TOXINS TARGETED TO THE CELL MEMBRANE--DISRUPTION IN SIGNAL TRANSDUCTION

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Cholera toxin (CT) inhibits the induction of bombesin-mediated signals including increased intracellular calcium ([Ca2+]i) and phosphatidylinositol turnover in human small cell lung(SCLC) carcinoma cells. This effect occurs concomitant with the increase in cyclic AMP(cAMP) induced by the toxin. In addition, the toxin inhibits the growth of SCLC cells which bear the receptor for CT, the ganglioside G(M1). Recently we have completed an analysis of the effect of CT on the growth of a series on non-small cell lung carcinoma(NSCLC) cells. In contrast to CT-mediated inhibition of growth of G(M1)(+) SCLC cells, CT in approximately 50% of NSCLC cell lines could bind to NSCLC cells, increase cAMP, yet not decrease cell growth. These results raise the possibility that a fraction of NSCLC cell lines are refractory to the consequences of increased cAMP. In SCLC, recent experiments indicate that a consequence of CT action is inhibition of membrane lipid synthesis including phosphatidylinositol, phosphatidylinositol-4'-phosphate(PIP),l and phosphatidylinositol-4,5-bisphosphate(PIP)2. These results would suggest that CT acts to disrupt the normal substrate upon which bombesin peptides act to initiate signal transduction. These results further suggest that selective delivery of CT A chain, which activates adenylate cyclase through covalent modification of G1, would be a useful means of targeting bombesin peptide mediated signal transduction. In addition, the CT-B chain could be used to deliver novel toxic moieties to the cell surface and perhaps obviate the necessity to internalize the toxin to observe specific cytotoxicity. Further efforts will focus on constructing such molecules in an effort to design antineoplastic therapeutic strategies to disrupt normal membrane signalling processes. The clinical use of membrane-targeted toxins is being developed in ongoing clinical trials with anti-CD22 deglycosylated A chain immunotoxin in B-cell lymphoma, and an IL2-diphtheria toxin A chain fusion protein in cutaneous T-cell lymphoma.