Immunoprecipitation studies with specific antibodies to desmoplakin, a major protein of the desmosome plaque, and rab 5, a small GTPase with known activity in endocytic processes, confirmed the presence of desmoplakin-associated isoprenylated- and small GTP-binding proteins. These proteins are also present in nonionic detergent-insoluble desmosome-enriched preparations. Our studies suggest that isoprenylated proteins may be components of a signalling pathway for desmosome internalization. The HGF-mediated cell scattering response (which includes disassembly of intercellular junctions) was found to be inhibited by a novel class of tyrosine kinase inhibitors synthesized by Dr. T. Burke, Lab. of Medicinal Chemistry, DTP. The analysis of this response was facilitated by the development of a reproducible quantitative assay for scattering. Whether novel tyrosine kinase(s) and/or substrates are associated with desmosomal junctions is currently under investigation. Isoprenylation inhibitors such as lovastatin may find utility as anticancer agents in combination with selected hydroxysterol analogs. Combination studies were undertaken for the first time with the NCI in vitro drug screening program. These studies, which were recently reported upon at the AACR meeting, indicate that lovastatin, a growth inhibitory drug in most tumor cell panels, can be potentiated by 7Beta,25-OH sterol; the combination shows cytotoxic activity in renal, CNS, colon and melanoma panels. The feasibility of reducing lovastatin to clinically tolerated levels by combining it with water soluble hydroxysterol analogs is currently being explored.
