Variant small cell lung cancer (SCLC) is distinguished from the classic histology by changes in growth characteristics and morphology, c-myc amplification, a loss of some biochemical markers, and relative chemo- and radioresistance. Three variant SCLC lines were incubated in 1 microM all-trans retinoic acid. After 8-10 days, a marked change in morphology was noted in all three lines, with tight cell aggregation and central necrosis of large floating spheroids similar to classic SCLC. The retinoid-treated cells demonstrated decreases in growth rate and cloning efficiency to levels comparable with classic SCLC cell lines. Retinoic acid incubation caused a reproducible decrease in c-myc expression in variant SCLC cells, but was not noted to increase L-dopa decarboxylase, an enzyme which biochemically distinguishes classic from variant SCLC cell lines. Retinoid exposure led to an increase in HLA and Leu-7 antigens, but a reduction of antibody binding to 3-fucosyllactosamine, a dominant SCLC glycolipid antigen. Clonogenic assays revealed that the variant cells, after incubation in retinoic acid, became more sensitive to etoposide, but more resistant to Adriamycin. We conclude that exposure of variant SCLC cells to retinoic acid can lead to a morphologic phenotype similar to classic SCLC, but with substantial differences in cell biology. ?