Guanine-nucleotide binding proteins (G-proteins) transduce signals from cell surface receptors coupled to adenylate cyclase, phospholipases, and ion channels. This laboratory has sought to develop drugs which alter the action of G-proteins or their effectors in human lung and prostate carcinoma cell lines. These studies will lead to clinical trials to extend these studies to human subjects. Bombesin agonist receptors, coupled to phospholipase-C through a pertussis toxin-insensitive G-protein, have been studied in lung tumor cell lines. We have found that bombesin-peptide receptors are of two types: a form with higher affinity for [Tyr4] bombesin than for neuromedin B, and a second type with higher affinity for neuromedin B. These receptors are expressed in approximately 80% of human small cell lung carcinoma (SCLC) cell lines, and in approximately 20% of non-SCLC cell lines. The structure of human bombesin receptors led to a consideration of features of the molecules important for its action. Mastoparans are wasp venom toxins with structural similarity to the third intracytoplasmic loop of the bombesin receptor(s). Mastoparans inhibit small cell lung carcinoma cell growth, perhaps by altering G-protein-receptor coupling. A transfected neuromedin B receptor-bearing cell line has been developed that will allow the further definition of the mechanism of growth modulation by bombesin-related peptides. The stimulatory protein of adenylate cyclase, G8, causes increased cyclic AMP. Increased CAMP inhibits prostate carcinoma cell growth in vitro. A clinical protocol in relapsed prostate carcinoma has been developed to examine whether increases in cyclic AMP effected by the phosphodiesterase inhibitor pentoxifylline leads to stabilization or improvement of disease.
