EXPERIMENTAL RADIOTHERAPY, CARCINOGENESIS, AND PROTECTOR

这项调查的目的是(1)描述反应的特征 从正常和肿瘤组织到电离辐射和/或选择的细胞 化疗药物作为治疗方案的功能和(2) 使用化学修饰剂，如辐射防护剂来阐明潜在的 导致观察到的效果的作用机制。这项研究将 专注于最大化治疗收益，同时将诱导效应降至最低 辐射对正常人诱变和致癌过程的影响 治疗过程中暴露的组织。体外和体内细胞系统 将用于评估选定的辐射防护器的有效性， 包括2-[(氨丙基)氨基]乙硫醇(WR1065) [S-2-(3-氨基丙氨基)乙基硫代磷酸](WR2721) 将对V79中国仓鼠细胞进行诱变研究 检测辐射和/或药物引起的突变 次黄嘌呤-鸟嘌呤磷酸核糖转移酶(HGPRT)基因座函数 辐射防护剂浓度和给药时间的关系。活体内 系统将包括用于评估的新生SpragueDawley大鼠系统， 在相对较短的时间内，癌前病变的诱导 (改变的肝细胞病灶)作为辐射暴露的函数， 化疗药物和/或辐射防护剂。肿瘤系统将用于 评估治疗收益包括甲基胆蒽诱导的纤维肉瘤 (FSA)、自发性纤维肉瘤(NFSA)和自发性 初发乳腺癌(MCA-K)。这些肿瘤会在这两个地方生长 明确的菌群和常规维持的C3Hf/SED小鼠。时间剂量 将进行研究，以评估尊重的治疗效果 对肿瘤控制以及诱变和致癌过程的诱导 在非肿瘤细胞系统中。DNA损伤和修复将被测量 通过碱性洗脱和中性洗脱技术。如有需要， 将使用诸如离心淘洗等生物物理技术来 分离独特的细胞群体以供研究。通过整合 这些系统将有可能评估化学物质的有用性 辐射防护剂等修饰剂不仅可以提高治疗收益，而且 还可显著降低与治疗相关的风险 暴露的正常组织的诱变和致癌作用。

The objectives of this investigation are (1) to characterize the response of cells from normal and tumor tissue to ionizing radiation and/or selected chemotherapeutic agents as a function of therapeutic protocol and (2) to use chemical modifiers such as radioprotectors to elucidate the underlying mechanisms of action leading to the observed effects. This study will focus on maximizing therapeutic gain while minimizing the inductive effects of radiation on the processes of mutagenesis and carcinogenesis in normal tissues exposed during treatment. Both in vitro and in vivo cell systems will be used to assess the effectiveness of selected radioprotectors, which include 2-[(aminopropyl)amino] ethanethiol (WR1065) and [S-2-(3-aminopropylamino) ethyl phosphorothioic acid] (WR2721). Mutagenesis studies will be performed with V79 Chinese hamster cells by assaying for radiation and/or drug-induced mutations at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus as a function of radioprotector concentration and timing of administration. In vivo systems will include a neonatal Sprague Dawley rat system used to assess, in relatively short periods of time, the induction of preneoplastic lesions (altered hepatocyte foci) as a function of exposure to radiation, chemotherapy agents, and/or radioprotectors. Tumor systms to be used to assess therapeutic gain include a methylcholanthrene-induced fibrosarcoma (FSa), a spontaneously arisen fibrosarcoma (NFSA), and a spontaneously arisen mammary carcinoma (MCa-K). These tumors will be grown in both defined flora and conventionally maintained C3Hf/Sed mice. Time dose studies will be performed to assess therapeutic effectiveness with respect to both tumor control and induction of mutagenic and carcinogenic processes in non-neoplastic cell systems. DNA damage and repair will be measured through the techniques of alkaline and neutral elution. Where required, biophysical techniques such as centrifugal elutriation will be used to isolate unique cell populations for study. Through the integration of these systems it will be possible to evaluate the usefulness of chemical modifiers such as radioprotectors to not only improve therapeutic gain but also significantly reduce the associated risk of therapy-induced mutagenesis and carcinogenesis in exposed normal tissues.