VP-16 and alkylating agents activate a common metabolic pathway for suppression of DNA replication
The cytotoxic effects of etoposide (VP-16) are mediated by topoisomerase II production of protein crosslinked DNA strand breaks. Previous studies have shown that alkylating agent induced DNA damage results in expansion of dTTP pools and reduction of dCTP pools and DNA replication. Studies were conducted with V79 cells to determine whether the metabolic consequences of VP-16 treatment were similar to those induced by alkylating agents. Treatment with 0.5..mu..M VP-16 prolonged the doubling time of V79 cells from 12 to 18 hrs and caused cell volume to increase from 1.1 to 1.6 x 10/sup -12/l. 2mM caffeine completely blocked the volume increase and substantially prevented the prolongation of doubling time. 5..mu..M VP-16 reduced the rate of (/sup 3/H)TdR incorporation by 70%, whereas in the presence of 2mM caffeine, VP-16 caused only a 10% decrease in the rate of (/sup 3/H)TdR incorporation. 4 hr treatment with 5.0..mu..M VP-16 increased dTTP levels from 65 +/- 10 pmol/10/sup 6/ cells to 80 +/- 13 pmol/10/sup 6/ cells and caused dCTP level to decline from 113 +/- 23 pmol/10/sup 6/ cells to 92 +/- 17 pmol/10/sup 6/ cells. These results indicate that the metabolic consequences of VP-16 treatment are similar to alkylating agent treatment and that an increase in dTTP pools with a subsequent effect on ribonucleotide reductase may be a final common pathway by which many cytotoxic agents suppress DNA synthesis.
- Research Organization:
- Case Western Reserve Univ., Cleveland, OH
- OSTI ID:
- 6905062
- Report Number(s):
- CONF-8606151-; TRN: 87-004069
- Journal Information:
- Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States), Vol. 45:6; Conference: 76. annual meeting of the Federation of American Society for Experimental Biology, Washington, DC, USA, 8 Jun 1986
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
59 BASIC BIOLOGICAL SCIENCES
ALKYLATING AGENTS
GENETIC EFFECTS
DNA REPLICATION
INHIBITION
BIOLOGICAL PATHWAYS
CAFFEINE
FIBROBLASTS
HAMSTERS
ISOMERASES
LUNGS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
ANALEPTICS
ANIMAL CELLS
ANIMALS
AROMATICS
AZAARENES
BIOLOGICAL EFFECTS
BODY
CENTRAL NERVOUS SYSTEM AGENTS
CONNECTIVE TISSUE CELLS
DRUGS
ENZYMES
HETEROCYCLIC COMPOUNDS
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
MAMMALS
NUCLEIC ACID REPLICATION
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
PURINES
RESPIRATORY SYSTEM
RODENTS
SOMATIC CELLS
VERTEBRATES
XANTHINES
560300* - Chemicals Metabolism & Toxicology
550201 - Biochemistry- Tracer Techniques