Anticancer Agent Pharmacodynamics in Acute Leukemia

急性白血病抗癌剂药效学

• 批准号: 7025718
• 负责人: MARY V RELLING
• 金额: $ 49.85万
• 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 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7025718
• 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）的最有效药物之一，也广泛用于乳腺癌、肺癌、卵巢癌和睾丸癌。 虽然ALL现在在70%-80%的患者中是可治愈的，但其治疗因治疗相关的急性髓细胞白血病（t-AML）的发展而复杂化，其中高达12%的儿童已经治愈了他们的ALL。 由于这种t-AML具有几乎一致的致死性预后，因此目前正在尝试限制对拓扑异构酶II抑制剂（例如依托泊苷和蒽环类柔红霉素和阿霉素）的暴露，但这种经验性策略的成功及其对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基因与许多伴侣基因之一的非同源重组，导致致白血病基因组融合。 在该资助的最后一个资助期内，我们已经证明依托泊苷可以直接诱导体外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，我们已经开发了用于测试拓扑异构酶II抑制导致的重组发生的模型。 我们还确定了一种临床遗传宿主因素，即低硫嘌呤甲基转移酶（TPMT）活性，使接受硫嘌呤和依托泊苷治疗的患者易于发生拓扑异构酶II受体诱导的t-AML。 随后，TPMT中的这种遗传多态性通过一个独立的ALL治疗组与t-AML相关，即使在仅暴露于拓扑异构酶II抑制剂的儿童中，包括效力较低且毒性较小的致白血病蒽环类药物。此外，我们确定TPMT的遗传性缺陷显著地使患者倾向于治疗诱导的脑肿瘤。 因此，越来越多的证据表明，硫嘌呤有助于肿瘤发生，特别是在TPMT基因缺陷的患者中。 在这个项目的继续过程中，我们将使用临床前实验室和转化临床研究的组合来（1）确定TPMT对同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）确定接受硫嘌呤和蒽环类药物治疗ALL的儿童体内非同源重组的程度是否与TPMT的状态。 我们的假设是，遗传宿主因素（如TPMT缺陷）和治疗相关因素（拓扑异构酶II抑制剂加促进药物，如硫嘌呤）的不合时宜的并发症使一部分患者处于不可接受的高风险t-AML中。 我们的长期目标是确定t-AML的宿主和治疗相关风险因素，以便我们能够设计出致白血病性更低的抗癌治疗方案，提高原发性ALL的疗效。

项目成果

Comparison of native E. coli and PEG asparaginase pharmacokinetics and pharmacodynamics in pediatric acute lymphoblastic leukemia.

• DOI: 10.1038/clpt.2009.162
• 发表时间: 2009-12
• 期刊: Clinical pharmacology and therapeutics
• 影响因子: 6.7

Etoposide causes illegitimate V(D)J recombination in human lymphoid leukemic cells

• DOI: 10.1182/blood.v88.6.2210.bloodjournal8862210
• 发表时间: 1996-09-15
• 期刊: BLOOD
• 影响因子: 20.3
• 作者: Chen, CL;Fuscoe, JC;Relling, MV
• 通讯作者: Relling, MV

A mouse model for glucocorticoid-induced osteonecrosis: effect of a steroid holiday.

• DOI: 10.1002/jor.20733
• 发表时间: 2009-02
• 期刊: JOURNAL OF ORTHOPAEDIC RESEARCH
• 影响因子: 2.8
• 作者: Yang, Lei;Boyd, Kelli;Kaste, Sue C.;Kamdem, Landry Kamdem;Rahija, Richard J.;Relling, Mary V.
• 通讯作者: Relling, Mary V.

Simultaneous quantitation of etoposide and its catechol metabolite in human plasma using high-performance liquid chromatography with electrochemical detection.

• DOI: 10.1016/s0378-4347(99)00110-3
• 发表时间: 1999-05
• 期刊: Journal of chromatography. B, Biomedical sciences and applications
• 作者: X. Cai;M. H. Woo;M. Edick;M. Relling

Genetic studies of a cluster of acute lymphoblastic leukemia cases in Churchill County, Nevada.

• DOI: 10.1289/ehp.9025
• 发表时间: 2007-01
• 期刊: Environmental health perspectives
• 影响因子: 10.4
• 作者: Steinberg KK;Relling MV;Gallagher ML;Greene CN;Rubin CS;French D;Holmes AK;Carroll WL;Koontz DA;Sampson EJ;Satten GA
• 通讯作者: Satten GA