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 sens itivity to cisplatin (DDP) in MIA-PaCa2 human pancreatic cancer cells in tissue culture (I). In this study, we examined the ability of MK-32 9 to modulate DDP sensitivity in vivo using MIA-PaCa2 pancreatic cance r xenografts growing subcutaneously in athymic nude mice. Twenty-four hours after tumor inoculation, mice received either DDP intraperitonea lly, 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 gr owth. The combination of DDP and MK-329 resulted in enhanced tumor gro wth delay compared to DDP or MK-329 treated mice. Although MK-329 alon e was not nephrotoxic, the addition of MK-329 to DDP treatment resulte d 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-tumo r 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.