4Aminopyrazolo (3,4d) pyrimidine: an Inhibitor of the Synthesis of Purines and Proteins in Ehrlich Ascites Cells

Carcinostatic activity of 4-(substituted amino)-pyrasolo(3,4-d pyrimidines was found to be confined to compounds whose basic dissociation constants approximated that of adenine (1, 2). In addition, the toxicity of 4-aminopyrazolo(3,4d)pyrimidine could be reversed by adcnine or adenine-containing compounds in a number of biological systems (1, 3-7). These findings led to the hypothesis that the antineoplastic properties of aminopyrazolo(3,4-d)pyrimidines might be due to interference with the utilization of adenine or of an adenine derivative (2). This hypothesis stimulated interest in the mode of action of 4-APP,’ and subsequent initial reports from this and other laboratories (7-11) indicated that this compound interfered with purine biosynthesis. These findings supported earlier observations that 4-.4PP caused a decrease in ribonucleic acid of mouse liver and in deoxyribonucleic acid of Sarcoma 180 (12). The present communication presents the effects of 4-APP on the utilization of isotopic precursors of nucleic acid purines by the Ehrlich ascites carcinoma* in uiuo. Evidence is presented for the presence of two metabolic blocks along the pathway de nova to polynucleotide purines and for a marked decrease in the rate of amino acid uptake into cellular protein.