Cells from patients with ataxia telangiectasia are abnormally sensitive to the cytotoxic effect of a tumor promoter, phorbol-12-myristate-13-acetate

https://doi.org/10.1016/0027-5107(85)90035-1Get rights and content

Abstract

Fibroblast strains from 6 patients with ataxia telangiectasia (A-T) were found to be markedly hypersensitive to the cytotoxic action of the tumor promoter phorbol-12-myristate-13-acetate (PMA), their D37 values being 5 times lower than those of two normal controls. Two A-T heterozygous strains were slightly hypersensitive to PMA, while a third one showed normal sensitivity. It is concluded that the DNA lesion which is critical in A-T cells in an important component of the damage caused by PMA-induced free radicals and may play a role both in the tumor-promoting activity of PMA and the cancer proneness of A-T patients.

References (24)

  • I. Emerit et al.

    Suppression of tumor promoter-myristate acetate-induced chromosome breakage by antioxidants and inhibitors of arachidonic acid metabolism

    Mutation Res.

    (1983)
  • H.C. Birnboim

    DNA strand breakage in human leucocytes exposed to a tumor promoter, phorbol myristate acetate

    Science

    (1982)
  • C. Borek et al.

    Modifiers of free radicals inhibit in vitro the oncogenic actions of X-rays, bleomycin and the tumor promoter 12-o-tetradecanoyl phorbol 13-acetate

  • L.R. DeChatelet et al.

    Effect of phorbol myristate acetate on the oxidation metabolism of human polymorphonuclear leucocytes

    Blood

    (1976)
  • L. Diamond et al.

    Tumor promoters and the mechanism of tumor promotion

    Adv. Cancer Res.

    (1980)
  • P.E. Driedger et al.

    Specific binding of phorbol ester tumor promoters

  • I. Emerit et al.

    Tumor promoter phorbol-12-myristate-13-acetate induces chromosomal damage via indirect action

    Nature (London)

    (1981)
  • I. Emerit et al.

    Tumor promoter phorbol 12-myristate-13-acetate induces a clastogenic factor in human lymphocytes

  • I. Emerit et al.

    Clastogenic action of tumor promoter phorbol-12-myristate-13-acetate in mixed human leucocyte cultures

    Carcinogenesis

    (1983)
  • P.C. Huang et al.

    Genetic and biochemical studies with ataxia-telangiectasia

    Hum. Genet.

    (1981)
  • T.W. Kensler et al.

    Inhibition of tumor promotion by a biomimetic superoxide dismutase

    Science

    (1983)
  • A.R. Lehmann

    The cellular and molecular responses of ataxia-telangiectasia cells to DNA damage

  • Cited by (14)

    • Ataxia-telangiectasia (A-T): An emerging dimension of premature ageing

      2017, Ageing Research Reviews
      Citation Excerpt :

      This function of ATM may explain the moderate, variable sensitivity of ATM-deficient cells to a broad range of DNA damaging agents. Among them are UV radiation, alkylating agents, crosslinking agents, hydrogen peroxide, 4-Nitroquinoline 1-oxide, phorbol-12-myristate-13-acetate and topoisomerase 1 poisons (Alagoz et al., 2013; Barfknecht and Little, 1982; Fedier et al., 2003; Hannan et al., 2002; Henderson and Ribecky, 1980; Hoar and Sargent, 1976; Jaspers et al., 1982; Katyal et al., 2014; Lee et al., 2006; Leonard et al., 2004; Mirzayans et al., 1989; Paterson et al., 1976; Scudiero, 1980; Shiloh et al., 1985; Smith et al., 1989; Smith and Paterson, 1980; Speit et al., 2000; Teo and Arlett, 1982; Ward et al., 1994; Yi et al., 1990; Zhang et al., 1996). ATM-deficient cells also exhibit reduced efficiency in resolving Topoisomerase I-DNA covalent intermediates (Alagoz et al., 2013; Katyal et al., 2014).

    • ATM: Expanding roles as a chief guardian of genome stability

      2014, Experimental Cell Research
      Citation Excerpt :

      This suggests that a spectrum of deficiency exists amongst these cells in coping with a broad array of DNA lesions, not only DSBs. Similar observations were made during the course of our early studies about the sensitivity of A-T cells to DNA damaging agents [98–102] (and unpublished data). An example of documented ATM-mediated pathway in response to UV radiation is the stabilization of ribonucleotide reductase via ATM-mediated phosphorylation of its subunit, p53R2 [103].

    • Ataxia-telangiectasia: a variant with altered in vitro phenotype of fibroblast cells

      1989, Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
    View all citing articles on Scopus

    Present address: Division of Genetics, The Children's Hospital of Boston, 300 Longwood Avenue, Boston, MA 02115, U.S.A.

    View full text