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De Novo Guanylate Synthesis in the Commitment to Replication in Hepatoma 3924A Cells¹

Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis, Indiana 46223

This work tested the relationship of guanylate and adenylate biosynthesis during the display of the proliferative program of rat hepatoma 3924A cells. Since serine, the major source of one-carbon units, competed with the substrate [¹⁴C]formate for purine labeling, serine-free medium was used in the assays. The initial rates of purine de novo synthesis with [¹⁴C]formate or L-[3-¹⁴C]serine followed Michaelis-Menten kinetics yielding similar V_max values with apparent K_ms of 0.5 and 0.038 mM, respectively. During the transition of cancer cells from plateau phase into logarithmic proliferation the specific activity of 5-phosphoribosyl 1-pyrophosphate synthase (EC 2.7.6.1, ribose phosphate pyrophosphokinase) increased 2.2-fold, followed by a 14-fold elevation of the concentration of 5-phosphoribosyl 1-pyrophosphate with a subsequent 8-fold rise in de novo purine synthesis. The ratio of guanylate to adenylate synthesis from IMP in plateau phase cells was 0.24 to 1. After replating the resting cells there was a sharp increase in the relative labeling of guanylates with a concurrent marked decrease in that of the adenylates, reaching an 8-fold rise in the ratio of guanylate to adenylate synthesis from IMP at the maximum deviation in the late lag phase at 20 to 24 h after seeding. This 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 supports the potential significance of this pathway as a target of chemotherapy.

¹ Supported by United States Public Health Service, National Cancer Institute Grant CA-13526, and by Outstanding Investigator Grant CA-42510 to G. W.

² To whom requests for reprints should be addressed, at Laboratory for Experimental Oncology, Indiana University School of Medicine, 702 Barnhill Drive, Indianapolis, IN 46223.

Received 7/30/87. Revised 10/16/87. Accepted 10/21/87.

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