title: Therapeutic efficacy of aortic administration of N-acetylcysteine as a chemoprotectant against bone marrow toxicity after intracarotid administration of alkylators, with or without glutathione depletion in a rat model.
abstract: Modulation of thiol levels may alter both the efficacy and toxicity of chemotherapeutic agents. We investigated cytoenhancement, using L-buthionine-[S,R]-sulfoximine (BSO) to reduce cellular glutathione levels prior to intracarotid alkylator administration. We also evaluated chemoprotection against chemotherapy-induced systemic toxicity when the thiol agents N-acetylcysteine (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 and s.c. tumor. BSO treatment significantly enhanced the toxicity of chemotherapy with carboplatin, melphalan, and etoposide phosphate against granulocytes, 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 thiosulfate, was administered via aortic infusion prior to chemotherapy, the magnitude 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, although 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. As a result, aortic infusion of NAC to perfuse bone marrow and minimize myelosuppression and toxicity to visceral organs could be performed without interfering with the CNS cytotoxicity of intracarotid alkylators, even after BSO depletion of CNS glutathione.
authors.affiliation: Department of Neurology, Oregon Health Sciences University, Portland, Oregon 97201, USA. neuwelte@ohsu.edu
authors.forename: E A
authors.initials: EA
authors.lastname: Neuwelt
authors.forename: M A
authors.initials: MA
authors.lastname: Pagel
authors.forename: B P
authors.initials: BP
authors.lastname: Hasler
authors.forename: T G
authors.initials: TG
authors.lastname: Deloughery
authors.forename: L L
authors.initials: LL
authors.lastname: Muldoon
mesh_terms: D000111:Acetylcysteine / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects*; D001013:Aorta, Thoracic; D001812:Blood-Brain Barrier; D001855:Bone Marrow Diseases / Q000139:chemically induced / Q000517:prevention & control*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005978:Glutathione / Q000172:deficiency* / Q000378:metabolism; D007261:Infusions, Intra-Arterial; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000963:Antimetabolites; D018906:Antineoplastic Agents, Alkylating; D019328:Buthionine Sulfoximine; D005978:Glutathione; D000111:Acetylcysteine