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 ih of a single injection of -G was associated with a 60% decline in tumor blood flow. To determine 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 (125I-BSA) permeability and metabolic (32P) labelling of cultured endothelial cells. Treatments for ih produced no endothelial cell leakage, but 24h exposures to either -G (5 microM) or +G (50 microM) produced complete permeability of the monolayers to 125I-BSA. In contrast, 0.5-I.Oh exposures to -G (4 microM) produced 2 to 3-fold increases in phosphorylated 27 kDa 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.
Benz
C C
CC
Cancer Research Institute, University of California, San Francisco 94143.
Iyer
S B
SB
Asgari
H S
HS
Matlin
S A
SA
Aronson
F R
FR
Barchowsky
A
A
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001783:Blood Flow Velocity / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006072:Gossypol / Q000494:pharmacology*; D008297:Male; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000255:Adenosine Triphosphate; D006072:Gossypol