A Methionine-free Diet Associated with Nitrosourea Treatment Down-regulates Methylguanine-DNA Methyl Transferase Activity in Patients with Metastatic Cancer

Abstract

Background: Methionine (MET) depletion used in association with chemotherapy improves the therapeutic index in animal models. This potentiating effect may be due to tumor cell sensitization to chloroethylnitrosoureas through their MET dependency and the down-regulation of O⁶-methylguanine-DNA methyltransferase (MGMT). Our purpose was to evaluate the impact of the association of a dietary MET restriction with nitrosourea treatment on MGMT activity in peripheral blood mononuclear cells (PBMCs). Patients and Methods: Six patients with metastatic cancer (melanoma and glioma) received 4 cycles of a MET-free diet with cystemustine (60 mg/m²). Results: MGMT activity in PBMCs decreased by an average of 13% from 553±90 fmol/mg before the diet to 413±59 fmol/mg after the diet + chemotherapy period (p=0.029). The decrease of MGMT activity was not affected by the duration of the MET-free diet period but seems to be correlated to the plasma MET depletion induced by the MET-free diet.