Schunior A, Mullenix P J, Zengel A E, Landy H, Howes A, Tarbell N J
Department of Toxicology, Forsyth Research Institute, Boston, Massachusetts 02115.
Pediatr Res. 1994 Apr;35(4 Pt 1):416-23.
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 of the agents.
儿童白血病的中枢神经系统治疗会对生长和认知产生不良影响。这些缺陷的原因尚不清楚。在一个大鼠模型中，我们确定了中枢神经系统治疗中的哪种药物或药物组合会影响生长。将幼年斯普拉格-道利大鼠单独或联合使用两种或三种药物，分别给予头颅照射（1000 cGy）、甲氨蝶呤（2或4 mg/kg，腹腔注射）或泼尼松龙（18或36 mg/kg，腹腔注射）。匹配的对照组接受适当的假照射、腹腔注射生理盐水或两者。记录14至150日龄大鼠的体重。在150日龄处死大鼠后，记录体长，并取出头部和左股骨以确定身体和颅面比例。单独的头颅照射会永久性地阻碍生长并改变颅面比例，而单独使用甲氨蝶呤或泼尼松龙则不会。当这些药物联合使用时，甲氨蝶呤和泼尼松龙会改变对头颅照射的生长反应。在头颅照射前给予甲氨蝶呤可防止雄性大鼠出现辐射性生长迟缓。当甲氨蝶呤剂量增加、联合使用泼尼松龙或研究雌性大鼠时，这种保护作用消失。对雄性大鼠的保护作用对生长和行为缺陷均有效。这些结果表明，在剂量、性别和药物相互作用的背景下，能更好地理解中枢神经系统治疗的身体和行为副作用。
