An inhibitor of glycinamide ribonucleotide formyltransferase is selectively cytotoxic to cells that lack a functional G1 checkpoint

Cancer Chemotherapy and Pharmacology
C C ZhangR C Jackson

Abstract

We studied the effects of purine depletion on the cell cycle using a specific inhibitor of de novo purine biosynthesis, AG2034, an inhibitor of glycinamide ribonucleotide formyltransferase (GARFT). Cytotoxicity was determined by clonogenic assays, and cell cycle perturbations by flow cytometry. Ribonucleotide pools were measured by anion exchange high-pressure liquid chromatography, and DNA strand-breaks were determined by alkaline elution and by the TUNEL assay. When cells were maintained in standard tissue culture medium, which contained 2.2 microM folic acid, AG2034 was cytostatic in all the cell lines tested. Under low-folate conditions (50 nM folic acid), AG2034 caused up to 50% cell death in cell lines that possessed a functional G1 checkpoint (A549, MCF-7), but was only cytostatic to the remaining cells, even at very high concentrations (100 microM). In contrast, AG2034 at 10 nM or 100 nM killed all the cells in cultures of HeLa/S3 or SW480 cells, which lack a functional G1 checkpoint. Flow cytometry studies indicated that in G1 checkpoint-competent cells, AG2034 caused a G1 arrest. Those cells (up to 50%) that were already in S phase died, but the cells that were in G1 arrest maintained viability, based upon clonogenic ...Continue Reading

Citations

Apr 5, 2002·Journal of Inorganic Biochemistry·Zhuo ZhangXianglin Shi
Oct 13, 2006·Proceedings of the National Academy of Sciences of the United States of America·Iryna ZubovychMichael G Roth
May 20, 1999·Annual Review of Pharmacology and Toxicology·D G Johnson, C L Walker
Oct 1, 2003·The Journal of Biological Chemistry·Julie L Bronder, Richard G Moran
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