CELLULAR PHARMACOLOGY IN CANCER CHEMOTHERAPY

本申请的目的是 建立药理学和生物化学基础，了解临床 响应和指导协议设计和评估。这 应用程序扩展了正在进行的关于药物的假设评估 作用和相互作用的人白血病细胞在治疗过程中， 在实体瘤卵巢癌中的类似研究。以识别 吉西他滨的代谢和作用之间的相关性 在II期临床试验中， 吉西他滨在人卵巢中的代谢和药效学 将研究治疗期间的癌细胞，这些 将在患者之间比较参数。虽然这方面 项目重点是核苷类似物， （氟达拉滨）或新兴（吉西他滨）抗肿瘤活性，第一个 下一代药物的临床和药效学评价 还提出了一类药物（氯法拉滨和阿拉伯糖基鸟嘌呤）。 这些研究将确定活性药物的药代动力学 这些药物在治疗过程中在白血病细胞中的核苷酸， 与抑制DNA合成相关的药效学作用， 核糖核苷酸还原酶将寻求与临床 I期和II期单药试验期间的反应。新目标 当静止时， 诱导白血病群体进行DNA修复。这一战略 将在慢性淋巴细胞白血病（CLL）细胞中进行， 接受氟达拉滨和环磷酰胺治疗的患者。的 链间DNA交联形成和去除的动力学 环磷酰胺治疗期间的循环白血病淋巴细胞 将被确定，以及先前氟达拉滨输注对 将对这些过程进行研究。提取物的固有能力， CLL细胞修复4-氢过氧环磷酰胺诱导的加合物， 将在患者中比较体外质粒DNA以寻求相关性 这些参数与环磷酰胺的临床反应之间的关系/ 氟达拉滨治疗。最后，因为所有这些代理人诱导 CLL淋巴细胞通过启动细胞凋亡死亡，这种疾病将是 用作研究参与的分子机制的模型， 这个死亡过程。相关性将寻求之间的感应 CLL中的高分子量DNA片段化（细胞凋亡的量度） 治疗期间的细胞和对核苷类似物的临床应答 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治疗的一种机制， 阻力将被调查。

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.