INTERACTIONS OF STEROID, METHOTREXATE, AND RADIATION DETERMINE NEUROTOXICITY IN AN ANIMAL-MODEL TO STUDY THERAPY FOR CHILDHOOD LEUKEMIA

Children with leukemia receive CNS therapy to improve long-term surviv al. Neurotoxic effects, such as cognitive impairment, have been associ ated with this therapy. A rat model was developed to determine which a gent, or combination of agents, in CNS therapy causes neurotoxicity. T he agents examined were cranial irradiation (1000 cGy), methotrexate ( 2 or 4 mg/kg, intraperitoneally), and prednisolone (18 or 36 mg/kg, in traperitoneally). Young Sprague-Dawley rats were exposed to each agent alone or to two- or three-agent combinations. Each therapy had matche d controls that received sham radiation and/or intraperitoneal saline. Subsequent to exposure, spontaneous behavior was tested using a compu ter pattern recognition system, which recorded and classified behavior in a novel environment. Behavioral initiations, total times, and time structures were compared in therapy and control groups. Combined rath er than single-agent therapies had more behavioral effects, and these were dose- and sex-dependent. Synergistic interactions between agents caused behavioral deficits, and components of the combination determin ed the abnormality. Some combinations interacted antagonistically, and thus mitigated behavioral deficits. Prednisolone was clearly pivotal to behavioral outcome. A low prednisolone dose antagonized methotrexat e preventing deficits, whereas a higher prednisolone dose altered beha vior by enhancing effects of methotrexate and radiation. These finding s emphasize that steroids are important in agent interactions. Their r ole in morbidity associated with leukemia treatment protocols may be e qually important as that of methotrexate and cranial irradiation.