Increased resistance to cis-diamminedichloroplatinum(II) in NIH 3T3 cells transformed by ras oncogenes.

The genetic basis of cellular resistance to the anticancer drug cis-diamminedichloroplatinum(II) (CP) is not well understood. In the course of identifying genes from human tumors capable of conferring resistance to CP, we tested the ability of several types of cellular and viral ras oncogene (H, K, and N) to alter the CP response of mouse cells. Using clonogenic assays, we found that NIH 3T3 fibroblasts transformed with missense mutation-activated ras oncogenes demonstrated substantially increased resistance to 1-h exposures to CP (P less than 0.05 to less than 0.001, at different drug concentrations), with 50% inhibitory concentration ratios (compared to NIH 3T3) of 4.5-8.5. Cells transformed with v-mos v-fms, and with a normal ras protooncogene activated by overproduction driven by an MLV ltr, demonstrate intermediate resistance (50% inhibitory concentration ratio, approximately 2.0). Cells transfected with the pSV2neo plasmid or with human genomic DNA that is not transforming had survival curves no different from those of NIH 3T3. ras genes are highly conserved in mammalian cells. Should these findings also prove to apply to human tumors, the presence of activated ras genes might help predict clinical response to CP.