- Cisplatin is a widely used antitumor agent. To investigate the role of oncogenes in drug resistance to cisplatin we determined the sensitivity to the drug of Balb/c 3T3 cells, transfected with H-ras or v-myc. H-ras cells were more resistant than control or v-myc cells. H-ras + v-myc cells were extremely sensitive. Several drug resistance mechanisms were investigated: Intracellular levels of glutathione, methallothioneins and cisplatin accumulation. No single mechanism tested was solely responsible for the pattern of cisplatin resistance. Topoisomerase I amounts and activity was reduced in resistant, H-ras cells, compared to sensitive ras + myc transfected cells. In addition, ras + myc transfected cells, showed unusually high amounts of p53 levels. The pattern of cisplatin sensitivity corresponded directly to the ability of our cells to undergo apoptosis by this drug. We conclude that the oncogenes H-ras and v-myc can modulate drug resistance through apoptosis, in conjunction with changes in p53 and topo I activity.