Trial of mesna to prevent doxorubicin-induced plasma protein oxidation and TNFa r

美司钠预防阿霉素诱导的血浆蛋白氧化和 TNFα 的试验

• 批准号: 8254452
• 负责人: John Hayslip
• 金额: $ 18.8万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8254452
• 关键词: Adverse effects; Affect; Alkylating Agents; Animal Model; Animals; Anthracyclines; Antibodies; Antineoplastic Agents; Antioxidants; Back; Blinded; Blood; Blood - brain barrier anatomy; Brain Injuries; Cancer Patient; Cardiac; Cardiomyopathies; Cardiotoxicity; Cell Line; Cells; Chemotherapy-Oncologic Procedure; Child; Clinic; Clinical Research; Clinical Trials; Cognitive; Cyclophosphamide; Cystitis; Dose; Doxorubicin; Drug Interactions; Effectiveness; Functional disorder; Goals; Heart; Hematopoietic; Hour; Ifosfamide; Impaired cognition; Impairment; In Vitro; Injury; Intravenous; Mediating; Mesna; Modeling; Modification; Moscow; Mus; Myopathy; Neuraxis; Neurologic; Non-Hodgkin' s Lymphoma; Participant; Patient Schedules; Patients; Pharmaceutical Preparations; Plasma Proteins; Principal Investigator; Production; Proteins; Proteomics; Reactive Oxygen Species; Regimen; Risk; Saline; Schedule; Series; Stress; Syndrome; TNF gene; Testing; Tissues; Toxic effect; Treatment Protocols; brain tissue; cancer therapy; chemobrain; chemotherapy; eligible participant; extracellular; macrophage; malignant breast neoplasm; novel; oxidation; oxidative damage; pilot trial; prevent; programs; prospective; public health relevance; randomized trial; therapy outcome

DESCRIPTION (provided by applicant): Cognitive dysfunction after cancer chemotherapy, or 'chemobrain', occurs after anthracycline- containing regimens. Since anthracyclines, such as doxorubicin, do not enter the central nervous system, the mechanism behind this debilitating sequela of therapy has remained obscure. In contrast, cardiomyopathy is a well-established toxicity of doxorubicin therapy. We propose two paradigm- shifting hypotheses to 1) explain the cognitive and cardiac toxicities of anthracycline chemotherapy, and 2) to propose a remedy. In animal models, doxorubicin-induced CNS and cardiac damage can be reversed with anti-TNF-1 antibody and with the antioxidant 3-GCEE. In an initial clinical study, we observed a significant decrease in oxidative modification of plasma proteins after doxorubicin administration in children who were coincidentally receiving mesna, a drug closely related to 3-GCEE, compared to children who were not coincidentally receiving mesna. Mesna has an extracellular mechanism of action, and is frequently given in combination chemotherapy regimens to prevent hemorrhagic cystitis associated with the alkylating agents ifosfamide and high-dose cyclophosphamide, and is commonly coincidentally co-administered with anthracyclines without affecting cancer therapy outcomes. One of the plasma proteins oxidized by doxorubicin in these patients was APOA1. In further animal studies, we found that mesna abrogates doxorubicin-induced oxidative modification of plasma proteins and prevents induction of stress markers in heart and brain tissues, and in further in vitro studies we have shown that reduced APOA1 inhibits LPS-induced TNF- 1 release from the J774.4 macrophage cell line, while oxidized APOPA1 activates LPS-induced TNF- 1 release from the J774.4 cells. Therefore, we hypothesize mesna will prevent doxorubicin-induced oxidative modification of plasma proteins, including APOA1, and thus prevent TNF-1 production. We will test this hypothesis in a blinded prospective clinical trial. Eligible participants will be cancer patients with breast cancer scheduled to receive the standard regimen A/C (doxorubicin and cyclophosphamide) and non-Hodgkin lymphoma patients scheduled to receive doxorubicin in CHOP or R-CHOP regimens. Participants will receive one cycle with mesna 360 mg/m2 and another cycle with saline prior to and 3 hours after doxorubicin. The primary endpoint will be determination of difference in oxidation of plasma proteins and TNF-1 levels at 6 hours post doxorubicin between the mesna-containing cycles and the saline-containing cycles. If our initial findings are confirmed in this pilot trial, 1) plasma protein oxidation will be established as a novel mechanism of toxicity, 2) a hitherto unknown drug interaction between doxorubicin and mesna will be established, and 3) a larger randomized trial would be justified to study mesna to prevent the sequelae of doxorubicin therapy. PUBLIC HEALTH RELEVANCE: Cancer patients receiving chemotherapy regimens that include the anthracycline drugs such as doxorubicin are at risk for developing cognitive and cardiac impairment. We propose a novel hypothesis that these side effects are due to direct oxidative damage of plasma proteins by doxorubicin, and we have demonstrated in an animal model that the drug mesna, which is used to prevent other complications of other chemotherapy drugs, prevents doxorubicin-induced plasma protein oxidative damage and the subsequent induction of markers of neurologic and cardiac injury. Goal: This clinical study will determine whether mesna prevents doxorubicin-induced damage of plasma proteins in cancer patients, and will establish plasma protein oxidation as a potential mechanism of anthracycline-induced cognitive and cardiac dysfunction.

描述（由申请人提供）：癌症化疗后的认知功能障碍，或“化学邻胺”，在含有邻苯二烯的方案后发生。由于诸如阿霉素之类的蒽环类药物不会进入中枢神经系统，因此这种令人衰弱的治疗续集背后的机制仍然晦涩难懂。相比之下，心肌病是阿霉素治疗的公认毒性。我们提出两个范式转移假设为1）解释蒽环类化疗的认知和心脏毒性，以及2）提出一种补救措施。在动物模型中，阿霉素诱导的中枢神经系统和心脏损伤可以用抗TNF-1抗体和抗氧化剂3-gcee逆转。在一项最初的临床研究中，我们观察到阿霉素给药后血浆蛋白的氧化修饰显着降低，而与没有偶然接受梅斯纳的儿童相比，与未接受梅斯纳的儿童相比，偶然接受梅斯纳的儿童（一种与3类粘液密切相关的药物）。 MESNA具有细胞外的作用机制，并且经常在组合化疗方案中给出，以防止与烷基化剂Ifosfamide和高剂量的环磷酰胺相关的出血性膀胱炎，并且通常是与无影响癌症治疗的拟人疗法相关的。在这些患者中用阿霉素氧化的血浆蛋白之一是apoA1。 In further animal studies, we found that mesna abrogates doxorubicin-induced oxidative modification of plasma proteins and prevents induction of stress markers in heart and brain tissues, and in further in vitro studies we have shown that reduced APOA1 inhibits LPS-induced TNF- 1 release from the J774.4 macrophage cell line, while oxidized APOPA1 activates LPS-induced TNF- 1 release from J774.4细胞。因此，我们假设MESNA将防止阿霉素诱导的血浆蛋白（包括APOA1）的氧化修饰，从而防止TNF-1产生。我们将在一项盲目的前瞻性临床试验中检验这一假设。符合条件的参与者将是计划接受标准方案A/C（阿霉素和环磷酰胺）的乳腺癌患者和计划在CHOP或R-CHOP方案中接受阿霉素的非霍奇金淋巴瘤患者。参与者将获得一个周期360 mg/m2的周期，而在阿霉素后3小时和3小时后，参与者将获得一个周期。主要终点是在阿霉素循环和含盐水的循环之间6小时后6小时确定血浆蛋白和TNF-1水平的氧化差异。如果我们在这项试验试验中确认了我们的最初发现，则1）血浆蛋白氧化将被确定为一种新型的毒性机制，2）迄今为止，迄今为止，将建立阿霉素和mesna之间的未知药物相互作用，3）3）一项更大的随机试验将是合理的，以便研究Mesna，以预防多克蛋白毒素治疗的peqeelae。 公共卫生相关性：接受化疗方案的癌症患者，包括阿京素药物（例如阿霉素）有患认知和心脏障碍的风险。 We propose a novel hypothesis that these side effects are due to direct oxidative damage of plasma proteins by doxorubicin, and we have demonstrated in an animal model that the drug mesna, which is used to prevent other complications of other chemotherapy drugs, prevents doxorubicin-induced plasma protein oxidative damage and the subsequent induction of markers of neurologic and cardiac injury.目标：这项临床研究将确定MESNA是否可以防止阿霉素诱导的血浆蛋白在癌症患者中损伤，并将血浆蛋白氧化作为邻氨基林诱导的认知和心脏功能障碍的潜在机制。