GOSSYPOL EFFECTS ON ENDOTHELIAL-CELLS AND TUMOR BLOOD-FLOW

Isomers (-,+) of the antitumor agent gossypol (G) were studied for their ability to reduce tumor ATP and blood flow in rats bearing subcutaneously implanted pancreatic tumors. A 50% reduction in tumor ATP/Pi within 1h of a single injection of -G was associated with a 60% decline in tumor blood flow. To detemine if these changes in tumor physiology could be due to a direct drug effect on tumor endothelium, G isomers were compared for their ability to alter protein (I-125-BSA) permeability and metabolic (P-32) labelling of cultured endothelial cells. Treatments for 1h produced no endothelial cell leakage, but 24h exposures to either -G(5-mu-M) or +G(50-mu-M) produced complete permeability of the monolayers to I-125-BSA. In contrast, 0.5-1.0h exposures to -G(4-mu-M) or +G(10-mu-M) produced 2 to 3-fold increases in phosphorylated 27kDa heat-shock protein, hsp-27. Hsp-27 phosphoprotein isoforms were differentially labelled following -G and +G exposures with the phosphorylation profile of -G appearing most similar to that of oxyradical producing agents known to induce hsp-27 and injure endothelial cells. We postulate that the tumor ischemic effects of -G are mediated by endothelial response to oxyradical production in a mechanism similar to that of tissue ischemia-reperfusion injury.