Obesity effects on cyclophosphamide-induced DNA damage in hematopoietic cell transplant recipients

Background: Cyclophosphamide, an alkylating agent, is metabolically activated to phosphoramide mustard, to form toxic DNA-DNA (G-NOR-G) crosslinks. Increased exposure to cyclophosphamide metabolites has been associated with treatment-related toxicity. The effect of obesity on exposure to cyclophosphamide-induced G-NORG crosslinks is not known. Therefore we sought to determine whether obesity affects the formation of cyclophosphamide-specific G-NOR-G crosslinks. Patients and Methods: Plasma cyclophosphamide concentrations and blood cell G-NOR-G amounts were measured. Results: Overweight/obese patients received a significantly higher daily cyclophosphamide dose (median 3000 vs. 4450 mg, p<0.01). Despite the higher doses, overweight/obese patients had lower exposure to cyclophosphamide compared to lean patients with an area under the curve (AUC_0-∞) =529.24 vs. 867.99 μcg/ml*h respectively, p<0.01. G-NOR-G amounts were similar in overweight/obese and lean subjects, AUC_0-∞=142.8 vs. 147.0 adducts/10⁶ nucleotides*h, respectively, p=0.59. Conclusion: Overweight/obese patients have altered metabolism and disposition of cyclophosphamide. This altered exposure may be an important determinant of efficacy and may play a role in treatment-related mortality.