Enhanced sensitivity to camptothecin in ataxia-telangiectasia cells and its relationship with the expression of DNA topoisomerase I

Int J Radiat Biol. 1989 Feb;55(2):217-31. doi: 10.1080/09553008914550271.

Abstract

The antitumour drug camptothecin (CPT) can trap covalently bound topoisomerase I-DNA intermediates as complexes which conceal single-strand scissions. In an attempt to evaluate the cytotoxic potential of these lesions in human cells we have measured: (1) cell cycle delay and cell killing by CPT in primary and transformed fibroblasts, and in lymphoblastoid lines derived from normal, X-ray sensitive ataxia-telangiectasia (A-T) and xeroderma pigmentosum (XP) donors; (2) the properties of sublines obtained by high-dose selection in CPT: (3) levels of drug-induced DNA strand scission in intact cells; (4) the cellular availability of extractable topoisomerase I. The drug induced a marked cell cycle block in G2 phase, the magnitude of the block being closely related to cell kill. XP group A cells showed normal sensitivity to CPT, whereas A-T derived cells were consistently hypersensitive (3-5 fold) in a manner which could not be related to a primary deficiency in topoisomerase I activity, abnormal capacity for complex formation or anomalies in the intracellular generation of DNA strand breaks. A CPT-resistant A-T subline had reduced topoisomerase I activity but retained the characteristic of hypersensitivity to X-radiation. The subline lost resistance upon in vitro passage with evidence that resistance was initially an unstable feature of a subpopulation of cells. The findings have implications for the role of topoisomerase I in the in vitro phenotype of A-T cells, and the contribution made by topoisomerase I-dependent damage to the cytotoxic action of CPT.

MeSH terms

  • Ataxia Telangiectasia / enzymology*
  • Ataxia Telangiectasia / pathology
  • Camptothecin / pharmacology*
  • Cell Cycle / drug effects
  • Cell Line
  • Cell Line, Transformed
  • Cell Survival / drug effects
  • DNA Topoisomerases, Type I / metabolism*
  • Drug Screening Assays, Antitumor
  • Fibroblasts / drug effects
  • Humans
  • In Vitro Techniques
  • Xeroderma Pigmentosum / enzymology
  • Xeroderma Pigmentosum / pathology

Substances

  • DNA Topoisomerases, Type I
  • Camptothecin