Anticancer Agent Pharmacodynamics in Acute Leukemia

急性白血病抗癌剂药效学

• 批准号: 6862712
• 负责人: MARY V RELLING
• 金额: $ 49.6万
• 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 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6862712
• 关键词: DNA topoisomerases; acute lymphocytic leukemia; acute myelogenous leukemia; adolescence (12-20); carcinogenesis; cell line; child (0-11); daunorubicin; doxorubicin; drug adverse effect; enzyme inhibitors; etoposide; genetic polymorphism; genetic recombination; genetic susceptibility; human subject; laboratory mouse; methyltransferase; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; patient oriented research; pharmacogenetics; pharmacokinetics; purine /pyrimidine metabolism; purine /pyrimidine metabolism disorder; thiopurine

Topoisomerase II inhibitors, including etoposide and anthracyclines, are among the most effective drugs for the treatment of childhood acute lymphoblastic leukemia (ALL) and are also widely used for breast, lung, ovarian, and testicular cancers. Although ALL is now curable in 70 percent-80 percent of patients, its treatment is complicated by the development of a therapy-related acute myeloid leukemia (t-AML) in up to 12 percent of children who have been cured of their ALL. As this t- AML carries an almost uniformly fatal prognosis, attempts are now being made to limit exposure to topoisomerase II inhibitors (e.g. etoposide and the anthracyclines daunorubicin and doxorubicin), but the success of this empiric strategy and its impact on the efficacy of ALL chemotherapy and the frequency of t-AML remain unknown. T-AML is a distinct clinical and biologic entity, characterized by a unique molecular signature: nonhomologous recombination of the MLL gene with one of a number of partner genes, resulting in leukemogenic genomic fusions. During the last funding period for this grant, we have demonstrated that etoposide can directly induce site-specific nonhomologous recombination in vitro, we have documented recombinogenesis in vivo in children with ALL, and we have developed models for testing recombinogenesis that results as a consequence of topoisomerase II inhibition. We have also identified a clinical genetic host factor, low thiopurine methyltransferase (TPMT) activity, that predisposed patients treated with thiopurines and etoposide to development of topoisomerase II inhibitor-induced t- AML. Subsequently, this genetic polymorphism in TPMT has been linked to t-AML by an independent ALL treatment group, even in children whose only topoisomerase II-inhibitor exposure included the less potent and putatively less leukemogenic anthracyclines. Moreover, we determined that an inherited defect in TPMT significantly predisposes patients to therapy-induced brain tumors. Thus, evidence is mounting that thiopurines contribute to tumorigenesis, particularly in patients with a genetic defect in TPMT. In the continuation of this project, we will use a combination of pre-clinical laboratory and translational clinical studies to (1) determine the contribution of TPMT to etoposide- and anthracycline-induced nonhomologous recombination in isogenic hematopoietic cell lines and in pre-clinical murine models and (2) determine whether the degree of nonhomologous recombination in vivo in children receiving thiopurines and anthracyclines for treatment of ALL is related to their TPMT status. Our hypothesis is that the inopportune concurrence of genetic host factors (such as defective TPMT) and therapy related factors (topoisomerase II inhibitors plus facilitating drugs, such as thiopurines) place a subset of patients at unacceptably high risk of t-AML. Our long- term goal is to identify host- and treatment-related risk factors for t-AML so that we can design less leukemogenic anticancer treatment regimens, with improved efficacy for the primary ALL.

拓扑异构酶 II 抑制剂，包括依托泊苷和蒽环类药物，是治疗儿童急性淋巴细胞白血病 (ALL) 最有效的药物之一，也广泛用于乳腺癌、肺癌、卵巢癌和睾丸癌。 尽管目前 70%-80% 的 ALL 患者可以治愈，但由于 ALL 已治愈的儿童中高达 12% 会发展为与治疗相关的急性髓性白血病 (t-AML)，因此其治疗变得复杂。 由于这种 t-AML 的预后几乎都是致命的，因此现在正在尝试限制拓扑异构酶 II 抑制剂（例如依托泊苷和蒽环类药物柔红霉素和阿霉素）的暴露，但这种经验性策略是否成功及其对 ALL 化疗疗效和 t-AML 频率的影响仍然未知。 T-AML 是一种独特的临床和生物学实体，其特征在于独特的分子特征：MLL 基因与许多伙伴基因之一的非同源重组，导致白血病基因组融合。 在本次资助的最后一个资助期内，我们已经证明依托泊苷可以在体外直接诱导位点特异性非同源重组，我们已经记录了 ALL 儿童体内的重组发生，并且我们开发了用于测试由于拓扑异构酶 II 抑制而产生的重组发生的模型。 我们还发现了一种临床遗传宿主因素，即低硫嘌呤甲基转移酶 (TPMT) 活性，该因素使接受硫嘌呤和依托泊苷治疗的患者容易发生拓扑异构酶 II 抑制剂诱导的 t-AML。 随后，独立的 ALL 治疗组将 TPMT 的这种遗传多态性与 t-AML 联系起来，即使是在唯一接触过拓扑异构酶 II 抑制剂的儿童中，该抑制剂也包括效力较弱且可能致白血病性较低的蒽环类药物。此外，我们确定 TPMT 的遗传缺陷显着使患者容易患上治疗引起的脑肿瘤。 因此，越来越多的证据表明硫嘌呤会导致肿瘤发生，特别是对于具有 TPMT 遗传缺陷的患者。 在该项目的后续工作中，我们将结合临床前实验室和转化临床研究来（1）确定 TPMT 对等基因造血细胞系和临床前小鼠模型中依托泊苷和蒽环类药物诱导的非同源重组的贡献，以及（2）确定接受硫嘌呤治疗的儿童体内非同源重组的程度是否与 治疗 ALL 的蒽环类药物与其 TPMT 状态有关。 我们的假设是，遗传宿主因素（例如有缺陷的 TPMT）和治疗相关因素（拓扑异构酶 II 抑制剂加上促进药物，例如硫嘌呤）不合时宜地同时发生，使一部分患者处于不可接受的高 t-AML 风险中。 我们的长期目标是确定 t-AML 的宿主和治疗相关危险因素，以便我们能够设计白血病细胞较少的抗癌治疗方案，提高原发性 ALL 的疗效。