POLYAMINE ANALOG AND INHIBITOR REGULATION OF CELL CYCLE

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The therapeutic potential of cell cycle regulatory discoveries is just being realized and while they provide clear opportunity for the development of new and novel anticancer agents, their more immediate potential resides in improving the use of existing drugs. DNA-damaging agents are an obvious example of drugs being investigated from this perspective. On the basis of recent findings, we believe that two polyamine antagonists developed with the active involvement of this laboratory and currently undergoing clinical evaluation, have previously unrealized potential as modulators of cell cycle regulatory pathways. This belief is predicated on our recent observation that the polyamine analog N1, N11-diethylnorspermine (DENSPM) and the polyamine enzyme inhibitor CGP-48664 potently activate the p53, p21, Rb pathway and induce G1 cell cycle arrest in MALME-3M human melanoma cells containing wild- type p53. In SK-MEL-28 melanoma cells containing mutated p53, DENSPM induces a rapid and massive apoptotic response. The findings represent the first linkage between polyamines and the cell cycle regulatory machinery. The proposed studies will investigate the therapeutic and biological significance of these findings in human melanoma cell lines. This disease-focus is based on relative high sensitivity of melanoma to these agents in preclinical systems; the targeting of melanoma in Phase II clinical trials and the fact that melanoma tends to differ from other solid tumors with respect to p53 expression levels and mutation frequency. Thus, the following Specific Aims propose: (1) to examine the cell cycle regulatory pathways responsible for polyamine analog and inhibitor induction of G1 arrest in MALME-3M melanoma cells, focusing initially on the contribution of p53 and p21; (2) to identify the effectors responsible for polyamine analog induction of apoptosis in SK-MEL- 28 cells; (3) to investigate the polyamine-related initiating event(s) responsible for analog- and inhibitor-induced growth arrest and apoptosis; and (4) to confirm that specific analog- and inhibitor-induced effects that occur in vitro also occur in vivo. It is our belief that an understanding of cell cycle regulatory events by the two polyamine antagonists will contribute rationally to their deployment as anticancer agents and/or chemopreventive agents and at the same time, provide new insights into how the well-recognized polyamine requirement for cell growth interfaces with the complex pathways that control cell cycle progression and apoptosis.