The survival of children afflicted with acute lymphoblastic leukemia (ALL) is prolonged when central nervous system (CNS) prophylactic therapy is administered to prevent relapse of the disease. This essential therapy, however, has adverse consequences such as retarded growth and impaired mental ability. Clinical investigations are testing different treatment regimens with the hope of reducing toxicity without altering efficacy. However, clinical protocols cannot be manipulated to answer questions of toxicity because CNS treatment is crucial to survival. To the limited extent they can be manipulated, it takes many years to realize the outcome associated with any one protocol. This project provides a valid animal model which can hasten this process and focus on toxicity concerns. Making use of the short life span of the rat, young male and female animals are exposed to various CNS prophylactic treatments involving cranial irradiation, methotrexate, and prednisolone. The relative neurotoxicity of these agents alone or in combination will be distinguished. The impact of dose, sequence of administration and age at exposure also will be analyzed. Behavioral toxicity is detected in the rat using a computer pattern recognition system which identifies individual acts and quantifies their initiations, total time and temporal structure. Effects on growth are detected by measures of body weight, body proportions and craniofacial dimensions. The brains are serially sectioned and stained to visualize neuropathology associated with growth and behavioral changes. Preliminary studies have verified that indeed behavior and growth are permanently disrupted by combined therapy consisting of 1000 cGy radiation, 2 mg/kg methotrexate and 18 mg/kg prednisolone. Radiation alone has minimal behavioral consequences although it severely affects growth. These doses extrapolate to levels within the range used clinically, and more importantly, the overall pattern of neurotoxicity in this animal model mimics the consequences found in children treated for ALL. Consequently, this animal model can provide important information on how CNS prophylactic therapies can be manipulated to reduce neurotoxicity.
| Schunior, A; Mullenix, P J; Zengel, A E et al. (1994) Radiation effects on growth are altered in rats by prednisone and methotrexate. Pediatr Res 35:416-23 |
| Mullenix, P J; Kernan, W J; Schunior, A et al. (1994) Interactions of steroid, methotrexate, and radiation determine neurotoxicity in an animal model to study therapy for childhood leukemia. Pediatr Res 35:171-8 |
