We have investigated the induction of an important polyamine metabolic enzyme, spermidine/spermine N1-acetyltransferase, in two human lung cancer cell lines which respond differently to treatment with the bis(ethyl)polyamine analogues. The human small cell lung carcinoma line NCI H82 has previously been shown to be minimally affected by treatment with these analogues, whereas the large cell undifferentiated lung carcinoma line, NCI H157, responds in a rapid cytotoxic manner (R.A. Casero, Jr., S. J. Ervin, P. Celano, S. B. Baylin, and R. J. Bergeron, Cancer Res., 49:639-643, 1989). The mechanisms underlying the differential response are unknown. In the responsive NCI H157 cells, the bis(ethyl)polyamines were found to induce spermidine/spermine N1-acetyltransferase in a time- and dose-dependent manner to maximum levels greater than 1700-fold over baseline. By contrast, the unresponsive NCI H82 cells exhibit minimal induction of spermidine/spermine N1-acetyltransferase to less than 7-fold increase after bis(ethyl)polyamine treatment, regardless of time or concentration examined. The results of the current study suggest that the differential induction of this key enzyme, which is rate limiting in the back conversion pathway of polyamine metabolism, may play a role in determining cell specific to the bis(ethyl)polyamine analogues.