Cytogenetic, Cytotoxic, and Cell-Cycle Effects of 3-Aminobenzamide in Human Lymphoblastoid Cells Proficient or Deficient in Nucleotide Biosynthesis

  • Jeffrey L. Schwartz
  • Ralph R. Weichselbaum
Part of the Proceedings in Life Sciences book series (LIFE SCIENCES)

Abstract

In some recent studies it has been reported that 3-aminobenzamide (3AB), an inhibitor of poly(ADP-ribose) polymerase [7, 10] also inhibits the pathway for de novo synthesis of DNA precursors. Specifically, 3AB inhibits the metabolism of glucose and methionine into precursors of DNA in WI-L2 lymphoid cells [6], C3H mouse fibroblasts [1], and Chinese hamster ovary (CHO) cells [4]. It has been suggested that some of the reported effects of 3AB, such as its effect on cell-cycle progression [8], may be due to a disturbance in nucleotide precursor pathways rather than an inhibition of poly(ADP-ribose) synthesis [1–4, 6]. To test this hypothesis, we have examined the effects of 3AB on SCE induction, cytotoxicity, and cell-cycle progression in three different human lymphoblastoid cell lines; two deficient in salvage nucleotide synthesis pathways and one competent in both salvage and de novo nucleotide synthesis. We hypothesized that if 3AB inhibits de novo nucleotide synthesis pathways, then cells deficient in salvage nucleotide synthesis pathways should be more sensitive to the various effects of 3AB, especially its cytotoxic and cell-cycle effects.

Keywords

Toxicity Adenosine Methionine Streptomycin Thymidine 

Abbreviations

3AB

3-aminobenzamide

CHO

Chinese hamster ovary

HGPRT

hypoxanthine-guanine phosphoribosyl transferase

6TGR

6-thioguanine-resistant

TK

thymidine kináse

TFTR

trifluorothymidine-resistant

SCE

sister chromatid exchange

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Borek C, Morgan WF, Ong A, Cleaver JE (1984) Inhibition of malignant transformation in vitro by inhibitors of poly(ADP-ribose) synthesis. Proc Natl Acad Sci USA 81:243–247PubMedCrossRefGoogle Scholar
  2. 2.
    Cleaver JE, Bodell WJ, Morgan WF, Zelle B (1983) Differences in the regulation of poly(ADP-ribose) of repair of DNA damage from alkylating agents and ultraviolet light according to cell type. J Biol Chem 258:9059–9068PubMedGoogle Scholar
  3. 3.
    Cleaver JE, Bodell WJ, Borek C, Morgan WF, Schwartz JL (1983) Poly(ADP-ribose): spectator or participant in excision repair of DNA damage. In: Miwa M et al. (eds) ADP-ribosylation, DNA repair and cancer. Jpn Sci Soc Press, Tokyo/VNU Science Press, Utrecht, pp 195–207Google Scholar
  4. 4.
    Cleaver JE (1984) Differential toxicity of 3-aminobenzamide to wild-type and 6-thioguanine-resistant Chinese hamster cells by interference with pathways of purine biosynthesis. Mutat Res 131:123–127PubMedGoogle Scholar
  5. 5.
    Liber HL, Thilly WG (1982) Mutation assay at the thymidine kinase locus in diploid human lymphoblasts. Mutat Res 94:467–485PubMedCrossRefGoogle Scholar
  6. 6.
    Milam KM, Cleaver JE (1984) Inhibitors of poly(ADP-ribose) synthesis also affect other metabolic processes. Science 223:589–591PubMedCrossRefGoogle Scholar
  7. 7.
    Oikawa A, Tohda H, Kanai M, Miwa M, Sugimura T (1980) Inhibitors of poly(adenosine diphosphate ribose) polymerase induce sister chromatid exchanges. Biochem Biophys Res Commun 97:1311–1316PubMedCrossRefGoogle Scholar
  8. 8.
    Schwartz JL, Morgan WF, Kapp LN, Wolff S (1983) Effects of 3-aminobenzamide on DNA synthesis and cell cycle progression in Chinese hamster ovary cells. Exp Cell Res 143:377–382PubMedCrossRefGoogle Scholar
  9. 9.
    Schwartz JL, Banda MJ, Wolff S (1982) 12-O-Tetradecanoylphorbol-13-acetate (TPA) induces sister-chromatid exchanges and delays in cell cycle progression in Chinese hamster and human cell lines. Mutat Res 92:393–409PubMedCrossRefGoogle Scholar
  10. 10.
    Sims JL, Sikorski GW, Catino DM, Berger SJ, Berger N (1982) Poly(adenosine diphosphoribose)polymerase inhibitors stimulate unscheduled deoxyribonucleic acid synthesis in normal human lymphoblasts. Biochemistry 21:1813–1821PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1985

Authors and Affiliations

  • Jeffrey L. Schwartz
  • Ralph R. Weichselbaum
    • 1
  1. 1.Department of Cancer BiologyHarvard School of Public HealthBostonUSA

Personalised recommendations