Trial of Mesna to Prevent Doxorubicin-induced Plasma Protein Oxidationand TNFa Release - Butterfield Scope

Page 6 Principallnvestigator/Program Director (Last, fir" "'1iddle): Moscow, Jeffrey, Arnold Program Director/Principallnvestigator (Last, First, Middle): Moscow, Jeffrey A. Abstract Cognitive dysfunction after cancer chemotherapy, or 'che~?brain', occurs after anthracyclinecontaining 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 cont~ast, cardiomyopathy is a well-established toxicity of doxorubicin therapy. We propose two paradlgmshifting 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-a antibody and with the antioxidant y-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 y-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 APOA 1. 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 APOA 1 inhibits LPS-induced TNFa release from the J774.4 macrophage cell line, while oxidized APOPA1 activates LPS-induced TNFa release from the J774.4 cells. Therefore, we hypothesize mesna will prevent doxorubicin-induced oxidative modification of plasma proteins, including APOA 1, and thus prevent TNF-a 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 NC (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-a 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. PHS 398/2590 (Rev. 11/07) Page _ Continuation Format Page Project Description