G-PROTEIN EFFECTORS AS TARGETS FOR ANTINEOPLASTIC THERAPIES

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Bombesin-like peptides have been implicated as growth factors for certain lung, breast, and prostate carcinoma cells. These peptides are known to transduce growth regulatory signals through guanine nucleotide binding proteins(G-proteins) to such effectors as phospholipases. Due to the heterogeneity of growth factor receptor expression, it is possible that the optimal therapeutic manipulation of this system will occur at the post-receptor level. In an effort to disrupt the interaction of G- protein-coupled receptors such as the Gastrin-releasing peptide (GRP) and neuromedia B (NMB) peptides were synthesized based on mastoparan, a wasp venom toxin known to interact with and stimulate the GTPase activity of the Gi family of G-proteins. Structure activity analysis of this series revealed that cell growth was inhibited by peptides which retain a spacing of charge and amphilicity similar to the parent compound. Merely producing peptides with alpha-helical content or with positive charge did not allow cytotoxicity to occur. Evidence of membrane disruption with release of lactate dehydrogenase and increase of intracellular calcium concentration appeared to occur at cytotoxic concentrations. Therefore, mastoparan-like peptides appear to mediate growth inhibition of the lung tumor and Swiss 3T3 cells by a membrane cytolytic effect rather than discrete regulation of known G-protein-coupled effectors. Further studies will define in subcellular factions whether these peptides can regulate discrete G-protein coupled effector systems. The results of these studies may suggest lead structures for avoiding the membrane lytic effect and regulating G-protein function.