Effect of protein-intake on dihydrofolate-reductase activity of host and tumor-tissues

Although previous laboratory research has found that methotrexate toxicity is significantly increased by protein depletion, the cause of this phenomenon is unclear. Protein depletion can potentially increase methotrexate toxicity by altering methotrexate pharmacokinetics, changing levels of its target enzyme, dihydrofolate reductase, or by other mechanisms. To determine the specific effect of protein malnutrition on dihydrofolate reductase activity of tumor and host tissues, 30 Lewis/Wistar rats with subcutaneous mammary tumor implants (AC-33) were randomized to receive a standard protein diet (22.0% protein; 4.20 kcal/g) or protein-depleted diet (0.03% protein; 4.27 kcal/g) ad libitum per os. At sacrifice, specific activity of dihydrofolate reductase was determined in critical host target tissues (bone marrow, liver, gastrointestinal mucosa) and tumors. Our results indicate a differential effect of protein depletion on dihydrofolate reductase activity of tumor and various host tissues. Protein depletion reduced enzyme activity in bone marrow and tumors to 50% and 85%, respectively, of levels found in animals receiving standard protein intake (p<0.05). In contrast, dihydrofolate reductase activity in liver was unchanged and in gastrointestinal mucosa was increased to 136% with protein depletion compared to standard protein intake. Thus, increased myelosuppression from methotrexate in depleted animals may result, in part, from reduced dihydrofolate reductase activity in bone marrow. Other mechanisms must be implicated to account for increased hepatic or gastrointestinal toxicity observed in the protein-depleted, tumor-bearing host.