeling and cyclin B1/cdc2 kinase activity. In contrast, pretreatment with flavopiridol prevents cells from entering mitosis by inhibiting cyclin B1/cdc-2 kinase activity, thus antagonizing the docetaxel effect. The testing of this combination against MKN-74 xenografts confirms the sequence dependency. Treatment of MKN-74 tumor-bearing xenografts with docetaxel at a dose of 10 mg/kg followed 3-7 h later by flavopiridol at a dose of 2.5 mg/kg resulted in a 1-18% decrease in tumor volume. In contrast, treatment with docetaxel alone at this same dose resulted in a 394% increase in tumor volume. When flavopiridol was given immediately after docetaxel, the effect was not statistically different from that of docetaxel alone. The reverse combination of flavopiridol followed 7 h later by docetaxel was similar to treatment with docetaxel alone. Flavopiridol alone had no effect in this tumor model. Thus, flavopiridol, when combined with docetaxel in a sequence-specific manner, may provide a completely new therapeutic approach in the treatment of gastric cancer.
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PMID:Flavopiridol enhances the effect of docetaxel in vitro and in vivo in human gastric cancer cells. 1281 34