INHIBITORY EFFECTS OF A CHOLECYSTOKININ ANTAGONIST, LOXIGLUMIDE (CR-1505), ON THE GROWTH OF FRESHLY SEPARATED AND XENOGRAFTED HUMAN PANCREATIC-CANCER

The effects of cholecystokinin (CCK) and a CCK antagonist, loxiglumide (CR-1505), on four freshly separated and six xenografted human pancre atic cancers, were investigated. The level of DNA synthesis in only on e of five tested pancreatic cancers was enhanced by CCK at concentrati ons of 0.01-10 nM, while in the other four cancers DNA synthesis was n ot affected. The levels of DNA, RNA, and protein synthesis (by H-3-thy midine, H-3-uridine, and H-3-leucine incorporation tests, respectively ) in al the tested cancers were dose-dependently inhibited by loxiglum ide at concentrations of 20-2000 muM, and the IC50 of loxiglumide for DNA synthesis in pancreatic cancers was 156 +/- 80 muM (means +/- SD). The in vivo effect of loxiglumide was assessed using a xenografted li ne (PC-HN) transplanted in nude mice. The in vivo 50% lethal dose of l oxiglumide for nude mice was about 500 mg/kg. Death was caused by resp iratory failure due to severe congestion of the lung after the adminis tration of a large dose of loxiglumide. The growth of a PC-HN transpla nted in the nude mice was significantly inhibited by subcutaneous loxi glumide at 250 mg/kg, twice a day for 28 days, which did not cause dea th. It is suggested that loxiglumide inhibits the in vivo and in vitro growth of human pancreatic cancer, perhaps independently of its actio n as a CCK antagonist, and this study also suggests that loxiglumide m ay be a new type of therapeutic agent to be used for the treatment of human pancreatic cancer.