Antitumour activity and schedule dependency of 8-chloroadenosine-3',5'-monophosphate (8-ClcAMP) against human tumour xenografts.
8-Chloroadenosine-3',5'-monophosphate (8-ClcAMP) is a novel antitumour agent currently undergoing phase I clinical trials in several European centres. In this study, its antitumour activity against human tumour xenografts and its dependence on schedule were investigated. When administered by continuous infusion at doses of 100 or 50 mg/kg/day to nude mice bearing human tumour xenografts, 8-ClcAMP inhibited the growth of the HT 29 colorectal, ZR-75-1 breast, HOX 60 and PE04 ovarian and PANC-1 pancreatic carcinoma xenografts. However, these infusion schedules produced hypercalcaemia and severe weight loss. In an attempt to optimise antitumour activity and minimise toxicity, several other schedules were studied. In comparison with continuous administration of 8-ClcAMP at 50 mg/kg/day for 14 days which, although producing complete growth inhibition in the HOX 60 model, was associated with a marked body weight loss, schedules in which the infusion was interrupted (infusion on either days 0-4; 7-11 or days 0-2; 6-8) produced minimal weight loss but also reduced antitumour activity. However, co-administration of salmon calcitonin with continuous infusion of 8-ClcAMP prevented both hypercalcaemia and body weight loss in 3/6 animals while still producing marked inhibition of tumour growth. These data indicate that 8-ClcAMP has broad-spectrum antitumour activity and the major side-effect of hypercalcaemia may at least in part be ameliorated by the use of salmon calcitonin.
Langdon
S P
SP
ICRF Medical Oncology Unit, Western General Hospital, Edinburgh, U.K.
Ritchie
A A
AA
Muir
M
M
Dodds
M
M
Howie
A F
AF
Leonard
R C
RC
Stockman
P K
PK
Miller
W R
WR
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000139:chemically induced; D007262:Infusions, Intravenous; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D014183:Transplantation, Heterologous; D015431:Weight Loss
D000970:Antineoplastic Agents; D015124:8-Bromo Cyclic Adenosine Monophosphate; C044258:8-chloro-cyclic adenosine monophosphate