Pizzorno G, Yee L, Burtness B A, Marsh J C, Darnowski J W, Chu M Y, Chu S H, Chu E, Leffert J J, Handschumacher R E, Calabresi P
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Clin Cancer Res. 1998 May;4(5):1165-75.
Benzylacyclouridine (BAU, IND 039655) is a potent and specific inhibitor of uridine phosphorylase (UrdPase; EC 2.4.2.3). This enzyme plays a major role in regulating uridine homeostasis and also catalyzes the conversion of fluoropyrimidine nucleosides to their respective bases. Inhibition of UrdPase enzyme activity 18-24 h after 5-fluorouracil (5-FU) administration increased plasma levels of uridine and enhanced the therapeutic index of 5-FU by rescuing normal tissues. Moreover, in vitro preclinical studies have also shown that inhibiting UrdPase enzyme activity by BAU prior to administration of 5-FU increased cytotoxicity in a number of human cancer cell lines. A series of preclinical studies was performed in dogs and pigs to evaluate the pharmacological and pharmacodynamic properties of BAU. These data showed a sustained elevation in plasma uridine concentration in both animal models. The rapid degradation of a tracer dose of uridine into uracil was virtually arrested by BAU administered both p.o. or i.v. The t1/2 of BAU was 1.8-3.6 h in dogs, with bioavailability levels of 85% (30 mg/kg) and 42.5% (120 mg/kg). In pigs, the half-life varied from 1.6 to 2.3 h, with a bioavailability of 40% at 120 mg/kg. The drug was distributed into most tissues with a tissue: plasma ratio of approximately 0.7. On the basis of these preclinical studies, we performed a Phase I clinical trial of BAU in patients with advanced cancer. Patients received 200, 400, 800, and 1600 mg/m2 BAU as a single oral dose. Toxicities included grade 2 anemia, grade 1 fever, grade 1 fatigue, grade 1 constipation, and grade 1 elevation in alkaline phosphatase; none of these toxicities were observed to be dose dependent. The maximum tolerated dose and dose-limiting toxicity were not reached at the doses given. BAU plasma concentrations and area under the curve correlated linearly with the oral dose level. The pharmacokinetics of BAU were consistent with a first-order clearance, with average peak concentrations ranging from 19 microM (200 mg/m2) to 99 microM (1600 mg/m2) and tbeta1/2 ranging from 3.0 to 3.9 h at the four dose levels. Compared with baseline plasma uridine, treatment of patients with 200, 400, 800, and 1600 mg/m2 BAU increased peak uridine concentrations by 120, 150, 250, and 175%, respectively. On the basis of this clinical study, the suggested Phase II starting dose of BAU in combination with 5-FU is 800 mg/m2. Studies combining BAU with 5-FU and incorporating appropriate molecular and biochemical end points to assess the effects of this drug combination on tumor and/or surrogate tumor tissue are under way.
苄基阿糖胞苷（BAU，IND 039655）是尿苷磷酸化酶（UrdPase；EC 2.4.2.3）的一种强效且特异性抑制剂。该酶在调节尿苷稳态中起主要作用，还催化氟嘧啶核苷转化为其相应碱基。在给予5-氟尿嘧啶（5-FU）后18 - 24小时抑制UrdPase酶活性可增加尿苷的血浆水平，并通过挽救正常组织提高5-FU的治疗指数。此外，体外临床前研究还表明，在给予5-FU之前用BAU抑制UrdPase酶活性可增加多种人类癌细胞系的细胞毒性。在犬和猪身上进行了一系列临床前研究，以评估BAU的药理和药效学特性。这些数据表明，在两种动物模型中血浆尿苷浓度均持续升高。口服或静脉注射BAU几乎可阻止微量尿苷快速降解为尿嘧啶。在犬中，BAU的t1/2为1.8 - 3.6小时，生物利用度水平分别为85%（30 mg/kg）和42.5%（120 mg/kg）。在猪中，半衰期为1.6至2.3小时，120 mg/kg时生物利用度为40%。该药物分布到大多数组织中，组织与血浆的比率约为0.7。基于这些临床前研究，我们对晚期癌症患者进行了BAU的I期临床试验。患者接受200、400、800和1600 mg/m² BAU作为单次口服剂量。毒性包括2级贫血、1级发热、1级疲劳、1级便秘和1级碱性磷酸酶升高；未观察到这些毒性与剂量相关。在给定剂量下未达到最大耐受剂量和剂量限制性毒性。BAU血浆浓度和曲线下面积与口服剂量水平呈线性相关。BAU的药代动力学符合一级清除，在四个剂量水平下平均峰值浓度范围为19 μM（200 mg/m²）至99 μM（1600 mg/m²），tβ1/2范围为3.0至3.9小时。与基线血浆尿苷相比，用200、400、800和1600 mg/m² BAU治疗患者分别使尿苷峰值浓度增加了120%、150%、250%和175%。基于这项临床研究，建议BAU与5-FU联合使用的II期起始剂量为800 mg/m²。正在进行将BAU与5-FU联合使用并纳入适当分子和生化终点以评估该药物组合对肿瘤和/或替代肿瘤组织影响的研究。
