ENHANCED SENSITIVITY TO 1-BETA-D-ARABINOFURANOSYLCYTOSINE AND TOPOISOMERASE-II INHIBITORS IN TUMOR-CELL LINES HARBORING ACTIVATED RAS ONCOGENES

We used human tumor cell lines from the National Cancer Institute's In Vitro Antineoplastic Drug Screen to assess whether sensitivity to any of the similar to 45,000 compounds tested previously correlated with the presence of a ras oncogene. Among these cell lines, the mutations in Ki-ras2 clustered in non-small cell lung and colon carcinoma subpan els, and five of the six leukemia lines contained mutations in either N-ras or Ki-ras2. These analyses revealed a striking correlation with 1-beta-D-arabinofuranosylcytosine (Ara-C) and 2,2'-O-cyclocytidine sen sitivity in the cell lines harboring ras mutations compared to the tum or lines with wild-type ras alleles. Strong correlations were also fou nd with topoisomerase (topo) II inhibitors, especially 3'-hydroxydauno rubicin and an olivacine derivative. These differential sensitivities persisted in an additional 22 non-small cell lung carcinoma lines (ras mutations, n = 12 and wild-type ras, n = 10). Thus, the association w ith Ara-C sensitivity was greatest while topo II inhibitors showed a l ower, but significant, correlation. These results suggest that the ras oncogene may play a determinant role in rendering tumor cells sensiti ve to deoxycytidine analogues and topo II inhibitors.