The N',N"-bis(ethyl) polyamine analogues demonstrate great potential as chemotherapeutic agents for lung cancer. This study examines how the expression of two oncogenes frequently associated with a worsened prognosis in lung cancer, c-myc and mutated ras, as well as the phenotypic transition induced by these genes, affects the sensitivity of small cell lung cancer (SCLC) cells to these polyamine analogues. Treatment with N1,N12-bis(ethyl)spermine (BE-Spm), a representative analogue, depresses polyamine levels and is cytostatic for the NCI H209 classic SCLC cell line. Both the overexpression of c-myc and the expression of oncogenic v-Ha-ras in these cells produce phenotypes that retain sensitivity to this growth inhibition. This sensitivity to BESpm is mediated by distinct pathways in these oncogene-expressing cells. c-myc overexpression markedly increases the expression of ornithine decarboxylase, which is then down-regulated by BESpm. In contrast, v-Ha-ras expression highly induces the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase. These findings suggest that the bis(ethyl)polyamine compounds may have broad utility for the treatment of both SCLC and non-SCLC, including those expressing oncogenic c-myc and ras.