THE “INDUCTION” OF DIHYDROFOLIC REDUCTASE ACTIVITY IN LEUKOCYTES AND ERYTHROCYTES OF PATIENTS TREATED WITH AMETHOPTERIN*

Abstract

After administration of amethopterin, the appearance of measurable levels of dihydrofolic reductase has been observed in the leukocytes of seven patients with nonhematologic diseases. In five patients (three with nonhematologic neoplasms, one with chronic myelocytic leukemia, and one with chronic lymphocytic leukemia), a single 20-mg infusion of amethopterin was given. In all instances, dihydrofolic reductase activity appeared in the leukocytes and erythrocytes within 1 week. In the subject with chronic myelocytic leukemia, a tenfold rise over the pretreatment value occurred in the level of the enzyme. Studies of the induced enzyme from the leukocytes of the nonhematologic patients showed that the kinetic properties, including inhibition by amethopterin, were similar to those reported previously for the enzyme isolated from leukemic leukocytes. In leukocytes from a patient with chronic myelocytic leukemia treated with amethopterin, the accumulation of inhibitor paralleled the increase in dihydrofolic reductase activity. These observations suggest that the mechanism of reductase inhibition involves the uptake of amethopterin by immature cells, inhibition of dihydrofolic reductase activity, and a resultant decrease in the formation of tetrahydrofolate. This sequence could lead to a decreased synthesis of some metabolite that ordinarily represses the synthesis of dihydrofolic reductase. Thus, the enzyme level ultimately rises and remains elevated during the life-span of the cell.