Forced feeding has been shown to effectively stimulate tumor metabolism in numerous animal models. Significant acceleration of tumor growth by exogenous nutrient administration is generally considered to be detrimental to the host. The present study was performed to determine if substrate-induced alterations in tumor metabolism could be exploited to enhance tumor response to cycle-specific chemotherapy. Following subcutaneous mammary tumor implantation (AC-33) and protein depletion, 39 female Lewis/Wistar rats were randomly assigned to one of four nutritional regimens for 48 hr: (1) protein-depleted food (0.03% protein) ad libitum po, (2) parenteral carbohydrate (18.6% dextrose), (3) parenteral amino acids (2.8% amino acids), or (4) total parenteral nutrition (18.6% dextrose/2.8% amino acids). Methotrexate (5 mg/kg im) was administered to all animals 2 hr after initiating these nutritional regimens. Tumor volume and host toxicity were monitored throughout the study. At sacrifice, significant reduction in tumor volume was observed in animals receiving parenteral amino acids (0.37 +/- 0.24 cm3) and total parenteral nutrition (0.25 +/- 0.18 cm3) compared to the group receiving protein-depleted food po (0.70 +/- 0.22 cm3) (p less than 0.01). In this animal model, the parenteral administration of amino acids with or without the addition of hypertonic dextrose was found to effectively potentiate tumor response to methotrexate without increasing host toxicity.