In vivo modulation of cisplatin cytotoxicity by the cholecystokinin antagonist MK-329 in human pancreatic cancer xenografts.
We have previously reported that the cholecystokinin antagonist MK-329 (also known as L-364,718 or devazepide) synergistically enhances sensitivity to cisplatin (DDP) in MIA-PaCa2 human pancreatic cancer cells in tissue culture. In this study, we examined the ability of MK-329 to modulate DDP sensitivity in vivo using MIA-PaCa2 pancreatic cancer xenografts growing subcutaneously in athymic nude mice. Twenty-four hours after tumor inoculation, mice received either DDP intraperitoneally, MK-329 subcutaneously, both DDP and MK-329 or drug vehicles alone. Both DDP and MK-329 alone caused a reduction in the rate of tumor growth. The combination of DDP and MK-329 resulted in enhanced tumor growth delay compared to DDP or MK-329 treated mice. Although MK-329 alone was not nephrotoxic, the addition of MK-329 to DDP treatment resulted in a significant increase in weight loss and nephrotoxicity compared to mice treated with DDP alone; this was reflected by an increase in the plasma BUN levels. Although we believe that the enhanced anti-tumor effect of DDP/MK-329 combination therapy may be independent MK-329's capability to block CCK receptors, the role of CCK receptor blockade in potentiating DDP-induced nephrotoxicity less clear.
Jamshidipour
R
R
Department of Surgery, University of California, San Diego, La Jolla 92093.
Pinho
E B
EB
Howell
S B
SB
D000818:Animals; D001570:Benzodiazepinones / Q000627:therapeutic use* / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D002945:Cisplatin / Q000627:therapeutic use* / Q000633:toxicity*; D020109:Devazepide; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D001570:Benzodiazepinones; D002766:Cholecystokinin; D020109:Devazepide; D002945:Cisplatin