POTENTIATION OF RADIATION THERAPY BY CARBOPLATIN (CBDCA)

卡铂 (CBDCA) 增强放射治疗

• 批准号: 3180553
• 负责人: EVAN BARR DOUPLE
• 金额: $ 17.3万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-04-01 至 1993-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3180553
• 关键词: DNA repair; DNA replication; buthionine sulfoximine; cell death; cis platinum compound; combination cancer therapy; crosslink; drug adverse effect; flow cytometry; hairless mouse; hypoxia; laboratory mouse; melanoma; neoplasm /cancer radiation therapy; perfusion; radiation recovery; radiation sensitivity; synchronous cell division; tissue /cell culture

A new platinum complex diammine(1,1-cyclobutanedicarboxylato)platinum(II) [Carboplatin or CBDCA] promies to replace or complement Cisplatin (cis-DDP) as an important anti-tumor agent based on clinical trials that have demonstrated efficacy without dose-limiting nephro- or gastrointestinal toxicity. Since the parent complex, cis-DDP, and several platinum analogs have been shown to potentiate radiation-induced cell kill in vitro and radiation therapy (RT) in animal tumors, this project proposes to test for two types of interaction when CBDCA is combined with RT and to compare the results with those obtained using cis-DPP. The study is divided into three parts. First, we will test for, and distinguish between, two interactions: the radiosensitization (RS) of hypoxic and euoxic cells, and (b)\radiation-induced enhanced chemotoxicity (EC) that results when platinum complexes are added after irradiation, which may result from the inhibition of radiation damage repair mechanisms. Second, we will determine whether both RS of hypoxic cells by platinum and post-radiation EC are demonstrable and important in human tumor cells treated as xenografts in nude mice. Third, we will measure the concentrations of CBDCA and cis-DDP in cells and in tumors and correlate total free and DNA-bound platinum levels, with the magnitude of interactions produced. The in vitro studies will employ two "normal" cells lines: the rodent line V79 and the human fetal lung fibroblast HFL. In addition, the human malignant melanoma cell line HX34 will be used along with two strains of a rodent tumor (Walker 256), one of which (WS) is more sensitive to platinum than the other (WR). The cell kill resulting from combined modalities will be assessed using colony forming unit (CFU) analysis on petri dish surfaces or in agar. The xenograft studies will employ the human malignant melanoma HX34, and cell survival will be evaluated using CFU analysis of cells explanted into agar following treatment in situ. Platinum levels will be measured using atomic absorption spectroscopy (AAS). These studies are designed to answer such questions as: (a) Does this second generation platinum complex interact more extensively with radiation than does Cisplatin? (b) Is this interaction greatest when cellular levels of total or free platinum are at their highest or when maximum platinum is bound to DNA?; and (c) Do these interactions occur in solid tumor? The results of this project will contribute directly to a rationale for combining CBDCA or cis-DDP with RT and are necessary to the formulation of appropriate designs for the clinical protocols that are being planned to exploit these interactions.

一种新的铂配合物二氨（1，1-环丁烷二甲酸）合铂（II） [卡铂或CBDCA]有望取代或补充顺铂（cis-DDP） 作为一种重要的抗肿瘤药物， 已证实疗效，无剂量限制性肾或胃肠道 毒性 由于母体复合物顺式DDP和几种铂类似物 已显示在体外增强辐射诱导的细胞杀伤， 放射治疗（RT）在动物肿瘤，该项目提出测试 CBDCA与RT结合时的两种相互作用并比较 结果与使用cis-DPP获得的结果一致。 研究分为三个部分 零件. 首先，我们将测试并区分两种交互： 低氧和常氧细胞的放射增敏（RS），和 (b)辐射诱导的增强化学毒性（EC），当 铂络合物在照射后加入，这可能是由于 抑制辐射损伤修复机制。 二是 确定是否通过铂和辐射后缺氧细胞的RS EC在治疗的人肿瘤细胞中是可证明的和重要的， 在裸鼠中的异种移植物。 第三，我们将测量 细胞和肿瘤中的CBDCA和顺式-DDP以及相关的总游离和 DNA结合铂水平，以及产生的相互作用的大小。 体外研究将使用两种“正常”细胞系： V79和人胎肺成纤维细胞HFL。 此外，人类 恶性黑色素瘤细胞系HX 34将沿着两株 啮齿动物肿瘤（步行者256），其中一种（WS）对铂更敏感 另一个（WR）。 由组合方式产生的细胞杀伤将 使用培养皿表面上的菌落形成单位（CFU）分析进行评估 或在琼脂中。 异种移植研究将使用人类恶性黑色素瘤 HX 34，并将使用细胞的CFU分析来评价细胞存活 在原位处理后接种到琼脂中。 白金级别将是 使用原子吸收光谱法（AAS）测量。 这些研究 旨在回答以下问题：（a）第二代 铂络合物与辐射的相互作用比 顺铂？ (b)这种相互作用是否在细胞水平的 或游离铂处于其最高值时，或当最大铂与 DNA？和（c）这些相互作用是否发生在实体瘤中？ 的结果 该项目将直接有助于将CBDCA或 顺式DDP与RT，并有必要制定适当的设计 用于临床方案， 交互.