RADIATION AND CHEMOSENSITIZATION WITH IODODEOXYURIDINE

碘脱氧尿苷（IdUrd）作为一种新的免疫抑制剂， 放射和某些化疗药物的临床增敏剂，包括 博莱霉素和顺铂。 本提案的总体目标是研究 IdUrd放射和化学增敏差异的潜在机制 （博来霉素，顺铂）在人膀胱癌和结肠癌细胞系中的作用 与正常细胞相比。 虽然IdURd的主要临床策略 放射增敏是选择活跃的分裂，放射反应差， 肿瘤（如结肠转移到肝脏和膀胱癌）被包围 通过不分裂的正常组织（肝、膀胱），其在临床上是可行的。 IdUrd细胞代谢的生化调节可能导致 进一步差异化敏化。 IdUrd可能是一种理想的敏化剂， 人膀胱癌放射线和顺铂联合增敏 细胞毒 IdUrd是胸苷（dThd）类似物，与dThd竞争掺入 转化为DNA IdUrd-DNA掺入被认为是 对放射和化学增敏都是必需的。 细胞代谢 IdUrd（如dThd）涉及两个关键的调节酶，胸苷激酶 (TK)和胸苷酸合成酶（TS）。 我们将调查 这些调节酶（纯化的和体外）在肿瘤和 正常细胞 这些生化调节的方法将被测试， 增加IdUrd化学增敏和放射增敏。 这些IdUrd放射增敏的方法也将使用 nu/nu小鼠中的人肿瘤异种移植物。 将研究两种肿瘤模型 包括结肠癌转移到肝脏和原发性膀胱 carcinoma. 持续输注IdUrd和其他调节药物（例如， 5 '-AT、FdUrd、MTX）将通过血浆药代动力学研究进行监测。 IdUrd-DNA掺入肿瘤和正常组织将通过 HPLC和流式细胞术技术。 治疗反应（XRT+IdUrd+ 将使用生长延迟（或肿瘤治愈）来评估（例如，“调节”药物）。 皮下肿瘤植入和使用存活时间在小鼠肝脏 转移或原发性膀胱肿瘤。

There is considerable renewed interest in iododeoxyuridine (IdUrd) as a clinical sensitizer to radiation and certain chemotherapy drugs including bleomycin and cisplatinum. The overall goal of this proposal is to study potential mechanisms of differential IdUrd radio- and chemosensitization (bleomycin, cisplatinum) in human bladder and colon cancer cell lines compared to normal cells. While a major clinical strategy for IdURd radiosensitization is to select actively dividing, poorly radioresponsive tumors (like colon metastases to liver and bladder carcinomas) surrounded by non-dividing normal tissues (liver, bladder), it is clinically feasible that biochemical modulation of IdUrd cellular metabolism may lead to further differential sensitization. IdUrd may be an ideal sensitizer in human bladder cancer if it can sensitize both radiation and cisplatinum cytotoxicity. IdUrd is a thymidine (dThd) analog and competes with dThd for incorporation into DNA in dividing cells. IdUrd-DNA incorporation is felt to be necessary for both radio-and chemosensitization. Cellular metabolism of IdUrd (like dThd) involves two key regulatory enzymes, thymidine kinase (TK) and thymidylate synthase (TS). We will investigate the activity of these regulatory enzymes (purified and in vitro) to IdUrd in both tumor and normal cells. These approaches of biochemical modulation will be tested to increase IdUrd chemosensitization and radiosensitization. These approaches to IdUrd radiosensitization will also be tested using human tumor xenografts in nu/nu mice. Two tumor models will be studied including colon carcinoma metastases to liver and primary bladder carcinoma. Continuous infusions of IdUrd and other modulating drugs (e.g. 5'-AT, FdUrd, MTX) will be monitored by plasma pharmacokinetic studies. IdUrd-DNA incorporation into tumor and normal tissue will be determined by HPLC and flow cytometry techniques. Response to treatment (XRT+IdUrd+ "modulating" drugs) will be assessed using growth delay (or tumor cure) in subcutaneous tumor implants and using survival time in mice with liver metastases or primary bladder tumors.