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.
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.
|Hayslip, John; Dressler, Emily V; Weiss, Heidi et al. (2015) Plasma TNF-Î± and Soluble TNF Receptor Levels after Doxorubicin with or without Co-Administration of Mesna-A Randomized, Cross-Over Clinical Study. PLoS One 10:e0124988|