EXTRACHROMOSOMAL DNA--A NEW TARGET FOR ANTITUMOR DRUGS

染色体外DNA(上染色体)可以对 包括拓扑异构酶II在内的DNA相互作用抗癌药物的作用 目标特工。此外，与基因相关的上体元件 肿瘤细胞和肿瘤中的扩增被发现是 双微小染色体和均匀染色区域的前体。 这类DNA通常包含与肿瘤发生相关的基因(例如c-myc)和 耐药性(如P-糖蛋白)。这项计划的目标是 以内异体为新靶点开发化疗策略 DNA活性药物的评价。一种小鼠成纤维细胞组织培养细胞 LINE(935.11)被异体分子转化成肿瘤 评价药物介导的染色体外损伤及其修复 脱氧核糖核酸体外靶点。这些相同的细胞也可以作为皮下组织培养 (S.C.)允许在体内评价药物诱导的小鼠肿瘤 对圣公会的破坏。对935.11细胞表型的损伤程度 体内试验中的序列与治疗效果相关。基座 对DNA活性药物作用机理的认识 上体成分。我们将探索这种病毒的生物学后果 优惠性药物对上皮体的损伤。 具体目标： 1)对药物所致的外体成分损害进行特征描述和评估 靶向染色体外DNA作为一种改良手段的潜力 药物治疗策略。抗肿瘤药物与异构体的相互作用将 使用935.1体外模型系统进行研究。这项研究包括 基于拓扑图的DNA损伤定量研究 环状DNA的转化及其影响因素的阐明 有助于染色体外相对于基因组DNA的优先损伤。 将对表观染色体的损伤和细胞毒活性进行比较。 2)评估疗效和选择性之间的关系 靶向赋予肿瘤表型的上体DNA。药物诱发 上皮体的损伤和相应的治疗效果 其特征是小鼠携带935.1细胞作为固体S.C.肿瘤。 对上皮体的定量和定性损伤将是 选择和安排具有更高治疗价值的药物。 3)评估作为治疗策略的基础，增强靶向性 抗肿瘤药物对自发发生的内切体的影响 耐药与致癌因素。抗肿瘤药物将是 研究它们对双链霉菌表型前体的损伤能力 分钟和含有扩增序列的均一染色区 耐药与致癌因素。我们将寻求关系 在这些DNA上的药物效应和导致 细胞死亡或表型改变。

Extrachromosomal DNA (episomes) can be extraordinally sensitive to the actions of DNA inter-active antitumor drugs including topoisomerase II targeted agents. Furthermore, episomal elements associated with gene amplification in neoplastic cells and tumors have been found to be precursors of double minute chromosomes and homogeneously staining regions. Such DNAs often contain genes associated with oncogenesis (e.g. c-myc) and drug resistance (e.g. p-glycoprotein). The goal of this program is to develop chemotherapeutic strategies based upon episomes as new targets for evaluation of DNA reactive drugs. A mouse fibroblast tissue culture cell line (935.11) neoplastically transformed by an episomal element is used to evaluate drug mediated damage and its repair on a define extrachromosomal DNA target in vitro. These same cells can also be grown as a sub-cutaneous (s.c.) tumor in mice which allows for in vivo evaluation of drug-induced damage to the episome. The extent of damage to 935.11 cell episomal sequences in the in vivo assay correlates with therapeutic efficacy. Based upon an understanding of the mechanisms of action of DNA reactive drugs on episomal elements. We shall explore the biological consequences of preferential drug induced damage to episomes. SPECIFIC AIMS: 1) To characterize drug-induced lesions on episomal elements and evaluate the potential for targeting extrachromosomal DNA as a means for improving drug treatment strategies. Antitumor drug interaction with episomes will be investigated using the 935.1 in vitro model system. This study includes quantitation of DNA lesions in episomes based on topological forms conversion of the circular DNA as well as elucidation of factors contributing to preferential damage of extrachromosomal versus genomic DNA. Comparisons will be made between damage to episomes and cytotoxic activity. 2) To assess relationships between therapeutic efficacy and selective targeting of episomal DNA that confer neoplastic phenotypes. Drug-induced damage of episomes and corresponding therapeutic efficacy will be characterized in mice bearing the 935.1 cells as a solid s.c. tumor. Quantitative and qualitative damage to the episomes will be the basis for selecting and scheduling drugs with improved therapeutic value. 3) To evaluate as a basis for therapeutic strategies, enhanced targeting of antitumor drugs toward spontaneously occurring episomes which harbor drug resistance and oncogenic factors. Anti-tumor drug will be investigated for their abilities to damage episomal precursors of double minutes and homogenous staining regions containing amplified sequences of drug resistance and oncogenic factors. Relationships will be sought between drug effects on these DNAs and biological responses that lead to cell death or phenotypic changes.