THE GROWTH-INHIBITORY EFFECT OF N-1,N-12-BIS(ETHYL)SPERMINE IN SMALL-CELL LUNG-CANCER CELLS IS MAINTAINED IN CELLS EXPRESSING THE C-MYC ANDHA-RAS ONCOGENES

The N',N''-bis(ethyl) polyamine analogues demonstrate great potential as chemotherapeutic agents for lung cancer. This study examines how th e expression of two oncogenes frequently associated with a worsened pr ognosis in lung cancer, c-myc and mutated ras, as well as the phenotyp ic transition induced by these genes, affects the sensitivity of small cell lung cancer (SCLC) cells to these polyamine analogues. Treatment with N-1,N-12-bis(ethyl)spermine (BESpm), 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 sens itivity to this growth inhibition. This sensitivity to BESpm is mediat ed by distinct pathways in these oncogene-expressing cells. c-myc over expression markedly increases the expression of ornithine decarboxylas e, which is then down-regulated by BESpm. In contrast, v-Ha-ras expres sion highly induces the polyamine catabolic enzyme spermidine/spermine N-1-acetyltransferase. These findings suggest that the bis(ethyl)poly amine compounds may have broad utility for the treatment of both SCLC and non-SCLC, including those expressing oncogenic c-myc and ras.