The ultimate objective of my research program is the development of therapeutic agents which specifically block the induction of prostate cancer invasion by the sequences of plasma fibronectin, a ubiquitous, soluble component of the blood, lymph and interstitial fluid. A Prostate SPORE Faculty Development Grant supported research in my laboratory whose goal was to identify the plasma fibronectin (pFn) sequence which functioned to elicit the invasion of selectively permeable basement membranes by metastatic prostate carcinoma cells under serum-free conditions. With this support, we identified the invasion-inducing sequence as the PHSRN """"""""synergy sequence"""""""" located in the ninth model of the pFn cell-binding domain. Based on the structure of this sequence, a potent PHSRN inhibitor, the PHSCN peptide was devised. This peptide exhibited log-linear anti-invasive dose response behavior, and eliminated metastatic human DU 145 and rat MLL prostate carcinoma invasion in vitro at concentrations less than 1 microgram per ml. When intravenous doses of the PHSCN peptide were employed to treat groups 10 rats injected with MatLyLu (MLL) metastatic Dunning rat prostate carcinoma cells, the numbers of lung metastases, the masses of intraperitoneal metastatic tissue, and the growth of MLL tumors at their injection sites were reduced very significantly without significant toxic or immunosuppressive effects. This application proposed to define the structure activity relationship for PHSRN invasion-promoting sequence and for its PHSCN inhibitor in vitro employing human or rat prostate carcinoma cell lines like DU 145 or MLL, and serum-optional SU-ECM invasion substrates. This application also proposes to define optimal strategies for utilizing the most active invasion inhibitors as suppressors of prostate cancer invasion and metastasis in rats injected with MLL or less aggressive rat prostate cancer cells. The treatment strategies developed will also be extended to human prostate cancer cells injected into immuno-deficient nude mice.
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