Kinsella T J, Kunugi K A, Vielhuber K A, McCulloch W, Liu S H, Cheng Y C
Department of Human Oncology, University of Wisconsin Medical School, Madison 53792.
Cancer Res. 1994 May 15;54(10):2695-700.
5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) was recently reported to be converted to 5-iodo-2'-deoxyuridine (IUdR) by an aldehyde oxidase, most concentrated in liver tissue. We questioned whether IPdR could be used as a p.o. hepatotropic prodrug to increase the percentage of IUdR-DNA incorporation into liver tumors compared to normal liver with acceptable systemic toxicity. Athymic nude mice with human colon cancer (HCT-116) xenograft tumors as liver metastases and s.c. flank tumors received daily p.o. boluses (via gastric tubes) of IUdR or IPdR for 6 days. The maximum tolerated dose of IUdR was 250 mg/kg/day and was associated with a > 10% weight loss and a high percentage of IUdR-DNA incorporation (> 5%) into normal bone marrow and intestine. In contrast, animals tolerated escalating doses of IPdR to 1 gm/kg/day without weight loss and with less (1.5-4%) IUdR-DNA incorporation in normal tissues. Pharmacokinetic analysis of p.o. IPdR showed peak plasma levels of IPdR and IUdR within 15-45 min, suggesting efficient conversion of IPdR to IUdR. Aldehyde oxidase activity was found in normal liver tissue but not in other normal or tumor tissues. Additionally, we found a 2-3 times greater percentage of IUdR-DNA incorporation in tumor with IPdR than IUdR at the highest doses used. However, no differential effect in the percentage of IUdR-DNA incorporation was noted between liver metastases and s.c. tumors with either IPdR or IUdR. We conclude that p.o. IPdR offers a greater therapeutic index for tumor incorporation (and presumably radiosensitization) than a similar schedule of IUdR.
5-碘-2-嘧啶酮-2'-脱氧核糖（IPdR）最近被报道可被醛氧化酶转化为5-碘-2'-脱氧尿苷（IUdR），醛氧化酶在肝脏组织中最为富集。我们质疑IPdR是否可以作为一种口服的肝脏靶向性前药，与正常肝脏相比，在可接受的全身毒性下增加IUdR-DNA掺入肝肿瘤的百分比。携带人结肠癌（HCT-116）异种移植瘤作为肝转移瘤和皮下侧腹肿瘤的无胸腺裸鼠，每天经口（通过胃管）给予IUdR或IPdR大剂量注射，持续6天。IUdR的最大耐受剂量为250mg/kg/天，这与体重减轻超过10%以及IUdR-DNA大量掺入（>5%）正常骨髓和肠道有关。相比之下，动物能够耐受高达1g/kg/天的递增剂量的IPdR，且没有体重减轻，正常组织中IUdR-DNA掺入较少（1.5 - 4%）。口服IPdR的药代动力学分析显示，IPdR和IUdR在15 - 45分钟内达到血浆峰值水平，表明IPdR能有效转化为IUdR。在正常肝脏组织中发现了醛氧化酶活性，但在其他正常或肿瘤组织中未发现。此外，在使用的最高剂量下，我们发现与IUdR相比，IPdR使肿瘤中IUdR-DNA掺入的百分比高2 - 3倍。然而，无论是IPdR还是IUdR，在肝转移瘤和皮下肿瘤之间，IUdR-DNA掺入百分比均未观察到差异。我们得出结论，与类似给药方案的IUdR相比，口服IPdR在肿瘤掺入（以及可能的放射增敏）方面具有更高的治疗指数。
