Distribution of kinase and deaminase of 1-beta-D-arabinofuranosylcytosine in tissues of man and mouse.

Abstract

Summary 1-β-d-Arabinofuranosylcytosine (ara-C), an important antitumor agent, must be converted to the nucleotide by deoxycytidine kinase (K) in order to be biologically active. It is inactivated by ara-C deaminase (D) to 1-β-d-arabinofuranosyluracil. The enzymes are widely distributed in normal and neoplastic tissues of both man and mouse. Low K and high D activities, thus low ratios of K to D, were demonstrated in chronic myelogenous leukemic cells and human normal peripheral white cells and marrow. Acute myelogenous leukemic and chronic lymphocytic leukemic cells either from peripherals or marrows had relatively high K/D ratios. A high K was demonstrated in spleens of man and mouse. The human spleen and liver had high D, whereas mouse kidney had high D. On the basis of equal body weight, human tissues contained more D than did mouse tissues. This corresponds well with the faster catabolic rate of ara-C in man than in mouse in vivo. In mice, the i.p. administration of a D inhibitor, tetrahydrouridine (100 mg/kg), decreased the amount of 1-β-d-arabinofuranosyluracil and proportionally increased the amount of ara-C excreted in urine. In view of the higher D in man than in mouse, tetrahydrouridine in combination with ara-C may be of more value clinically than ara-C alone.