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Abstract

We have investigated whether cellular transformation by different oncogenes alters their responsiveness to the chemotherapeutic agent cis-diamminedichloroplatinum(lI) (cDDP). Rat-6 (R6) embryo fibroblasts transformed by v-myc, rc-mos (rearranged mouse c-mos), v-src and activated c-H-ras oncogenes displayed differential sensitivities to cDDP, and the lC50 values of cDDP decreased by approximately 3.0-, 1.2-, 2.0- and 1.5-fold, respectively. Over-expression of rnyc, but not ras, srcor mos, induced apoptosis in R6 cells. Nevertheless, all oncogenes influenced cellular susceptibility to apoptosis triggered by cDDP as judged by the appearance of condensed chromatin, formation of apoptotic bodies and internucleosomal cleavage of genomic DNA to 180 bp multimers, yielding a “laddered” ectrophoretic profile on agarose gel. There was a correlation between the time- and concentration-dependent enhancement of cDDP-induced DNAfragmentation and potentiation of cDDP sensitivity by various oncogenes. Oncogenic transformation led to a decrease in expression of the PKCr isoform, and stable transfection of PKCr in R6 cells prevented cDDP-induced apoptosis and protected cells against cDDP cytotoxicity. Our results indicate that the differential sensitivity of oncogenetransformed cells to cDDP may be associated with the ability of various oncogenes to influence cDDP-induced apoptosis.