Seven independent research programs will interact in a concerted effort to identify inhibitors of polyamine biosynthesis and/or function as potential anticancer agents with the ultimate goal of improving the treatment and curability of human cancer. The impetus for this study is based mainly on the recent realization that polyamines and their biosynthesis are essential components of neoplastic cell proliferation. Agents to be synthesized by 3 chemistry programs include polyamine analogs and conjugates, inhibitors of spermidine and spermine synthases and inhibitors of S-adenosylmethionine biosynthesis and metabolism. These will be initially tested for inhibitory effects on polyamine metabolism (Dr. A. Pegg) and for antitumor activity in the in vitro and in vivo L1210 leukemia systems. Subsequent testing will include: drug interaction studies with DNA-reactive antineoplastics and drug effects on human small cell carcinoma growth and epithelial cell differentiation. Data generated by the various screening programs and by individual inquiries into polyamine metabolism and function will provide feed-back information for the design and synthesis of additional compounds. While it is the primary goal of this group effort to identify new and practical anticancer treatments the role and function that polyamines fulfill in the cell proliferation will also be examined using the polyamine analogs and inhibitors, thus enhancing our understanding of the neoplastic process in general.
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