In vivo modulation of cisplatin cytotoxicity by the cholecystokinin antagonist MK-329 in human pancreatic cancer xenografts
Jamshidipour, R.; Pinho, E.B.; Howell, S.B.
Anticancer Research 14(6b): 2611-2616
1994
ISSN/ISBN: 0250-7005 PMID: 7872689 Document Number: 425367
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 (1). In this study, we examined the ability of MK-329 to modulate DDP sensitivity in vivo using MIA-PaCa-2) 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-329s capability to block CCK receptors, the role of CCK receptor blockade in potentiating DDP-induced nephrotoxicity less clear.