The thrust of this proposal is to test the applicability of using prostaglandin (PG) analogues as a single agent or as part of a poly-chemotherapy strategy for the treatment of human cancers. This study will focus on human melanoma cells, but the results are probably extendable to other tumor types. The proposed research is designed: a) to select through structure-function studies prostaglandin analogues that have enhanced anti-neoplastic properties as measured by anchorage-independent growth in a colony forming assay. Promising analogues also will be tested on nude mice implanted with human melanoma to rank their effectiveness in prolonging survival, b) Measure the toxicity of these PG on the viability of normal human fibroblasts and human melanoma cells, c) determine whether these PG analogues can interact cooperatively with both non-cytotoxic and cytotoxic agents. Cooperative interactions have been observed in preliminary experiments between PGA, dexamethasone, difluoro-methyl-ornithine, Beta-trans retinoic acid, and cytotoxic drugs. Promising combinations containing prostaglandins, biological modifiers and cytotoxic agents will be tested on mice implanted with melonoma cells. The investigation will delineate whether prostaglandin analogues are practical anti-tumor agents and provide new information on the regulatory importance of prostaglandins in human neoplasms.
