Differential radiosensitization in DNA mismatch repair-proficient and -deficient human colon cancer xenografts with 5-iodo-2-pyrimidinone-2'-deoxyribose.
Differential radiosensitization in DNA mismatch repair-proficient and -deficient human colon cancer xenografts with 5-iodo-2-pyrimidinone-2'-deoxyribose.
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5-碘-2-嘧啶酮-2-脱氧核糖对 DNA 错配修复良好和缺乏的人结肠癌异种移植物的差异放射增敏。
DOI：
10.1158/1078-0432.ccr-04-1144
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发表时间：
2004
期刊：
影响因子：
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通讯作者：
Kinsella,TimothyJ
中科院分区：
文献类型：
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作者：
Seo,Yuji;Yan,Tao;Schupp,JaneE;Colussi,Valdir;Taylor,KerriL;Kinsella,TimothyJ
用途：5-碘-2-嘧啶酮-2'-脱氧核糖 (IPdR) 是 5-碘脱氧尿苷 (IUdR) 的嘧啶酮核苷前药，正在研究作为口服放射增敏剂。我们之前报道过，错配修复（MMR）蛋白（hMSH2 和 hMLH1）影响 IUdR-DNA 掺入的程度（百分比）以及随后在人肿瘤细胞系中体外 IUdR 介导的放射增敏。在本研究中，我们使用口服 IPdR 来评估 MMR 丰富 (MMR+) 和 MMR 缺陷 (MMR−) 人类结肠癌异种移植物的体内放射增敏作用。实验设计：我们测试了口服 IPdR 治疗（1 g/kg/d，持续 14 天）是否可以导致肿瘤细胞 DNA 中的 IUdR 掺入差异，以及在短期（每天，持续 4 天）分段放射后的放射增敏作用。通过使用具有一对同基因人类结肠癌异种移植物 HCT116（MMR−，hMLH1−）和 HCT116/3-6（MMR+，hMLH1+）的无胸腺裸鼠进行治疗。使用肿瘤再生测定来评估放射增敏作用。通过每日体重以及正常骨髓和肠道中 IUdR-DNA 掺入的百分比来评估全身毒性。 结果：经过 14 天每天一次的 IPdR 灌胃治疗后，与 HCT116/3-6 (MMR+) 肿瘤异种移植物相比，HCT116 (MMR−) 肿瘤异种移植物中发现 IUdR-DNA 掺入量显着更高。在 14 天的药物治疗和 4 天的放射治疗疗程（IPdR 第 11-14 天）后进行肿瘤再生测定，我们发现 HCT116 和 HCT116/3-6 肿瘤异种移植物均具有显着的放射增敏作用。然而，与 HCT116/3-6 (MMR+) 肿瘤异种移植物（每次 2 Gy 时 1.21，每次 4 Gy 时 1.20）相比，HCT116 (MMR-) 肿瘤异种移植物的增敏剂增强比 (SER) 显着更高（每次 2 Gy 时为 1.48，每次 4 Gy 时为 1.41）。治疗组中未发现明显的全身毒性。结论：这些结果表明，IPdR 介导的放射增敏可以成为治疗“耐药”MMR 缺陷型肿瘤以及 MMR 丰富型肿瘤的有效体内方法。
Purpose:5-Iodo-2-pyrimidinone-2′-deoxyribose (IPdR) is a pyrimidinone nucleoside prodrug of 5-iododeoxyuridine (IUdR) under investigation as an orally administered radiosensitizer. We previously reported that the mismatch repair (MMR) proteins (both hMSH2 and hMLH1) impact on the extent (percentage) of IUdR-DNA incorporation and subsequentin vitroIUdR-mediated radiosensitization in human tumor cell lines. In this study, we used oral IPdR to assessin vivoradiosensitization in MMR-proficient (MMR+) and -deficient (MMR−) human colon cancer xenografts.Experimental Design:We tested whether oral IPdR treatment (1 g/kg/d for 14 days) can result in differential IUdR incorporation in tumor cell DNA and subsequent radiosensitization after a short course (every day for 4 days) of fractionated radiation therapy, by using athymic nude mice with an isogenic pair of human colon cancer xenografts, HCT116 (MMR−, hMLH1−) and HCT116/3-6 (MMR+, hMLH1+). A tumor regrowth assay was used to assess radiosensitization. Systemic toxicity was assessed by daily body weights and by percentage of IUdR-DNA incorporation in normal bone marrow and intestine.Results:After a 14-day once-daily IPdR treatment by gastric gavage, significantly higher IUdR-DNA incorporation was found in HCT116 (MMR−) tumor xenografts compared with HCT116/3-6 (MMR+) tumor xenografts. Using a tumor regrowth assay after the 14-day drug treatment and a 4-day radiation therapy course (days 11–14 of IPdR), we found substantial radiosensitization in both HCT116 and HCT116/3-6 tumor xenografts. However, the sensitizer enhancement ratio (SER) was substantially higher in HCT116 (MMR−) tumor xenografts (1.48 at 2 Gy per fraction, 1.41 at 4 Gy per fraction), compared with HCT116/3-6 (MMR+) tumor xenografts (1.21 at 2 Gy per fraction, 1.20 at 4 Gy per fraction). No substantial systemic toxicity was found in the treatment groups.Conclusions:These results suggest that IPdR-mediated radiosensitization can be an effectivein vivoapproach to treat “drug-resistant” MMR-deficient tumors as well as MMR-proficient tumors.