Effect of v-rasH 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 microM 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.
Kaufmann
S H
SH
Oncology Center, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Kalemkerian
G P
GP
Jasti
R
R
Mabry
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology*; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004351:Drug Resistance; D005047:Etoposide / Q000494:pharmacology*; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics; D008668:Metallothionein / Q000032:analysis; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D012343:RNA, Transfer / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000032:analysis; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D012333:RNA, Messenger; D013438:Sulfhydryl Compounds; D005047:Etoposide; D012343:RNA, Transfer; D008668:Metallothionein; D002945:Cisplatin; D002166:Camptothecin