The ras oncogene-mediated sensitization of human cells to topoisomerase IIinhibitor-induced apoptosis

Background: Among the inhibitors of the enzyme topoisomerase II (an importa nt target for chemotherapeutic drugs) tested in the National Cancer Institu te's In Vitro Antineoplastic Drug Screen, NSC 284682 (3'-hydroxydaunorubici n) and NSC 659687 [9-hydroxy-5,6-dimethyl-1-(N-{2(dimethylamino)ethyl}carba moyl)-6H-pyrido-(4,3-b)carbazole] were the only compounds that were more cy totoxic to tumor cells harboring an activated ras oncogene than to tumor ce lls bearing wild-type ras alleles. Expression of the multidrug resistance p roteins P-glycoprotein and MRP (multidrug resistance-associated protein) fa cilitates tumor cell resistance to topoisomerase II inhibitors. We investig ated whether tumor cells with activated ras oncogenes showed enhanced sensi tivity to other topoisomerase II inhibitors in the absence of the multidrug -resistant phenotype. Methods: We studied 20 topoisomerase II inhibitors an d individual cell lines with or without activated ras oncogenes and with va rying degrees of multidrug resistance. Results: In the absence of multidrug resistance, human tumor cell lines with activated ras oncogenes were unifo rmly more sensitive to most topoisomerase II inhibitors than were cell line s containing wild-type ras alleles, The compounds NSC 284682 and NSC 659687 were especially effective irrespective of the multidrug resistant phenotyp e. The ras oncogene-mediated sensitization to topoisomerase II inhibitors w as far more prominent with the non-DNA-intercalating epipodophyllotoxins th an with the DNA-intercalating inhibitors. This difference in sensitization appears to be related to a difference in apoptotic sensitivity, since the l evel of DNA damage generated by etoposide (an epipodophyllotoxin derivative ) in immortalized human kidney epithelial cells expressing an activated ras oncogene was similar to that in the parental cells, but apoptosis was enha nced only in the former cells. Conclusions: Activated ras oncogenes appear to enhance the sensitivity of human tumor cells to topoisomerase II inhibit ors by potentiating an apoptotic response. Epipodophyllotoxin-derived topoi somerase II inhibitors should be more effective than the DNA-intercalating inhibitors against tumor cells with activated ras oncogenes.