Enhanced Sensitivity to 1-β-d-Arabinofuranosylcytosine and Topoisomerase II Inhibitors in Tumor Cell Lines Harboring Activated ras Oncogenes

Abstract

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 ∼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 subpanels, and five of the six leukemia lines contained mutations in either N-ras or Ki-ras2. These analyses revealed a striking correlation with 1-β-d-arabinofuranosylcytosine (Ara-C) and 2,2′-O-cyclocytidine sensitivity in the cell lines harboring ras mutations compared to the tumor lines with wild-type ras alleles. Strong correlations were also found with topoisomerase (topo) II inhibitors, especially 3′-hydroxydaunorubicin 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 with Ara-C sensitivity was greatest while topo II inhibitors showed a lower, but significant, correlation. These results suggest that the ras oncogene may play a determinant role in rendering tumor cells sensitive to deoxycytidine analogues and topo II inhibitors.