Effect of v-ras^H on sensitivity of NCI-H82 human small cell lung cancer cells to cisplatin, etoposide, and camptothecin

Expression of v-ras^H in NCI-H82 human small cell lung cancer (SCLC) cells results in a line (NCI-H82ras^H) with a non-small cell phenotype (Mabry et al., Proc Natl Acad Sci USA 85: 6523-6527, 1988). This v-ras^H-associated phenotypic change is prevented by treatment with trans-retinoic acid (tRA) (Kalemkarian et al., Cell Growth Differ 5: 55-60, 1994). The present studies were performed to examine changes in drug sensitivity that accompanied these phenotypic changes, v-ras^H expression was associated with increased metallothionein-IIa (MT-IIa) mRNA and decreased levels of nonprotein sulfhydryls in NCI-H82ras^H cells compared with -H82 cells. These changes were accompanied by the development of CdCl₂ resistance without any change in cisplatin sensitivity. In contrast, growth of parental NCI-H82 cells in 1 μM tRa resulted in increased MT-IIa mRNA without any change in nonprotein sulfhydryls. In these cells, a 3.3-fold increase in cisplatin ic₅₀ was observed. Examination of the action of topoisomerase (topo) poisons revealed that NCI-H82 and -H82ras^H cells had indistinguishable levels of topo II polypeptides and indistinguishable sensitivities to etoposide, an agent that is often combined with cisplatin clinically. On the other hand, v-ras^H expression was accompanied by a 2-fold increase in topo I activity and a 1.7-fold decrease in ic₅₀ for the topo I-directed agent camptothecin. These changes resulted in 30-fold lower survival of NCI-H82ras^H cells compared with -H82 cells at camptothecin concentrations as low as 10 nM. In summary, these studies demonstrate that chronic tRA treatment is accompanied by decreased cisplatin sensitivity in NCI-H82 human SCLC cells. In contrast, v-ras^H expression is not associated with any change in cisplatin or etoposide sensitivity, but is accompanied by increased camptothecin sensitivity.