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Effects of A-Methopterin on Nucleic Acid Synthesis in Leukemic Spleen Breis^*

M. Earl Balis and Joseph Dancis

( Laboratories of the Sloan-Kettering Institute for Cancer Research, New York 21, New York)

In studies in vitro, the incorporation of adenine and formate into the nucleic acids of spleens of normal and leukemic mice has been measured, and the effect thereon of A-methopterin has been determined. The addition of A-methopterin to the tissue brei lowers the incorporation of formate into purines and thymine. The utilization of formate by cells of a resistant strain of mouse leukemia was less than that by cells of the sensitive strain, and the effect of A-methopterin was less. This suggests the possibility that this resistance was the result of the partial elimination of an antifolic-sensitive pathway.

In studies in vivo, in which the A-methopterin could first be acted upon by the whole animal, its effect was to reduce extensively thymine synthesis from formate, but to increase purine formation from this source. The increased inhibition of thymine synthesis leads to the suggestion that A-methopterin is converted in vivo into another active form. The independent and opposite effects on thymine and purine synthesis are indicative of the existence of separate intermediates involved in the incorporation of the one-carbon moiety into these two molecules.

^* This investigation was supported by funds from the National Cancer Institute, National Institutes of Health, Public Health Service (Grant #C-471), and from the Atomic Energy Commission (Contract #AT(30-1)-910).

A preliminary report of this work was presented before the American Association for Cancer Research, Atlantic City, 1954.

Fellow of the National Foundation for Infantile Paralysis. Present address: Department of Pediatrics, Bellevue Hospital, New York City.

Received 5/ 6/55.