ALL-TRANS-RETINOIC ACID ALTERS MYC GENE-EXPRESSION AND INHIBITS IN-VITRO PROGRESSION IN SMALL-CELL LUNG-CANCER

Transitions between the small cell lung cancer and the non-small cell lung cancer phenotype occur during clinical tumor progression in small cell lung cancer. We have previously developed a culture model which mimics these transitions. In our model, the insertion of the v-Ha-ras oncogene into c-myc overexpressing NCI-H82 small cell lung cancer cell s induces features characteristic of non-small cell lung cancer. We no w report that treatment of NCI-H82 cells with 1 muM all-trans-retinoic acid resulted in decreased cellular growth, decreased c-myc mRNA leve ls, and increased L-myc mRNA levels. Retinoic acid treatment prior to v-Ha-ras insertion also inhibited the typical ras-induced phenotypic t ransition seen in untreated NCI-H82 cells. In contrast, retinoic acid treatment of NCI-H82 ras cells after ras-induced transition to the non -small cell lung cancer phenotype did not affect cellular phenotype, n or c-myc or L-myc gene expression. These data show that all-trans-reti noic acid, a clinically relevant compound, inhibits small cell lung ca ncer progression in our in vitro model and alters the expression of th e c-myc and L-myc oncogenes. These findings suggest mechanisms for the biological effects of retinoic acid in small cell lung cancer.