The colony-inhibitory effects of recombinant human tumor necrosis factor (rH-TNF) and recombinant human interferon-gamma (rH-IFN-gamma) were evaluated in four human lung cancer cell lines and their cisplatin-resistant sublines. The cell lines tested were PC-7 and PC-9 (adenocarcinoma), H69 and N231 (small cell lung cancer) and four cisplatin-resistant sublines, PC-7/1.0, PC-9/0.5, H69/0.2 and N231/0.2, which were 20.0, 7.1, 4.8 and 8.4 fold resistant to cisplatin, respectively, compared to the respective parental cell line in terms of IC50 in a soft agar colony assay. All parental cell lines were resistant to rH-TNF and rH-IFN-gamma, alone or in combination. However, two resistant sublines showed sensitivity to rH-TNF and rH-IFN-gamma. Colony formation by PC-9/0.5 was significantly inhibited, in the absence or presence of cisplatin, by 10(2) U/ml of rH-TNF (less than 50% of control) and the inhibition was synergistic with that produced by 10(3) or 10(4) U/ml of rH-IFN-gamma. RH-IFN-gamma inhibited the colony formation of H69/0.2 only at the highest concentration tested (10(4) U/ml) (less than 50% of control) and the combined effect with rH-TNF was additive. These results suggest that rH-TNF and rH-IFN-gamma may have some potential in overcoming cisplatin resistance by virtue of collateral sensitivity.