ABSTRACT. CNS therapy for childhood leukemia has adverse effects upon growth and cognition. The cause of these deficits is unknown. In a rat model, we determined which agent, or combination of agents, in CNS therapy affected growth. Young Sprague-Dawley rats were exposed to cranial irradiation (1000 cGy), methotrexate (2 or 4 mg[ kg, intraperitoneally), or prednisolone (18 or 36 mg[kg, intraperitoneally) alone or in two-or three-agent combinations. Matched control groups received appropriate sham radiation, intraperitoneal saline, or both. Body weight was recorded from 14 through 150 d of age. After the rats were killed at 150 d, body length was recorded and the head and left femur were removed to determine body and craniofacial proportions. Cranial irradiation alone, but not methotrexate or prednisolone alone, stunted growth permanently and altered craniofacial proportions. When these agents were combined, methotrexate and prednisolone modified the growth response to cranial irradiation. Methotrexate given before cranial irradiation prevented radiation stunting in males. This protection was lost when the dose of methotrexate was increased, when prednisolone was added to the combination, or when females were studied. The protection in males was effective against both growth and behavioral deficits. These results indicate that the physical and behavioral side effects of CNS therapy are better understood in the context of dose, sex, and interactions ofthe agents. (Pediatr Res 35: 416-423,1994) The cause of these adverse effects has been reported to be cranial irradiation alone (9-11), or cranial irradiation interacting with chemotherapy ( I, 4, 12).Cranial irradiation or methotrexate has been manipulated in CNS therapy in an attempt to prevent neurotoxic interactions (13-15). Yet, the impact of these manipulations is uncertain, considering that some cranial irradiation and methotrexate interactions may be protective rather than neurotoxic. Balsom et al. (16) found that preirradiation methotrexate protected against decreased intellectual function in ALL survivors, illustrating the importance of agent interactions and sequence of administration to long-term outcome.We developed an animal model to study growth and behavioral deficits associated with exposures to cranial irradiation, methotrexate, and prednisolone, either as single agents or as combinations (17,18). Cranial irradiation alone stunted growth without significantly altering behavior, whereas cranial irradiation combined with methotrexate and prednisolone disrupted behavior in addition to stunting growth. Further study of behavior (19) demonstrated how different agent interactions affected outcome: 1) behavioral "signatures" varied with the components of the agent combinations; 2) behavioral outcome was influenced by steroids as welI as by cranial irradiation and methotrexate; 3) behavioral outcome was sex dependent; and 4) behavioral outcome varied with dose, which determined whether agents interacted antagonistically or synergisticalIy. Therefore, not...
