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

描述（由申请人提供）：癌症化疗后的认知功能障碍，或“化疗蛋白”，发生在含蒽环类药物的治疗方案后。由于蒽环类药物，如阿霉素，不进入中枢神经系统，这种衰弱的治疗后遗症背后的机制仍然不清楚。相比之下，心肌病是多柔比星治疗的公认毒性。我们提出了两个范式转移假说，1）解释蒽环类药物化疗的认知和心脏毒性，2）提出一种补救措施。在动物模型中，阿霉素诱导的CNS和心脏损伤可以用抗TNF-1抗体和抗氧化剂3-GCEE逆转。在一项初步临床研究中，我们观察到与非巧合地接受美司钠的儿童相比，巧合地接受美司钠（一种与3-GCEE密切相关的药物）的儿童在给予多柔比星后血浆蛋白的氧化修饰显著降低。美司钠具有细胞外作用机制，经常在联合化疗方案中给药，以预防与烷化剂异环磷酰胺和高剂量环磷酰胺相关的出血性膀胱炎，并且通常与蒽环类药物同时给药，而不影响癌症治疗结局。这些患者中被阿霉素氧化的血浆蛋白之一是APOA 1。在进一步的动物研究中，我们发现美司钠消除了多柔比星诱导的血浆蛋白氧化修饰，并阻止了心脏和脑组织中应激标志物的诱导，在进一步的体外研究中，我们已经表明，APOA 1减少抑制了LPS诱导的J774.4巨噬细胞系TNF- 1的释放，而氧化的APOPA 1激活了LPS诱导的J774.4细胞TNF- 1的释放。因此，我们假设美司钠将阻止阿霉素诱导的血浆蛋白（包括APOA 1）氧化修饰，从而阻止TNF-1的产生。我们将在一项盲法前瞻性临床试验中检验这一假设。合格的参与者将是计划接受标准方案A/C（多柔比星和环磷酰胺）的乳腺癌癌症患者和计划接受CHOP或R-CHOP方案中多柔比星的非霍奇金淋巴瘤患者。受试者将接受一个周期的美司钠360 mg/m2，另一个周期的生理盐水之前和3小时后多柔比星。主要终点将是测定含美司钠周期和含生理盐水周期之间多柔比星给药后6小时血浆蛋白氧化和TNF-1水平的差异。如果我们的初步研究结果在这项初步试验中得到证实，1）血浆蛋白氧化将被确定为一种新的毒性机制，2）多柔比星和美司钠之间迄今未知的药物相互作用将被确定，3）一项更大的随机试验将被证明是合理的，以研究美司钠预防多柔比星治疗的后遗症。 公共卫生相关性：接受包括蒽环类药物（如阿霉素）在内的化疗方案的癌症患者有发生认知和心脏损害的风险。我们提出了一个新的假设，即这些副作用是由于多柔比星对血浆蛋白的直接氧化损伤，我们已经在动物模型中证明了用于预防其他化疗药物的其他并发症的药物美司钠可以预防多柔比星诱导的血浆蛋白氧化损伤以及随后诱导的神经和心脏损伤标志物。目标：这项临床研究将确定美司钠是否能预防癌症患者中阿霉素诱导的血浆蛋白损伤，并将确定血浆蛋白氧化是蒽环类药物诱导的认知和心脏功能障碍的潜在机制。

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.