Haskell C M, Wong M, Williams A, Lee L Y
Wadsworth Cancer Center, West Los Angeles VA Medical Center, CA 90073, USA.
Med Pediatr Oncol. 1996 Sep;27(3):165-73. doi: 10.1002/(SICI)1096-911X(199609)27:3<165::AID-MPO6>3.0.CO;2-C.
Adenosine 5'-triphosphate (ATP) has antineoplastic activity in vitro and in murine tumor systems, but there are no data in humans defining its potential use as an antineoplastic agent. We conducted a phase I study to determine the spectrum of toxicity, maximum safely tolerated dose (MTD), and pharmacokinetics of intravenous ATP. Fourteen men with advanced cancer received 96-hour infusions of ATP once monthly in doses ranging from 50 to 100 micrograms/kg/minute. Toxicity was assessed by standard National Cancer Institute (NCI) criteria, cardiac function was monitored serially by two-dimensional echocardiography, and whole blood ATP was measured serially in a subset of patients. ATP was generally well tolerated and no significant hematologic toxicity was noted. The dose-limiting toxicity was a cardiopulmonary reaction characterized by chest tightness and dyspnea that resolved within seconds of discontinuing ATP. Dose-limiting cardiopulmonary toxicity occurred in 3 of 3 patients at 100 micrograms/kg/minute, in 3 of 6 patients at 75 micrograms/kg/minute, and 4 of 11 patients at 50 micrograms/kg/minute. Whole blood ATP levels significantly 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 base-line at 50, 75, and 100 micrograms/kg/min, respectively. We conclude that prolonged infusions of ATP are feasible with acceptable toxicity and that 50 micrograms/kg/minute is both the MTD and the most appropriate dose rate for subsequent Phase II testing of 96-hour infusions of ATP in patients with advanced cancer.
5'-三磷酸腺苷（ATP）在体外和小鼠肿瘤系统中具有抗肿瘤活性，但尚无关于其作为抗肿瘤药物在人体中潜在用途的数据。我们进行了一项I期研究，以确定静脉注射ATP的毒性谱、最大安全耐受剂量（MTD）和药代动力学。14名晚期癌症男性患者每月接受一次ATP 96小时输注，剂量范围为50至100微克/千克/分钟。毒性通过标准的美国国立癌症研究所（NCI）标准进行评估，通过二维超声心动图连续监测心脏功能，并在一部分患者中连续测量全血ATP。ATP总体耐受性良好，未观察到明显的血液学毒性。剂量限制性毒性是一种心肺反应，表现为胸闷和呼吸困难，在停止ATP输注后数秒内缓解。在100微克/千克/分钟剂量下，3名患者中有3名出现剂量限制性心肺毒性；在75微克/千克/分钟剂量下，6名患者中有3名出现；在50微克/千克/分钟剂量下，11名患者中有4名出现。全血ATP水平随着治疗显著升高，在24小时达到稳态，并在治疗后1周恢复到或接近基线水平。在50、75和100微克/千克/分钟时，平台期水平分别比基线高63%、67%和116%。我们得出结论，延长ATP输注是可行的，毒性可接受，并且50微克/千克/分钟既是MTD，也是晚期癌症患者后续进行ATP 96小时输注II期试验的最合适剂量率。
