CELLULAR PHARMACOLOGY IN CANCER CHEMOTHERAPY

描述（改编自申请人的摘要）：本研究的目标 应用是建立药理学和生物化学基础， 了解人类白血病的临床反应并指导方案 设计 该项目集中于核苷类似物， （ara-C）或新发现的活性（氟达拉滨，2-氯脱氧腺苷） 和一种其活性正在研究中（二氟脱氧胞苷）。 的 生长因子（GM-CFS）与化疗的合理组合需要 了解其对药效学和药代动力学的影响 在人类白血病细胞治疗过程中的核苷酸类似物。 的 以下方法可作为重点。 1. 生化调节。 一 临床试验的目的是检验假设， 氟达拉滨和阿糖胞苷的特定输注方案将增加阿糖胞苷 慢性淋巴细胞白血病细胞中的5 '-三磷酸积累。 这些 研究将采用体外研究模型，以确定 氟达拉滨5 '-三磷酸和脱氧核苷三磷酸（dNTP）在 调节脱氧胞苷激酶。 2. 生物调制。 的作用 GM-CSF对阿糖胞苷5 '-三磷酸盐的药代动力学和药效学的影响 在慢性粒细胞性白血病中进行阿糖胞苷输注后进行研究 (CML)在GM-CSF处理三天之前和之后连续地观察胚细胞。 将平行离体评价集落形成性， 意义 3.反应的药理学决定因素。 相关性 在临床反应与临床指导阶段之间寻求 二氟脱氧胞苷治疗复发性急性白血病和慢性粒细胞白血病原始细胞的临床研究 危象和该药物在白血病细胞中的代谢和作用 治疗和治疗后离体。 4. 程序化细胞的机制 死亡 氟达拉滨和2-氯脱氧腺苷对人肝癌细胞的作用 将在体外和治疗期间研究淋巴细胞白血病。 这些研究将集中在已知的DNA损伤机制， 程序性细胞死亡：ATP、dNTP和NAD+池、ADP降低 核糖基化和DNA片段化。

DESCRIPTION (Adapted from the applicant's abstract): The goal of this application is to establish pharmacologic and biochemical bases for understanding clinical response of human leukemia and for guiding protocol design. The project concentrates on nucleoside analogues that have proven (ara-C) or newly discovered activity (fludarabine, 2-chlorodeoxyadenosine) and one whose activity is under investigation (difluorodeoxycytidine). The rational combination of growth factors (GM-CFS) with chemotherapy requires knowledge of their influence on the pharmacodynamics and pharmacokinetics of nucleotide analogues in human leukemia cells during therapy. The following approaches serve as focal points. 1. Biochemical modulation. A clinical trial has been designed to test the hypothesis that the schedule-specific infusion of fludarabine and ara-C will augment ara-C 5'-triphosphate accumulation in chronic lymphocytic leukemia cells. These investigations will be modeled with in vitro studies to determine the role of fludarabine 5'-triphosphate and dexoynucleoside triphosphates (dNTP) in modulating deoxycytidine kinase. 2. Biological modulation. The action of GM-CSF on ara-C 5'-triphosphate pharmacokinetics and pharmacodynamics will be investigated following ara-C infusions in chronic myelogenous leukemia (CML) blasts serially before and after three days of GM-CSF treatment. Colonogenicity will be evaluated ex vivo in parallel for prognostic significance. 3.Pharmacologic determinants of response. Correlations are being sought between clinical response to a pharmacologically guided phase I trial of difluorodeoxycytidine in relapsed acute leukemia and CML blast crisis and the metabolism and action of this drug in leukemia cells during therapy and ex vivo after treatment. 4. Mechanisms of programmed cell death. The action of fludarabine and 2-chlorodeoxyadenosine on cells of lymphocytic leukemia will be investigated in vitro and during therapy. These studies will focus on DNA damaging mechanisms known to be active in programmed cell death: lowered ATP, dNTP, and NAD+ pools, ADP ribosylation, and DNA fragmentation.