[Cell signaling and CDDP resistance]

Abstract

Although evidence exists that intracellular signaling through oncogene products may play a role in the resistance of anticancer drugs, the underlying mechanism remains to be clarified. Using a HAG-1 cell line as a human epithelial model, we have studied the alteration of drug sensitivity and determined the mechanism of resistance induced in HAG-1 cells transfected with various oncogenes, which are highly expressed and activated in human cancers. Non-tumorigenic HAG-1 cells acquired fully neoplastic phenotype and resistance to Cisplatin (CDDP) by transfection with v-src but not by activated ras oncogene. The src-transfected cells showed a significant decrease in the formation of CDDP-induced DNA interstrand cross-links with rapid removal of these lesions. Upon treatment with src kinase inhibitors, the level of CDDP resistance and the rate of removal were both reduced in src-transformed cells. These results suggest the ability of v-src oncogene product but not ras to induce CDDP resistance by modulating the certain DNA repair pathway. Thus, intracellular signaling may be the appropriate target for strategies to reverse the drug resistance. In this review, we discuss the role of oncogenes important for signal transduction such as ras and those with protein tyrosine kinase activity in the drug resistance.