P450 METABOLISM OF EPIPODOPHYLLOTOXINS IN CHILDREN

P450 儿童表鬼臼毒素的代谢

• 批准号: 2007797
• 负责人: MARY V RELLING
• 金额: $ 24.61万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2007797
• 关键词: acute lymphocytic leukemia; acute myelogenous leukemia; adolescence (12-20); antineoplastics; cancer risk; catechols; child (0-11); clinical research; cytochrome P450; drug adverse effect; drug carcinogenesis; drug metabolism; etoposide; gene mutation; human genetic material tag; human subject; hypoxanthine phosphoribosyltransferase; methylation; neoplasm /cancer chemotherapy; pediatric neoplasm /cancer; pediatric pharmacology; pharmacogenetics; pharmacokinetics; podophyllin; recombinase

The epipodophyllotoxins, teniposide and etoposide, are among the most effective drugs for the treatment of childhood acute lymphoblastic leukemia (ALL) and other cancers. Although ALL is curable in 70% of patients, therapy is complicated by the development of a secondary acute myeloid leukemia (AML) in up to 12% of children who have been cured of their primary ALL. Currently, it is not possible to identify those patients at highest risk for this fatal secondary AML. Epipodophyllotoxin- induced AML is a distinct clinical and biologic entity, characterized by a unique mechanism: illegitimate site-specific recombination of the MLL (mixed lineage leukemia) gene on chromosome 11 (region q23) with one of a number of partner genes, resulting in the leukemic phenotype and accompanied by translocations of 11q23. The distinctive molecular signature of illegitimately acting V(D)J recombinase has been found at the translocation breakpoints, indicating an ill-fated cellular attempt at inappropriate DNA recombination secondary to the epipodophyllotoxins' inhibition of normal recombination. There have been no prior attempts to determine whether epipodophyllotoxins or their metabolites induce site- specific illegitimate V(D)J-recombination, either in vivo or in vitro. We will define the quantitative relationship between epipodophyllotoxins or their metabolites and illegitimate recombination. We demonstrated that cytochrome P450 3A4 (CYP3A4) O-demethylates teniposide and etoposide in human liver. O-demethylation is important not only because it may represent a major route of elimination, but also because it indicates oxidative activation to reactive catechols. We have demonstrated 10-fold interpatient variability in the systemic clearance of the epipodophyllotoxins and in the formation of catechol metabolites in children. Our hypotheses are that this interpatient variability in CYP3A4- mediated O-demethylation accounts for variability in the overall disposition of epipodophyllotoxins, and that high systemic exposure to etoposide, its catechol, or both is the principal determinant of the mutagenic recombination caused by the epipodophyllotoxins. We will use in vivo pharmacokinetic studies in children with ALL to determine whether O- demethylation determines the clearance of the epipodophyllotoxins. We will evaluate whether high systemic exposure to etoposide, its catechol, or both are significantly related to the frequency of illegitimate V(D)J recombinase-mediated mutations in serial samples of children's leukocyte HPRT DNA, a specific marker of the biologically relevant mechanism of leukemogenesis in vivo. We have also developed in vitro model systems to determine whether illegitimate recombinase activity in specific cell lines is related to epipodophyllotoxin parent drug or metabolite concentrations and/or to the duration of exposure. Together, these laboratory and clinical studies will elucidate the contribution of pharmacokinetic and metabolic variability as determinants of the disposition and leukemogenic effects of the epipodophyllotoxins in children with cancer.

附生噬蛋白，teniposide和依托泊苷是最多的 治疗儿童急性淋巴细胞的有效药物 白血病（所有）和其他癌症。虽然一切都可以在70％ 患者，次要急性的发展使治疗变得复杂 多达12％的儿童已治愈的髓样白血病（AML） 他们的主要全部。目前，无法识别 这种致命的继发性AML风险最高的患者。表现生蛋白毒素 - 诱导的AML是一个独特的临床和生物学实体，其特征是 独特的机制：MLL的非法现场特定重组 （混合谱系白血病）基因11（区域Q23）与A之一 伴侣基因的数量，导致白血病表型和 伴随着11q23的易位。独特的分子 在 易位断点，表明命运不佳的细胞尝试 不适当的DNA重组继发于附生噬蛋白的继发于 抑制正常重组。 没有事先尝试 确定附生章毒素或其代谢物是否诱导位点 - 特定的非法V（d）J-结构化，无论是体内还是体外。我们 将定义附生植物毒素或 他们的代谢产物和非法重组。我们证明了这一点 细胞色素P450 3A4（CYP3A4）O-二甲基二酰胺和依托泊苷 人肝。 o-二甲基化不仅重要，因为它可能 代表了一条主要的淘汰途径，但也是因为它指示 反应性儿茶酚的氧化激活。我们已经证明了10倍 在全身清除率的室内变异性 表现噬毒素和在儿茶酚代谢物中的形成中 孩子们。我们的假设是CYP3A4-的这种室内变异性 介导的O-双甲基化解释了整体的可变性 epodophophlolotoxins的处置，以及高度的全身性暴露 依托泊苷，其儿茶酚或两者都是主要决定因素 诱变重组是由附生噬蛋白引起的。我们将使用 对患有所有人的儿童的体内药代动力学研究，以确定o-是否是否 脱甲基化确定了附生噬蛋白的清除。我们将 评估高度全身暴露于依托泊苷，其儿茶酚还是 两者都与非法V（d）J的频率显着相关 儿童白细胞系列样品中的重组酶介导的突变 HPRT DNA，是生物学相关机制的特定标记 体内的白血病发生。我们还开发了体外模型系统 确定是否在特定细胞系中是否非法重组酶活性 与附生噬蛋白毒素母体或代谢产物浓度有关 和/或暴露持续时间。这些实验室和 临床研究将阐明药代动力学和 代谢变异性作为处置和白血病的决定因素 附生噬蛋白在癌症儿童中的作用。