CELLULAR PHARMACOLOGY IN CANCER CHEMOTHERAPY

描述：(申请者摘要)本申请的目标是 建立了解临床的药理学和生化基础 回应，并用于指导方案设计和评估。这 应用程序延长了对有关药物的假说的持续评估 人类白血病细胞在治疗过程中的作用和相互作用 类似的研究对象是实体肿瘤--卵巢癌。要确定 吉西他滨代谢与作用的相关性研究 II期临床试验中肿瘤细胞中的核苷酸， 吉西他滨在人卵巢中的代谢及药效学 将对治疗过程中的癌细胞进行调查，这些 参数将在患者之间进行比较。尽管这其中的一些方面 项目重点是最近成立的核苷类似物 (氟达拉滨)或正在出现的(吉西他滨)抗肿瘤活性，第一 下一代该药的临床和药效学评价 还提出了一类药物(氯法拉滨和阿糖鸟苷)。 这些研究将确定活性药物的药代动力学。 治疗期间这些药物在白血病细胞中的核苷酸和 与抑制DNA合成有关的药效学作用和 核糖核苷酸还原酶。将寻求与临床的相关性 在I期和II期单药试验期间的反应。新目标 因为核苷酸类似物在静止时被结合到DNA中 白血病人群被诱导进行DNA修复。这一战略 将在慢性淋巴细胞白血病(CLL)细胞中进行研究 接受氟达拉滨和环磷酰胺治疗的患者。这个 链间DNA-交联链的形成和去除动力学 环磷酰胺治疗过程中的循环白血病淋巴细胞 将被确定，以及预先输注氟达拉滨对 将对这些过程进行研究。植物提取物的内在能力 CLL细胞修复4-羟基过氧环磷酰胺诱导的加合物 体外比较患者之间的质粒DNA以寻找相关性 这些参数与环磷酰胺临床疗效之间的关系 氟达拉滨疗法。最后，因为所有这些代理都会诱导 CLL淋巴细胞通过启动细胞凋亡而死亡，本病将 被用作研究涉及到的分子机制的模型 这个死亡过程。将寻求在归纳和分析之间的相关性 慢性淋巴细胞性白血病中的高分子量DNA断裂(一种细胞凋亡的指标) 治疗过程中的细胞和核苷类似物的临床反应 治疗。假设氟达拉滨不能诱导 执行细胞凋亡所需的蛋白质是药物的一种机制 将对耐药性进行调查。

DESCRIPTION: (Applicant's Abstract) The goal of this application is to establish pharmacologic and biochemical bases for understanding clinical response and for guiding protocol design and evaluation. This application extends ongoing evaluations of hypotheses concerning drug actions and interactions in human leukemia cells during therapy to similar investigations in a solid tumor, ovarian carcinoma. To identify correlations between the metabolism and actions of gemcitabine nucleotides in tumor cells with clinical response in a phase II trial, the metabolism and pharmacodynamics of gemcitabine in human ovarian carcinoma cells during therapy will be investigated, and these parameters will be compared among patients. Although aspects of this project focus on nucleoside analogs with recently established (fludarabine) or emerging (gemcitabine) antitumor activity, the first clinical and pharmacodynamic evaluations of the next generation of this class of drugs (clofarabine and arabinosylguanine) is also proposed. These investigations will determine the pharmacokinetics of the active nucleotides of these drugs in leukemia cells during therapy and the pharmacodynamic actions relative to inhibition of DNA synthesis and ribonucleotide reductase. Correlations will be sought with clinical response during phase I and phase II single-drug trials. New targets for nucleotide analog incorporation into DNA are created when quiescent leukemia populations are induced to undergo DNA repair. This strategy will be pursued in the chronic lymphocytic leukemia (CLL) cells of patients receiving therapy with fludarabine and cyclophosphamide. The kinetics of interstrand DNA-cross link formation and removal in circulating leukemic lymphocytes during therapy with cyclophosphamide will be determined, and the effect of prior fludarabine infusion on these processes will be studied. The inherent ability of extracts from CLL cells to repair 4-hydroperoxycyclophosphamide-induced adducts on plasmid DNA in vitro will be compared among patients to seek correlations between these parameters and clinical response to cyclophosphamide/ fludarabine therapy. Finally, because all of these agents induce the death of CLL lymphocytes by initiating apoptosis, this disease will be used as a model for investigating the molecular mechanisms involved in this death process. Correlations will be sought between induction of high molecular weight DNA fragmentation (a measure of apoptosis) in CLL cells during therapy and clinical response to nucleoside analog treatment. The hypothesis that the inability of fludarabine to induce proteins required to execute apoptosis is a mechanism for drug resistance will be investigated.