Document Detail


An inhibitor of glycinamide ribonucleotide formyltransferase is selectively cytotoxic to cells that lack a functional G1 checkpoint.
MedLine Citation:
PMID:  9443639     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: 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). METHODS: 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. RESULTS: 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 assays, for many days. In G1 checkpoint-deficient cells, no G1 arrest was seen after AG2034 treatment, all cells progressed into S phase, and all cells died. Measurement of DNA strand-breaks, either by alkaline elution or by the dUTP end-labelling technique, indicated no DNA strand-breaks 24 h after AG2034 treatment, indicating that purine nucleotide depletion can trigger the G1 checkpoint in the absence of DNA damage. CONCLUSION: Purine depletion causes slow cell death in cells that have passed the G1 checkpoint, but cytostasis in cells that are arrested at the G1 checkpoint. The GARFT inhibitor, at physiological folate concentrations, thus causes selective cytotoxicity to cells lacking a functional G1 checkpoint.
Authors:
C C Zhang; T J Boritzki; R C Jackson
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Cancer chemotherapy and pharmacology     Volume:  41     ISSN:  0344-5704     ISO Abbreviation:  Cancer Chemother. Pharmacol.     Publication Date:  1998  
Date Detail:
Created Date:  1998-02-10     Completed Date:  1998-02-10     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7806519     Medline TA:  Cancer Chemother Pharmacol     Country:  GERMANY    
Other Details:
Languages:  eng     Pagination:  223-8     Citation Subset:  IM    
Affiliation:
Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
DNA, Neoplasm / drug effects
Enzyme Inhibitors / pharmacology*
Folic Acid / administration & dosage,  metabolism
G1 Phase / drug effects
Glutamates / pharmacology*
Hela Cells / drug effects*
Humans
Hydroxymethyl and Formyl Transferases / antagonists & inhibitors*
Mice
Phosphoribosylglycinamide Formyltransferase
Purines / biosynthesis*
Pyrimidines / pharmacology*
Chemical
Reg. No./Substance:
0/AG 2034; 0/DNA, Neoplasm; 0/Enzyme Inhibitors; 0/Glutamates; 0/Purines; 0/Pyrimidines; 120-73-0/purine; 59-30-3/Folic Acid; EC 2.1.2.-/Hydroxymethyl and Formyl Transferases; EC 2.1.2.2/Phosphoribosylglycinamide Formyltransferase

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