TOXICITY OF CORDYCEPIN IN COMBINATION WITH THE ADENOSINE-DEAMINASE INHIBITOR 2'-DEOXYCOFORMYCIN IN BEAGLE DOGS

For 3 consecutive days, the nucleoside cordycepin (3'-deoxyadenosine) was administered as 1-hr iv infusions (0, 1, 4, 8, 10, or 20 mg/kg/day ) to dogs. These doses were given 1 hr after a bolus iv injection (0.2 5 mg/kg/day) of 2'-deoxycoformycin (dCF), a potent inhibitor of adenos ine deaminase. The hypothesis was that dCF would affect the toxicity o f cordycepin. Plasma adenosine deaminase activity was strongly inhibit ed during the dose period and for 5 days following the final dose of d CF. Dogs given cordycepin alone showed no drug-related toxicities. In dogs given only dCF, drug-related toxicity to lymphoid tissue (lymphop enia and thymus lymphoid depletion), thrombocytopenia, and decreases i n food consumption were observed. Cordycepin in combination with dCF p roduced symptoms associated with severe gastrointestinal toxicity (dec reased body weights, emesis, diarrhea, decreased food consumption, and necrosis of the gastrointestinal tract) and bone marrow toxicity (lym phopenia, thrombocytopenia, and depletion of hematopoietic cells). The gastrointestinal tract and bone marrow were sites associated with dos e-limiting toxicities. In surviving dogs, most of the effects were rev ersible by Day 30. The maximum tolerated dose of cordycepin administer ed in combination with dCF was 8 mg/kg/day (160 mg/m(2)/day) given dai ly for 3 days. (C) 1997 Academic Press.