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An Animal Model to Study Toxicity of Central Nervous System Therapy for Childhood Acute Lymphoblastic Leukemia: Effects on Behavior¹

Department of Toxicology, Forsyth Research Institute, Boston, Massachusetts 02115 [P. J. M., A. S.]; Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Iowa State University, Ames, Iowa 50011 [W. J. K.]; Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655 [M. S. T.]; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115 [D. P. W.]; and Department of Radiation Therapy, Harvard Medical School, Boston, Massachusetts 02115 [A. H., N. J. T.]

Central nervous system prophylactic therapy used in the treatment of acute lymphoblastic leukemia can reduce intelligence quotient scores and impair memory and attention in children. Cranial irradiation, intrathecal methotrexate, and steroids are commonly utilized in acute lymphoblastic leukemia therapy. How they induce neurotoxicity is unknown. This study employs an animal model to explore the induction of neurotoxicity. Male and female Sprague-Dawley rats at 17 and 18 days of age were administered 18 mg/kg prednisolone, 2 mg/kg methotrexate, and 1000 cGy cranial irradiation. Another 18-day-old group was administered 1000 cGy cranial irradiation but no drugs. Matching controls received saline and/or a sham exposure to radiation. All animals at 6 weeks and 4 months of age were tested for alterations in spontaneous behavior. A computer pattern recognition system automatically recorded and classified individual behavioral acts displayed during exploration of a novel environment. Measures of behavioral initiations, total time, and time structure were used to compare treated and control animals. A permanent sex-specific change in the time structure of behavior was induced by the prednisolone, methotrexate, and radiation treatment but not by radiation alone. Unlike hyperactivity, the effect consisted of abnormal clustering and dispersion of acts in a pattern indicative of disrupted development of sexually dimorphic behavior. This study demonstrates the feasibility of an animal model delineating the agent/agents responsible for the neurotoxicity of central nervous system prophylactic therapy.

¹ The authors are grateful to the Amoco Foundation and the Mobil Foundation for partial support of this project.

² To whom requests for reprints should be addressed, at Forsyth Research Institute, 140 Fenway, Boston, MA 02115.

Received 11/28/89. Accepted 7/19/90.