Therapeutic efficacy of aortic administration of N-acetylcysteine as a chemoprotectant against bone marrow toxicity after intracarotid administrationof alkylators, with or without glutathione depletion in a rat model

Modulation of thiol levels may alter both the efficacy and toxicity of chem otherapeutic agents. We investigated cytoenhancement, using L-buthionine-[S ,R]-sulfoximine (BSO) to reduce cellular glutathione levels prior to intrac arotid alkylator administration. We also evaluated chemoprotection against chemotherapy-induced systemic toxicity when the thiol agents N-acetylcystei ne (NAC) and sodium thiosulfate were administered into the descending aorta to limit brain delivery. BSO treatment reduced rat brain and intracerebral tumor glutathione levels by 50-65%, equivalent to the reduction in liver a nd s.c. tumor. BSO treatment significantly enhanced the toxicity of chemoth erapy with carboplatin, melphalan, and etoposide phosphate against granuloc ytes, total white cells, and platelets. Intracarotid administration of NAC resulted in high delivery to the brain, whereas infusion via the descending aorta minimized brain delivery. When NAC, with or without sodium thiosulfa te, was administered via aortic infusion prior to chemotherapy, the magnitu de of the bone marrow toxicity nadir was minimized, even with BSO-enhanced myelosuppression. Thus, BSO depleted brain and brain tumor glutathione but thereby increased chemotherapy-induced myelosuppression. Surprisingly, alth ough NAC was found to readily cross the blood-brain barrier when given into the carotid artery, aortic infusion of NAC resulted in minimal exposure to the central nervous system (CNS) vasculature because of rapid clearance. A s a result, aortic infusion of NAC to perfuse bone marrow and minimize myel osuppression and toxicity to visceral organs could be performed without int erfering with the CNS cytotoxicity of intracarotid alkylators, even after B SO depletion of CNS glutathione.