Tumor-bearing animals provided with intravenous glucose and amino acids (TPN) exhibit enhanced response to S-phase-specific chemotherapeutic agents (H. M. Reynolds, J. M. Daly, B. Rowlands, S. J. Dudrick, and E. M. Copeland. Cancer 45: 3069, 1980; M. H. Torosian, J. L. Mullen, E. E. Miller, et al. J. Parenter. Enteral Nutr. 7: 337, 1983). To determine the mechanism of this response, DNA synthesis rate during starvation or a 48-hr infusion of glucose/amino acids (Glu/AA) was evaluated in tumor, liver, and terminal ileal cells of 68 rats. Tumor cells exhibited a rapid increase in DNA synthesis following the initiation of an infusion of Glu/AA. This increase was most marked after 2 hr of infusion and returned to control levels within 24 hr. Liver DNA synthesis rate increased in both starved and Glu/AA animals over 48 hr with a larger increase in animals receiving Glu/AA. Ileal DNA synthesis decreased equally in both groups. Short pulse Glu/AA produced transient increases in tumor DNA synthesis. Changes in host tissues occurred but followed a different temporal sequence. This may indicate the existence of a period of time following initiation of metabolic manipulation when tumor susceptibility to phase-specific chemotherapeutic agents will be enhanced while host tissues will be spared from increased toxicity.