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An Animal Model to Study Toxicity of Central Nervous System Therapy for Childhood Acute Lymphoblastic Leukemia: Effects on Growth and Craniofacial Proportion¹

Department of Toxicology, Forsyth Research Institute, Boston, Massachusetts 02115 [A. S., A. E. Z., P. J. M.]; Department of Radiation Therapy, Harvard Medical School, Boston, Massachusetts 02115 [N. J. T., A. H.]; and Department of Cell Biology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655 [M. S. T.]

Many long term survivors of childhood acute lymphoblastic leukemia have short stature, as well as craniofacial and dental abnormalities, as side effects of central nervous system prophylactic therapy. An animal model is presented to assess these adverse effects on growth. Cranial irradiation (1000 cGy) with and without prednisolone (18 mg/kg i.p.) and methotrexate (2 mg/kg i.p.) was administered to 17- and 18-day-old Sprague-Dawley male and female rats. Animals were weighed 3 times/week. Final body weight and body length were measured at 150 days of age. Femur length and craniofacial dimensions were measured directly from the bones, using calipers. For all exposed groups there was a permanent suppression of weight gain with no catch-up growth or normal adolescent growth spurt. Body length was reduced for all treated groups, as were the ratios of body weight to body length and cranial length to body length. Animals subjected to cranial irradiation exhibited microcephaly, whereas those who received a combination of radiation and chemotherapy demonstrated altered craniofacial proportions in addition to microcephaly. Changes in growth patterns and skeletal proportions exhibited sexually dimorphic characteristics. The results indicate that cranial irradiation is a major factor in the growth failure in exposed rats, but chemotherapeutic agents contribute significantly to the outcome of growth and craniofacial dimensions.

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.