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“化学障碍”，发生在含有蒽环类药物的方案之后。由于多柔比星等蒽环类药物不会进入中枢神经系统，这种治疗后遗症的机制仍不清楚。相比之下，心肌病是阿霉素治疗的一种公认的毒性。我们提出了两个范式转换假设：1)解释了蒽环类药物化疗的认知和心脏毒性；2)提出了一种治疗方法。在动物模型中，抗肿瘤坏死因子-1抗体和抗氧化剂3-GCEE可以逆转阿霉素引起的中枢神经系统和心脏损伤。在最初的临床研究中，我们观察到，与不同时接受MESNA治疗的儿童相比，同时接受MESNA(一种与3-GCEE密切相关的药物)的儿童在服用阿霉素后血浆蛋白的氧化修饰显著降低。MESNA具有细胞外作用机制，经常在联合化疗方案中使用，以预防与烷化剂异环磷酰胺和大剂量环磷酰胺相关的出血性膀胱炎，通常与蒽环类药物联合使用时不会影响癌症治疗结果。在这些患者中，被阿霉素氧化的血浆蛋白之一是APOA1。在进一步的动物研究中，我们发现Mesna取消了阿霉素诱导的血浆蛋白的氧化修饰，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，我们发现降低的APOA1抑制了脂多糖诱导的J774.4巨噬细胞系释放肿瘤坏死因子-1，而氧化的载脂蛋白1激活了内毒素诱导的J774.4细胞释放的肿瘤坏死因子-1。因此，我们假设MESNA将阻止阿霉素诱导的血浆蛋白的氧化修饰，包括APOA1，从而防止肿瘤坏死因子-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。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)治疗的乳腺癌患者，以及计划接受CHOP或R-CHOP方案阿霉素治疗的非霍奇金淋巴瘤患者。参与者将接受一个周期的MESNA 360 mg/m2和另一个周期的生理盐水在阿霉素之前和之后3小时。主要终点将是确定含MESNA周期和含生理盐水周期在阿霉素后6小时血浆蛋白氧化和肿瘤坏死因子-1水平的差异。如果我们的初步发现在这项试点试验中得到证实，1)血浆蛋白氧化将被确立为一种新的毒性机制，2)阿霉素和MESNA之间迄今未知的药物相互作用将被建立，以及3)一项更大规模的随机试验将被证明是研究MESNA以预防阿霉素治疗的后遗症的正当理由。 公共卫生相关性：接受包括多柔比星等蒽环类药物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阿霉素对血浆蛋白质的直接氧化损伤，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Mesna可以防止阿霉素引起的血浆蛋白质氧化损伤以及随后神经和心脏损伤标志物的诱导。目的：这项临床研究将确定梅斯纳是否能预防阿霉素引起的癌症患者血浆蛋白损伤，并将确立血浆蛋白氧化作为蒽环类药物引起认知功能障碍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.