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 phenotyp e (Mabry et al., Proc Natl Acad Sci USA 85: 6523-6527, 1988). This v-r as(H)-associated phenotypic change is prevented by treatment with tran s-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) expre ssion 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 develo pment of CdCl2 resistance without any change in cisplatin sensitivity. In contrast, growth of parental NCI-H82 cells in 1 mu M 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. E xamination 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 agen t 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 ac tivity and a 1.7-fold decrease in IC50 for the topo I-directed agent c amptothecin. These changes resulted in 30-fold lower survival of NCI-H 82ras(H) cells compared with -H82 cells at camptothecin concentrations as low as 10 nM. In summary, these studies demonstrate that chronic t RA treatment is accompanied by decreased cisplatin sensitivity in NCI- H82 human SCLC cells. In contrast, v-ras(H) expression is not associat ed with any change in cisplatin or etoposide sensitivity, but is accom panied by increased camptothecin sensitivity.