The overall objective of this project is to investigate the differential response of human cancer cells to inhibition of the polyamine pathway. We seek to determine those mechanisms which are responsible for the cytotoxic vs. cytostatic responses exhibited by human tumor cells to polyamine depletion by agents which act at different sites on the polyamine synthetic pathway. Specifically, we will extend our preliminary studies showing that small cell lung carcinoma cells respond cytotoxically to polyamine depletion by 2-difluoromethyl ornithine (DFMO) and only cytostatically to treatment with a new class of polyamine analogs N,N-bis(ethyl)polyamines, whereas, a human large cell undifferentiated lung cancer line responds only cytostatically to DFMO yet responds in a profoundly cytotoxic manner to polyamine depletion by the N,N-bis(ethyl)polyamines. We shall examine, in both cell types, before and after polyamine depletion by DFMO and the analogs, the regulation of ornithine decarboxylase, the first and generally rate limiting step in polyamine biosynthesis at the transcriptional, post- transcriptional, translational, and post-translational levels. Further, we shall examine the effects of polyamine depletion by DFMO and the newly synthesized polyamine analogs on the expression of growth related genes. We will attempt to extend our preliminary results which indicate that polyamine depletion leads to a specific, altered expression of the oncogene, c-myc at the transcriptional level. The above studies should be useful in determining the essential roles which polyamines play in the growth of individual types of human cancer cells. Additionally, the differential sensitivity exhibited to the above agents suggest a potential for selective targeting, a primary goal of any cancer therapy. Thereby, these studies may facilitate the design of new agents for the treatment of human neoplastic disease.
