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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Bone Marrow Chemoprotection without Compromise of Chemotherapy Efficacy in a Rat Brain Tumor Model

Departments of Neurology (E.A.N., L.L.M.) and Neurosurgery (E.A.N.), Division of Medical Informatics and Clinical Epidemiology (D.F.K.), and Department of Cell and Developmental Biology (L.L.M.), Oregon Health Sciences University, Portland, Oregon; Veterans Affairs Medical Center (E.A.N., M.A.P.), Portland, Oregon; and Departments of Physiology and Biophysics and Medicine (D.R.P.), Chicago Medical School, North Chicago, Illinois

Thiol chemoprotective agents can reduce chemotherapy side effects, but clinical use is limited due to concerns of impaired chemotherapeutic efficacy. We evaluated whether an optimized bone marrow chemoprotection regimen impaired the efficacy of enhanced chemotherapy against rat brain tumors. Nude rats with intracerebral human lung carcinoma xenografts were treated with carboplatin, melphalan, and etoposide phosphate delivered intra-arterially with osmotic blood-brain barrier disruption (n = 8/group). Thiol chemoprotection was N-acetyl-L-cysteine (1000 mg/kg) 60 min before chemotherapy and/or sodium thiosulfate (8 g/m²) 4 and 8 h after chemotherapy, when the blood-brain barrier is reestablished. Blood counts were obtained before treatment on day 3 and at sacrifice on day 9. N-acetylcysteine serum clearance half-life was 9 to 11 min. Pretreatment with N-acetylcysteine combined with delayed administration of sodium thiosulfate protected against toxicity toward total white cells, granulocytes, and platelets (P = 0.0016). Enhanced chemotherapy reduced intracerebral tumor volume to 4.3 ± 1.0 mm³ compared with 29.1 ± 4.1 mm³ in untreated animals (P < 0.0001). Tumor volume was 3.7 ± 0.6 mm³ in rats that received N-acetylcysteine before and sodium thiosulfate after chemotherapy. The data indicate the efficacy of enhanced chemotherapy for rat brain tumors was not affected by thiol chemoprotection that provided excellent protection for hematological toxicity. Negative interactions of thiols with antitumor efficacy were avoided by temporal and spatial separation of chemoprotectants and chemotherapy.

Address correspondence to: Dr. Edward A. Neuwelt, Oregon Health and Sciences University, L603, 3181 SW Sam Jackson Park Rd., Portland OR 97239. E-mail: neuwelte{at}ohsu.edu

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