Effects of 5-fluorouracil treatment of rat leukemia with concomitant inactivation of cobalamin.

The cytostatic activity of 5-fluorouracil (5-FU) can be modified by the addition of reduced folates, as well as antifolates. This is indicative of the complex involvement of folate metabolism in the effects of 5-FU. In the BN rat leukemia model, 5-FU treatment was combined with the inactivation of cobalamin (vitamin B12) by nitrous oxide (N2O). Exposure to nitrous oxide causes severe disturbance of folate metabolism through the inhibition of the cobalamin-dependent enzyme methionine synthetase, and leads to loss of folates from the cell. With regard to the effects on growth of leukemia, the addition of nitrous oxide did not antagonize 5-FU. On the contrary, therapeutic effects were enhanced by combined treatment, as was evident from a further reduction of leukemic infiltration in spleen and liver, from a decrease or even disappearance of leukemic cells in the peripheral blood, and from extended survival of rats. These findings were in accordance with metabolic studies in isolated leukemic cells of treated rats, in which combined treatment caused further impairment of thymidylate and DNA synthesis. Pretreatment with nitrous oxide, for a period of 3 days, was more effective than treatment after the administration of 5-FU. Folate levels, in plasma and intracellular, were reduced after combined treatment. It is concluded that in this leukemia, unlike observations in some models of solid tumors, the activity of 5-FU is enhanced with a depletion of folates. This effect is probably comparable to the combination of methotrexate pretreatment with 5-FU, and might be important to applications of 5-FU in combination chemotherapy of hematological neoplasms.