title: Flavopiridol enhances the effect of docetaxel in vitro and in vivo in human gastric cancer cells.
abstract: 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.
authors.affiliation: Gastrointestinal Oncology Research Laboratory, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Motwani
authors.forename: Carina
authors.initials: C
authors.lastname: Rizzo
authors.forename: Francis
authors.initials: F
authors.lastname: Sirotnak
authors.forename: Yuhong
authors.initials: Y
authors.lastname: She
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors; D002453:Cell Cycle; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D056744:Cyclin B1; D000077143:Docetaxel; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D008938:Mitosis; D009368:Neoplasm Transplantation; D010880:Piperidines / Q000494:pharmacology*; D011419:Propidium / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000628:therapy; D043823:Taxoids / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010880:Piperidines; D016160:Retinoblastoma Protein; D043823:Taxoids; D000077143:Docetaxel; D011419:Propidium; C077990:alvocidib; D016203:CDC2 Protein Kinase