Fosfomycin increases chromosome instability in lymphocytes from Fanconi Anemia patients

Abstract

Fanconi Anemia (FA) is a chromosome instability (CI) syndrome, clinically characterized by progressive bone marrow failure and increased cancer predisposition. Lymphocytes from FA patients have hypersensitivity to alkylating agents, particularly to diepoxybutane (DEB). The antibiotic fosfomycin (FOM) is an alkylating agent. FOM is used as a large spectrum antibiotic and also as a prophylactic pre-surgery agent. FOM has been considered non-genotoxic. However, no specific genotoxic evaluation directed to patients with hypersensitivity to alkylating agents was performed. As FA patients are very susceptible to infections and may be submitted to several surgeries, FOM can eventually be prescribed to them during their lifetime. In the present study we evaluated the putative genotoxic effect of FOM in cultured lymphocytes from FA patients, compared to cultured lymphocytes from healthy donors (HD). Cultures from FA patients and HD were treated with 0.5mM FOM or with 0.6mM DEB and CI was evaluated. Results showed that FOM significantly increases CI in cultured lymphocytes from FA patients, compared to lymphocytes from HD, in which no effect was found. Additionally, a direct correlation between DEB and FOM toxicity was observed in lymphocytes from FA patients, indicating similar susceptibility to both agents.