This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mead, J. A. R. Articles by Kwok, G. Search for Related Content PubMed PubMed Citation Articles by Mead, J. A. R. Articles by Kwok, G.

Pharmacologic Aspects of Homofolate Derivatives in Relation to Amethopterin-resistant Murine Leukemia¹

Drug Evaluation Branch, National Cancer Institute, Bethesda, Maryland (J. A. R. M. and A. G.), and Department of Pharmacology, Tufts University School of Medicine, Boston, Massachusetts (R. L. K., M. F., L. P., E. J. C., and G. K.)

Homofolate, dihydrohomofolate, and tetrahydrohomofolate have been examined for antileukemic activity against murine leukemia L1210 and an antifolate-resistant variant which is characterized by high levels of dihydrofolate reductase. Homofolate and dihydrohomofolate are regarded as potential substrates for a lethal synthesis by dihydrofolate reductase within the resistant cells because tetrahydrohomofolate, the end product of the reaction, is a potent inhibitor, in vitro, of thymidylate synthetase. With the limited treatment schedules employed, the antileukemic activities of homofolate and dihydrohomofolate were not definitive. When tetrahydrohomofolate was administered daily at a dose level of 400 mg/kg, it increased considerably the survival time of mice inoculated with the antifolate-resistant variant of L1210. At the same dose level it had much less effect against the parent sensitive strain. The antileukemic effect of tetrahydrohomofolate was reversed by 5-formyltetrahydrofolate. A single dose of 300 mg of homofolate/kg resulted in lethal toxicity to the mice, whereas multiple doses of 400 mg of dihydrohomofolate or tetrahydrohomofolate/kg caused no visible toxicity. The antileukemic activity of amethopterin was not altered by homofolate under the conditions employed. The prolongation of the survival time of leukemic mice by amethopterin was diminished by the concomitant administration of nontoxic and therapeutically inactive doses of dihydrohomofolate and tetrahydrohomofolate. However, the reduction in survival time by the reduced derivatives of homofolate was not as extensive as that produced by 5-formyltetrahydrofolate. In mice, pharmacokinetic studies showed that tetrahydrohomofolate had a plasma half life of about 50 min.

¹ These investigations were supported in part by the following grants: Public Health Service Research Grants 5 R10 CA-05997-05, from the National Cancer Institute, and 5 R01 GM-11871-02 CY, from the National Institute of General Medical Sciences, and National Science Foundation Grant GB-1890.

² R.L. Kisliuk is indebted to the Leukemia Society for a scholarship.

Received 2/10/66. Accepted 6/15/66.