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The Association of Increased Dihydrofolate Reductase with Amethopterin Resistance in Mouse Leukemia^*

( Department of Pharmacology, Tufts University School of Medicine, Boston, Massachusetts; and Laboratory of Chemical Pharmacology, National Cancer Institute, Bethesda, Maryland)

New antifolate-resistant sublines of mouse leukemia L1210 have been developed. Dihydrofolate reductase activities were determined during early stages of increasing resistance to the folate antagonists. A daily dosage level of 0.75 mg amethopterin/kg used to develop subline FR-1 yielded tumor cells with a tenfold increase of enzyme within three serial transplants. When a new selective influence was imposed by the dichloroamethopterin treatment of mice given implants of amethopterin-resistant subline FR-1, an increase to 40 times the activity of the original parent cells occurred.

When dichloroamethopterin was used alone for the development of subline FR-3 without any prior selection of resistant cells with amethopterin, partial resistance to the chloro-derivative occurred without any concomitant rise in dihydrofolate reductase. The development of full resistance to dichloroamethopterin resulted in a significant increase of dihydrofolate reductase activity.

^* This investigation was supported in part by research grant Cy-4167 from the National Cancer Institute, Public Health Service. A preliminary report of this work was presented at a symposium sponsored by the American Chemical Society in September, 1961 (8).

Received 12/ 1/61.

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