Kinsella T J, Vielhuber K A, Kunugi K A, Schupp J, Davis T W, Sands H
Department of Radiation Oncology, Case Western Reserve University School of Medicine and University Hospitals of Cleveland/Ireland Cancer Center, Ohio 44106-6068, USA.
Clin Cancer Res. 2000 Apr;6(4):1468-75.
In anticipation of an initial clinical Phase I trial in patients with high-grade gliomas of p.o. administered 5-iodo2-pyrimidinone-2'-deoxyribose (IPdR) given daily for 14 days as a prodrug for 5-iodo-2'-deoxyuridine (IUdR)-mediated tumor radiosensitization, we determined the systemic toxicities and the percentage IUdR-DNA incorporation in normal athymic mouse tissues and a human glioblastoma xenograft (U251) after this dosing schedule of IPdR. Using a tumor regrowth assay of s.c. U251 xenografts, we also compared radiosensitization with this IPdR-dosing schedule to radiation therapy (XRT) alone (2 Gy/day for 4 days) or to XRT after continuous infusion IUdR for 14 days at the maximum tolerated dose in mice (100 mg/kg/day). Athymic mice with and without U251 s.c. xenografts tolerated 750 or 1500 mg/kg/day of p.o. IPdR (using gastric lavage) for 14 days without weight loss or activity level changes during treatment and for a 28-day posttreatment observation period. The percentage IUdR-DNA incorporation in U251 tumor cells was significantly higher after p.o. IPdR (750 and 1500 mg/kg/day) for 14 days (3.1 +/- 0.2% and 3.7 +/- 0.3%, respectively) than continuous infusion IUdR for 14 days (1.4 +/- 0.1%). Compared to XRT alone, a significant sensitizer enhancement ratio (SER) was found with the combination of p.o. IPdR (1500 mg/kg/d) + XRT (SER = 1.31; P = 0.05) but not for the combination of continuous infusion IUdR + XRT (SER = 1.07; P = 0.57) in the U251 xenografts. The percentage IUdR-DNA incorporation after IPdR at 1500 mg/kg/day for 14 days in normal bone marrow, normal small intestine, and normal liver were 1.2 +/-0.2%, 3.3 +/- 0.3%, and 0.2 +/- 0.1%, respectively. We conclude that a 14-day p.o. schedule of IPdR at up to 1500 mg/kg/day results in no significant systemic toxicity in athymic mice and is associated with significant radiosensitization using this human glioblastoma multiforme xenograft model. Based on these data and our previously published data using shorter IPdR dosing schedules, which also demonstrate an improved therapeutic index for IPdR compared to IUdR, an initial clinical Phase I and pharmacokinetic study of p.o. IPdR daily for 14 days is being designed.
为了预期开展一项针对高级别胶质瘤患者的I期临床试验，该试验将口服5-碘-2-嘧啶酮-2'-脱氧核糖（IPdR），每日给药，持续14天，作为5-碘-2'-脱氧尿苷（IUdR）介导的肿瘤放射增敏的前体药物，我们测定了正常无胸腺小鼠组织和人胶质母细胞瘤异种移植瘤（U251）在这种IPdR给药方案后的全身毒性以及IUdR-DNA掺入百分比。使用皮下U251异种移植瘤的肿瘤再生长试验，我们还将这种IPdR给药方案的放射增敏作用与单独放疗（XRT，每天2 Gy，共4天）或在小鼠最大耐受剂量（100 mg/kg/天）下连续输注IUdR 14天后进行XRT的放射增敏作用进行了比较。有无皮下U251异种移植瘤的无胸腺小鼠耐受口服14天、剂量为750或1500 mg/kg/天的IPdR（采用洗胃法），治疗期间体重无减轻，活动水平无变化，治疗后观察期为28天。口服IPdR（750和1500 mg/kg/天）14天后，U251肿瘤细胞中IUdR-DNA掺入百分比（分别为3.1±0.2%和3.7±0.3%）显著高于连续输注IUdR 14天（1.4±0.1%）。与单独XRT相比，在U251异种移植瘤中，口服IPdR（1500 mg/kg/d）+XRT联合方案具有显著的增敏增强率（SER = 1.31；P = 0.05），而连续输注IUdR+XRT联合方案则无（SER = 1.07；P = 0.57）。正常骨髓、正常小肠和正常肝脏在口服1500 mg/kg/天的IPdR 14天后，IUdR-DNA掺入百分比分别为分别为1.2±0.2%、3.3±0.3%和0.2±0.1%。我们得出结论，在无胸腺小鼠中，每天口服剂量高达1500 mg/kg的IPdR，连续14天，不会产生显著的全身毒性，并且使用这种多形性胶质母细胞瘤异种移植模型具有显著的放射增敏作用。基于这些数据以及我们之前发表的使用较短IPdR给药方案的数据，这些数据也表明与IUdR相比，IPdR的治疗指数有所提高，目前正在设计一项口服IPdR、每日给药14天的I期初始临床和药代动力学研究。
