Budd G T, Jayaraj A, Grabowski D, Adelstein D, Bauer L, Boyett J, Bukowski R, Murthy S, Weick J
Cleveland Clinic Foundation, Ohio 44195.
Cancer Res. 1990 Nov 15;50(22):7206-11.
We have performed two Phase I trials of the combination of dipyridamole, 5-fluorouracil (5-FU), and folinic acid in patients with advanced refractory malignancy, based upon in vitro evidence that dipyridamole can modulate the cytotoxicity of 5-FU. In the first trial, patients were treated every 4 wk with dipyridamole (50 mg/m2) p.o. every 6 h on Days 0 to 6, beginning 24 h prior to the i.v. administration of folinic acid (200 mg/m2) and escalating doses of i.v. 5-FU on Days 1 to 5. The maximum tolerated daily dose of 5-FU that could be given with this combination was 375 mg/m2. Because dipyridamole is extensively bound to plasma proteins, it was hypothesized that the concentrations of free dipyridamole achieved with a dose of 50 mg/m2 were inadequate to modulate the cytotoxicity of 5-FU and folinic acid. Therefore, a second Phase I trial of escalating dose of p.o. dipyridamole was performed. Folinic acid (200 mg/m2) and 5-FU (375 mg/m2) were given i.v. on Days 1 to 5 every 4 wk, beginning 24 h after the start of therapy with dipyridamole; dipyridamole was administered p.o. on Days 0 to 6 at doses of 75, 100, 125, 150, 175, or 200 mg/m2/dose to successive cohorts of patients. Dose-limiting neutropenia, mucositis, and nausea were produced at a dose of 200 mg/m2/dose; the recommended dose of dipyridamole for use in Phase II studies is 175 mg/m2 p.o. every 6 h, or 700 mg/m2/day. At this dose, a mean peak plasma concentration of total dipyridamole of 16.32 mumol and a mean peak plasma concentration of free dipyridamole of 38.30 nmol were observed. Trough concentrations of free dipyridamole averaged 60% of the peak concentrations. Objective antitumor responses were seen in a number of tumor types; five of 13 patients with breast cancer treated with high-dose p.o. dipyridamole, 5-FU, and folinic acid responded. High-dose p.o. dipyridamole can produce plasma concentrations of free dipyridamole within the range shown to modulate the cytotoxicity of 5-FU and other agents. Phase II trials of this combination are justified.
基于双嘧达莫可调节5-氟尿嘧啶（5-FU）细胞毒性的体外证据，我们对晚期难治性恶性肿瘤患者进行了两项双嘧达莫、5-氟尿嘧啶和亚叶酸联合用药的I期试验。在第一项试验中，患者每4周接受一次治疗，在第0至6天，每6小时口服双嘧达莫（50mg/m²），从静脉注射亚叶酸（200mg/m²）前24小时开始，并在第1至5天递增静脉注射5-FU的剂量。该联合用药方案下可给予的5-FU最大耐受日剂量为375mg/m²。由于双嘧达莫与血浆蛋白广泛结合，因此推测50mg/m²剂量的游离双嘧达莫浓度不足以调节5-FU和亚叶酸的细胞毒性。因此，进行了第二项递增口服双嘧达莫剂量的I期试验。每4周在第1至5天静脉注射亚叶酸（200mg/m²）和5-FU（375mg/m²），从开始使用双嘧达莫治疗24小时后开始；在第0至6天，对连续几组患者口服给予双嘧达莫，剂量为75、100、125、150、175或200mg/m²/剂量。200mg/m²/剂量时出现剂量限制性中性粒细胞减少、粘膜炎和恶心；推荐用于II期研究的双嘧达莫剂量为口服175mg/m²，每6小时一次，即700mg/m²/天。在此剂量下，观察到双嘧达莫总血浆平均峰值浓度为16.32μmol，游离双嘧达莫血浆平均峰值浓度为38.30nmol。游离双嘧达莫谷浓度平均为峰值浓度的60%。在多种肿瘤类型中观察到了客观抗肿瘤反应；13例接受高剂量口服双嘧达莫、5-FU和亚叶酸治疗的乳腺癌患者中有5例有反应。高剂量口服双嘧达莫可使游离双嘧达莫血浆浓度达到可调节5-FU和其他药物细胞毒性的范围内。该联合用药方案的II期试验是合理的。
