PHASE-I TRIAL OF EXTRACELLULAR ADENOSINE 5'-TRIPHOSPHATE IN PATIENTS WITH ADVANCED CANCER

Adenosine 5'-triphosphate (ATP) has antineoplastic activity in vitro a nd in murine tumor systems, but there are no data in humans defining i ts potential use as an antineoplastic agent. We conducted a Phase I st udy to determine the spectrum of toxicity, maximum safely tolerated do se (MTD), and pharmacokinetics of intravenous ATP. Fourteen men with a dvanced cancer received 96-hour infusions of ATP once monthly in doses ranging from 50 to 100 mu g/kg/minute. Toxicity was assessed by stand ard National Cancer Institute (NCI) criteria, cardiac function was mon itored serially by two-dimensional echocardiography, and whole blood A TP was measured serially in a subset of patients. ATP was generally we ll tolerated and no significant hematologic toxicity was noted. The do se-limiting toxicity was a cardiopulmonary reaction characterized by c hest tightness and dyspnea that resolved within seconds of discontinui ng ATP. Dose-limiting cardiopulmonary toxicity occurred in 3 of 3 pati ents at 100 mu g/kg/minute, in 3 of 6 patients at 75 mu g/kg/minute, a nd 4 of 11 patients at 50 mu g/kg/minute. Whole blood ATP levels signi ficantly increased with treatment, reaching a steady state by 24 hours and returning to or near baseline by 1 week after treatment. Plateau levels were 63%, 67%, and 116% above baseline at 50, 75, and 100 mu g/ kg/min, respectively We conclude that prolonged infusions of ATP are f easible with acceptable toxicity and that 50 mu g/kg/minute is both th e MTD and the most appropriate dose rate for subsequent Phase II testi ng of 96-hour infusions of ATP in patients with advanced cancer. (C) 1 996 Wiley-Liss. Inc.