94 CHANNELING OF IMP INTO GUANYLATE SYNTHESIS IN THE GROWTH PROGRAM OF HEPATOMA 3924A CELLS

Abstract

The purpose was to elucidate the relationship of IMP utilization for de novo guanylate and adenylate synthesis during the display of the proliferative program of hepatoma 3924A cells. Purine compounds in the cells were labeled with [14C] formate or L- [3-14C]serine in a serine-free assay medium, hydrolyzed to purine bases, separated and counted. Under these assay conditions labeling of adenine or guanine was proportionate with incubation time and with number of cells. During the transition of hepatoma cells from plateau phase into logarithmic proliferation the concentration of PRPP increased 14-fold, followed by an 8-fold rise in purine de novo synthesis. In plateau phase cells predominantly adenylates were produced. After replating the resting cells there was a sharp increase in the relative labeling of guanine with a concurrent marked decrease in that of adenine in the late lag phase. The subsequent decline of the relative labeling of guanine was accompanied with the restoration in that of adenine with the increase in the cell density. The striking redirection in the distribution of label from IMP utilization to the preferential synthesis of guanylates during the expression of the biochemical proliferative program of cancer cells underlines the potential significance of this pathway as a target of chemotherapy. (Supported by Outstanding Investigator Grant CA-42510 to G.W.)