Induction of Apoptosis and Cell Cycle Arrest by CP-358,774, an Inhibitor of Epidermal Growth Factor Receptor Tyrosine Kinase

摘要: The epidermal growth factor receptor (EGFR) is overexpressed in a significant percentage of carcinomas and contributes to the malignant phenotype. CP-358,774 directly acting inhibitor human EGFR tyrosine kinase with an IC50 2 nM reduces autophosphorylation intact tumor cells 20 nM. This inhibition selective for relative other kinases we have examined, both assays isolated whole cells. At doses 100 mg/kg, completely prevents EGF-induced HN5 tumors growing as xenografts athymic mice hepatic treated mice. inhibits proliferation DiFi colon at submicromolar concentrations cell culture blocks cycle progression G1 phase. produces marked accumulation retinoblastoma protein its underphosphorylated form p27KIP1 cells, which may contribute block. Inhibition also triggers apoptosis these determined by formation DNA fragments criteria. These results indicate that has potential treatment are dependent on pathway or survival.