RADIATION AND CHEMOSENSITIZATION WITH IODODEOXYURIDINE

人们对碘脱氧尿苷(IdUrd)作为一种 临床上对辐射和某些化疗药物的敏感剂，包括 博莱霉素和顺铂。这项提案的总体目标是研究 不同IdUrd放射和化疗增敏的可能机制 (博莱霉素、顺铂)对人膀胱癌和结肠癌细胞株的作用 与正常细胞相比。虽然IDURD的主要临床策略 放射增敏是选择主动分割、放射反应差的 肿瘤(如转移到肝癌和膀胱癌的结肠)周围 不分割正常组织(肝、膀胱)，在临床上是可行的 IdUrd细胞代谢的生化调节可能导致 进一步的差异化敏化。IdUrd可能是一种理想的敏化剂 人膀胱癌--如果能同时增敏放射和顺铂 细胞毒性。 IdUrd是一种胸苷(DThd)类似物，与dThd竞争掺入 在细胞分裂过程中转化成DNA。IDUrd-DNA的掺入被认为是 对于放射和化学增敏都是必要的。细胞新陈代谢 IdUrd(和dThd一样)涉及两种关键的调节酶--胸苷激酶 (TK)和胸苷酸合酶(TS)。我们将调查 这些对IdUrd的调节酶(纯化的和体外的)在肿瘤和 正常细胞。这些生化调节的方法将被测试以 增加IdUrd化学增敏和放射增敏。 这些IdUrd辐射增敏方法也将进行测试，使用 人肿瘤在nu/nu小鼠体内的移植。将研究两种肿瘤模型 包括结肠癌肝转移和原发膀胱癌 癌症。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以下方法确定 高效液相色谱和流式细胞仪技术。治疗反应(XRT+IdUrd+ 将使用生长延迟(或肿瘤治愈)进行评估 荷瘤小鼠皮下埋植肿瘤与存活时间的关系 转移性或原发膀胱癌。

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.