Schedule-dependent drug effects of oral 5-iodo-2-pyrimidinone-2'-deoxyribose as an in vivo radiosensitizer in U251 human glioblastoma xenografts.
Schedule-dependent drug effects of oral 5-iodo-2-pyrimidinone-2'-deoxyribose as an in vivo radiosensitizer in U251 human glioblastoma xenografts.
复制标题
口服 5-碘-2-嘧啶酮-2-脱氧核糖作为 U251 人胶质母细胞瘤异种移植体内放射增敏剂的时间表依赖性药物作用。
DOI：
10.1158/1078-0432.ccr-05-1138
复制
发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Kinsella,TimothyJ
中科院分区：
文献类型：
--
作者：
Seo,Yuji;Yan,Tao;Schupp,JaneE;Radivoyevitch,Tomas;Kinsella,TimothyJ
目的：5-碘-2-嘧啶酮-2 ′-脱氧核糖（IPdR）是体内外放射增敏剂5-碘-2 ′-脱氧尿苷（IUdR）的口服前体药物。IPdR可通过肝醛氧化酶快速转化为IUdR。以前，我们发现IPdR向IUdR的酶促转化可以使用每日一次（q.d.）这可能影响IPdR介导的肿瘤放射增敏。实验设计：三种不同的IPdR治疗方案（每天三次，t.i.d.;隔日一次，每日一次;每3天，q.3.d.），与Q.D.相比，使用具有人胶质母细胞瘤（U251）的无胸腺裸鼠s.c.异种移植以血浆药代动力学、肿瘤和正常增殖组织中IUdR-DNA掺入、照射后肿瘤生长延迟和体重减轻作为终点。每日总剂量与q.d.相同。250、500或1，000 mg/kg/d的剂量可提高IPdR转化为IUdR的效率。因此，使用t.i.d.的IUdR-DNA掺入百分比较高。在肿瘤异种移植物中以及在正常小肠和骨髓中，每次给药使用固定剂量（500 mg/kg），q.o.d.和q.3.d。时间表也显示出比q.d.时间表，与下一次给药前肝醛氧化酶活性的更大恢复有关。在肿瘤再生长测定中，与没有IPdR的对照相比，所有IPdR治疗方案显示出再生长延迟的显著增加（q.o.d.，29.4天; q.d.，29.7天; t.i.d.，34.7单纯放疗组15.7天。T.I.D.与q.d.相比，schedule.此外，Q.O.D.结论：t.i.d.方案可显著降低全身毒性。和q.o.d.与q.d.相比，给药方案改善了治疗期间IPdR酶促活化为IUdR的效率，并改变了肿瘤放射增敏和/或全身毒性的程度。给药方案。这些给药方案将被考虑用于IPdR介导的人肿瘤放射增敏的未来临床试验。
Purpose:5-Iodo-2-pyrimidinone-2′-deoxyribose (IPdR) is an oral prodrug of 5-iodo-2′-deoxyuridine (IUdR), anin vitro/in vivoradiosensitizer. IPdR can be rapidly converted to IUdR by a hepatic aldehyde oxidase. Previously, we found that the enzymatic conversion of IPdR to IUdR could be transiently reduced using a once daily (q.d.) treatment schedule and this may affect IPdR-mediated tumor radiosensitization. The purpose of this study is to measure the effect of different drug dosing schedules on tumor radiosensitization and therapeutic index in human glioblastoma xenografts.Experimental Design:Three different IPdR treatment schedules (thrice a day, t.i.d.; every other day, q.o.d.; every 3rd day, q.3.d.), compared with a q.d. schedule, were analyzed using athymic nude mice with human glioblastoma (U251) s.c. xenografts. Plasma pharmacokinetics, IUdR-DNA incorporation in tumor and normal proliferating tissues, tumor growth delay following irradiation, and body weight loss were used as end points.Results:The t.i.d. schedule with the same total daily doses as the q.d. schedule (250, 500, or 1,000 mg/kg/d) improved the efficiency of IPdR conversion to IUdR. As a result, the percentage of IUdR-DNA incorporation was higher using the t.i.d. schedule in the tumor xenografts as well as in normal small intestine and bone marrow. Using a fixed dose (500 mg/kg) per administration, the q.o.d. and q.3.d. schedules also showed greater IPdR conversion than the q.d. schedule, related to a greater recovery of hepatic aldehyde oxidase activity prior to the next drug dosing. In the tumor regrowth assay, all IPdR treatment schedules showed significant increases of regrowth delays compared with the control without IPdR (q.o.d., 29.4 days; q.d., 29.7 days; t.i.d., 34.7 days; radiotherapy alone, 15.7 days). The t.i.d. schedule also showed a significantly enhanced tumor growth delay compared with the q.d. schedule. Additionally, the q.o.d. schedule resulted in a significant reduction in systemic toxicity.Conclusions:The t.i.d. and q.o.d. dosing schedules improved the efficiency of enzymatic activation of IPdR to IUdR during treatment and changed the extent of tumor radiosensitization and/or systemic toxicity compared with a q.d. dosing schedule. These dosing schedules will be considered for future clinical trials of IPdR-mediated human tumor radiosensitization.