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 pancreatic cancers, were investigated. The level of DNA synthesis in only one of five tested pancreatic cancers was enhanced by CCK at concentrations of 0.01-10 nM, while in the other four cancers DNA synthesis was not affected. The levels of DNA, RNA, and protein synthesis (by 3H-thymidine, 3H-uridine, and 3H-leucine incorporation tests, respectively) in all the tested cancers were dose-dependently inhibited by loxiglumide at concentrations of 20-2000 microM, and the IC50 of loxiglumide for DNA synthesis in pancreatic cancers was 156 +/- 80 microM (means +/- SD). The in vivo effect of loxiglumide was assessed using a xenografted line (PC-HN) transplanted in nude mice. The in vivo 50% lethal dose of loxiglumide for nude mice was about 500 mg/kg. Death was caused by respiratory failure due to severe congestion of the lung after the administration of a large dose of loxiglumide. The growth of a PC-HN transplanted in the nude mice was significantly inhibited by subcutaneous loxiglumide at 250 mg/kg, twice a day for 28 days, which did not cause death. It is suggested that loxiglumide inhibits the in vivo and in vitro growth of human pancreatic cancer, perhaps independently of its action as a CCK antagonist, and this study also suggests that loxiglumide may be a new type of therapeutic agent to be used for the treatment of human pancreatic cancer.
Morimoto
H
H
First Department of Surgery, Kyoto University Faculty of Medicine, Japan.
Nio
Y
Y
Tsubono
M
M
Tseng
C C
CC
Kawabata
K
K
Masai
Y
Y
Hayashi
H
H
Baba
N
N
Manabe
T
T
Hosokawa
Y
Y
D000818:Animals; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000188:drug therapy* / Q000235:genetics; D002766:Cholecystokinin / Q000037:antagonists & inhibitors* / Q000502:physiology; D004273:DNA, Neoplasm / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D011377:Proglumide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D012334:RNA, Neoplasm / Q000032:analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; C053737:loxiglumide; D002766:Cholecystokinin; D011377:Proglumide