Amplification and over-expression of oncogenes of the myc family are related to the prognosis of certain solid tumors such as small cell lung cancer (SCLC). For SCLC, c-myc is the oncogene most consistently found to correlate with the end stage behaviour of the tumour, in particular with survival after chemotherapeutic treatment. C-myc is important in many cellular processes such as proliferation, differentiation and apoptosis. In the present study the relationship between c-myc and differentiation was analyzed by down-regulation of endogenous c-myc protein, using two approaches: first by coculturing with antisense (AS) oligodeoxynucleotides (ODN) in the human SCLC cell line GLC4 and its 6-fold cisplatin resistant subline GLC4-CDDP, second by stable transfection of GLC4-CDDP with a dexamethasone-inducible AS c-myc expression vector. Basic characterization of the differentiation status of GLC4 and GLC4-CDDP showed a decrease in neuroendocrine differentiation in GLC4-CDDP compared to GLC4. Cytokeratin was absent in both cell lines. No significant differences in expression of adhesion molecules or myeloid antigens were observed between the lines. Vimentin expression was higher in GLC4-CDDP compared to GLC4.(AS c-myc ODN)-induced growth inhibition and down-regulation of endogenous c-myc protein further decreased neuroendocrine differentiation (CD57 positive cells) in GLC4-CDDP without affecting the expression of other antigens such as vimentin (intermediate filament), CD15 myeloid antigen) and VLA-α4 (adhesion molecule) and did not alter the expression of these antigens in GLC4. (AS c-myc RNA)-induced growth inhibition did not significantly afffect the expression of the tested antigens in the AS c-myc transfected GLC4-CDDP/AS cell line. No effect of nonsense c-myc ODN or dexamethasone-induced control RNA (controls) was observed.