POTENTIATION OF RADIATION THERAPY BY CARBOPLATIN (CBDCA)

一种新的铂配合物diammine(1，1-cyclobutanedicarboxylato)platinum(II) [卡铂或CBDCA]提示替代或补充顺铂(cis-DDP) 作为一种重要的抗肿瘤药物，临床试验表明 证明疗效不受肾脏或胃肠道的剂量限制 毒性。由于母体络合物顺式-DDP和几个铂类似物 已被证明在体外可以增强辐射诱导的细胞杀伤作用 放射治疗(RT)在动物肿瘤中的应用，该项目建议测试 CBDCA与RT结合时的两种类型的交互，并比较 结果与使用顺式-DPP获得的结果相一致。这项研究分为三个部分 零件。首先，我们将测试并区分两个交互： 低氧和正氧细胞的放射增敏(RS)，以及 (B)辐射诱导的增强化学毒性(EC)在以下情况下产生 铂络合物在照射后被添加，这可能是由于 抑制辐射损伤修复机制。第二，我们将 用铂和放射后测定缺氧细胞的RS EC在治疗后的人类肿瘤细胞中明显和重要 裸鼠异种移植。第三，我们将测量空气中的 CBDCA和顺式顺铂在细胞和肿瘤中的表达，并与总游离和 DNA结合的铂水平，以及产生的相互作用的大小。 体外研究将采用两种“正常”细胞系：啮齿类细胞系 V79和人胎肺成纤维细胞HFL。另外，人类 恶性黑色素瘤细胞株HX34将与两株A 啮齿动物肿瘤(Walker 256)，其中一种(WS)对铂更敏感 而不是另一个(WR)。由组合模式产生的细胞杀伤将 用培养皿表面的菌落形成单位(CFU)分析进行评估 或者在琼脂中。异种移植研究将使用人类恶性黑色素瘤 HX34，细胞存活将使用CFU分析细胞 在原位处理后移植到琼脂中。铂金水平将是 用原子吸收光谱仪(AAS)测量。这些研究是 旨在回答这样的问题：(A)这第二代 铂络合物与辐射的相互作用比 顺铂?(B)当细胞水平达到总水平时，这种相互作用是否最大 或游离铂金处于最高值，或者当最大铂金绑定到 以及(C)这些相互作用是否发生在实体肿瘤中？结果是 该项目将直接有助于将CBDCA或 具有RT的顺式DDP，对于制定适当的设计是必要的 对于正在计划利用这些技术的临床方案 互动。

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.