Cardiotoxicity is the non-hematologic dose limiting adverse effect of cyclophosphamide, and is a cause of morbidity and mortality in patients who receive intensive combinatorial therapy and bone marrow support. Investigators currently assume that the cardiac, pulmonary, and renal toxicity of high-dose cyclophosphamide are caused by 4- hydroxyclosphosphamide, its metabolites acrolein and phosphormide mustard, or there gluthatione conjugates, However, recent clinical an laboratory data have demonstrated saturation of ringhydroxylation but not dechloroethylation at high cyclophosphamide concentrations. Consistent with this, we have detected more chloroacetaldehyde by rat liver perfusion with 1mM cyclophosphamide, a concentration attainable in the clinic, than with equimolar ifosfamide. Chloroacetaldehyde and its metabolite monochloroacetate are cardiotoxic, which leads to the postulate that one of these products of decchloroethylation causes cyclophosphamide cardiotoxicity. We also have completed a series of laboratory studies and clinical trials which challenge the paradigm that the free-thiol mesna is irreversibly oxidized in the blood to the inert disulfide dimesna. Our data show organ-mediated reduction of dimesna that releases mesna into the venous system at the site of chloroacetaldehyde and 4-hydroxycyclophosphamide production. This leads to the postulate that a sufficient concentration of mesna may neutralize chloroacetaldehyde at the site of production and thereby prevent cardiotoxicity. Mesna also may stabilize 4-hydroxycyclophosphamide during its passage through the heart and lungs, facilitating its delivery to the site of the tumor as mafosfamide, which then exerts antitumor activity as 4- hydroxycyclophosphamide is reformed.
The specific aims of this proposal are to identify the metabolite(s) responsible for cyclophosphamide cardiotoxicity, and to determine if high-dose mesna may improve the efficacy of cyclophosphamide. To accomplish these aims, we propose a series of preclinical and in vitro studies to clarify the pharmacological interactions. To determine if high-dose mesna reduces the efficacy of cyclophosphamide, a promising, we will organize a phase I trial to assess the toxicity and efficacy of high- dose mesna with cyclophosphamide. These studies also will position us to test the effect of complex combinatorial therapies on cardiac and multi-organ toxicity.
| Goren, Marshall P; Epelman, Sidnei; Bush, Dorothy A (2004) Urine mesna excretion after intravenous and oral dosing in ifosfamide-treated children. Cancer Chemother Pharmacol 54:237-40 |
