ANTITUMOR-ACTIVITY AND SCHEDULE DEPENDENCY OF 8-CHLOROADENOSINE-3',5'-MONOPHOSPHATE (8-CLCAMP) AGAINST HUMAN TUMOR XENOGRAFTS

8-Chloroadenosine-3',5'-monophosphate (8-ClcAMP) is a novel antitumour agent currently undergoing phase I clinical trials in several Europea n centres. In this study, its antitumour activity against human tumour xenografts and its dependence on schedule were investigated. When adm inistered by continuous infusion at doses of 100 or 50 mg/kg/day to nu de 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 schedu les produced hypercalcaemia and severe weight loss. In an attempt to o ptimise antitumour activity and minimise toxicity, several other sched ules were studied. In comparison with continuous administration of 8-C lcAMP at 50 mg/kg/day for 14 days which, although producing complete g rowth inhibition in the HOX 60 model, was associated with a marked bod y weight loss, schedules in which the infusion was interrupted (infusi on on either days 0-4; 7-11 or days 0-2; 6-5) produced minimal weight loss but also reduced antitumour activity. However, co-administration of salmon calcitonin with continuous infusion of 8-ClcAMP IP prevented both hypercalcaemia and body weight loss in 3/6 animals while still p roducing marked inhibition of tumour growth. These data indicate that 8-ClcAMP has broad-spectrum antitumour activity and the major side-eff ect of hypercalcaemia may at least in part be ameliorated by the use o f salmon calcitonin. (C) 1998 Elsevier Science Ltd. All rights reserve d.