CELLULAR PHARMACOLOGY IN CANCER CHEMOTHERAPY

目标是利用对代谢和作用的理解， 抗肿瘤药物在癌细胞化疗过程中的优化设计 治疗方案的个体和特定血液学 疾病 在反应之间建立了强相关性， 难治性急性白血病患者接受大剂量阿糖胞苷治疗， 活性代谢物araCTP在白血病细胞中的药代动力学 在治疗期间。 这些观察结果得到了前瞻性的证实， 设计治疗方案，利用细胞药理学， araCTP a）指导araC和B）间歇给药之间的间隔 指示连续输注期间araC给药速率 方案. 本申请建议在几个方面扩展这些研究 方向 首先，将评估araCTP的细胞药理学 关于其他恶性血液病对高剂量 araC来确定这些发现的范围。 第二，细胞 F-araAMP的代谢和作用与araC有许多相似之处。 因此，活性代谢物F-araATP的细胞药理学将 在II期试验期间评价临床反应。 第三，高剂量阿糖胞苷治疗将与米托蒽醌和 顺铂，以寻求更高的反应率。 这提供了机会， 确定araCTP的细胞药理学是否继续提供 联合化疗期间的独立预后信息，以及 研究这些药物是否影响araCTP代谢。 四、DNA损伤 在用米托蒽醌或用 顺铂将通过碱性洗脱程序定量， 荧光检测 这种药物证据的预后价值 将对行动进行评估。 最后，在这些研究中获得的知识 抗白血病药物在肿瘤细胞中代谢和作用 治疗将用于设计新的治疗方案。

The goal is to utilize an understanding of the metabolism and action of antitumor drugs in cancer cells during chemotherapy to optimize the design of treatment regimens for individuals and for specific hematologic diseases. Strong correlations have been established between the response of patients with refractory acute leukemia to high-dose araC therapy and the pharmacokinetics of the active metabolite araCTP in leukemic cells during treatment. These observations were confirmed prospectively and used to design treatment protocols that utilize the cellular pharmacology of araCTP a) to direct the intervals between intermittent doses of araC and b) to indicate the rate of araC administration during a continuous infusion regimen. This application proposes to extend these studies in several directions. First, the cellular pharmacology of araCTP will be evaluated with respect to the response of other hematologic malignancies to high-dose araC to determine the scope of these findings. Second, the cellular metabolism and action of F-araAMP shares many similarities with araC. Therefore, the cellular pharmacology of the active metabolite F-araATP will be evaluated with respect to clinical response during Phase II trials. Third, high-dose araC treatment will be combined with mitoxantrone and with cisplatin to seek higher response rates. This provides the opportunity to determine whether the cellular pharmacology of araCTP continues to provide independent prognostic information during combination chemotherapy, and to investigate if these drugs affect araCTP metabolism. Fourth, DNA damage induced in leukemic cells during therapy with mitoxantrone or with cisplatin will be quantitated by alkaline elution procedures coupled with fluorescence detection. The prognostic value of this evidence of drug action will be evaluated. Finally, knowledge gained in these studies of the metabolism and action of antileukemic drugs in tumor cell during therapy will be used to design new treatment protocols.