Sensitization of human colon tumour cell lines to carmustine by depletion of O6-alkylguanine-DNA alkyltransferase

J Cancer Res Clin Oncol. 1995;121(4):225-9. doi: 10.1007/BF01366966.

Abstract

In nine human colon tumour cell lines the relationship between O6-alkylguanine-DNA alkyltransferase (O6-AGT) activity and carmustine resistance was investigated. Three lines with O6-AGT activity below 25 fmol/mg protein had carmustine ED50 values ranging from 5.0 microM to 11.9 microM; six lines displaying an O6-AGT activity above 240 fmol/mg protein had ED50 values ranging from 28.9 microM to 69.5 microM. In lines with low O6-AGT activity, depletion of the repair protein by O6-benzylguanine resulted in a marginal increase of carmustine cytotoxicity (sensitization factors less than 2). In the majority of cell lines with high O6-AGT activity, pretreatment with O6-benzylguanine resulted in a pronounced sensitization to carmustine. In one line, an optimal time schedule for sensitization of colon tumour cells by O6-benzylguanine was assessed; continuous exposure to O6-benzylguanine > or = 16 h after carmustine exposure) was superior to short-term exposure limited to a period before carmustine treatment.

MeSH terms

  • Carmustine / pharmacology*
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / enzymology*
  • Drug Resistance
  • Drug Screening Assays, Antitumor
  • Guanine / analogs & derivatives
  • Guanine / pharmacology
  • Humans
  • Methyltransferases / deficiency
  • Methyltransferases / metabolism*
  • O(6)-Methylguanine-DNA Methyltransferase
  • Streptozocin / pharmacology
  • Time Factors
  • Tumor Cells, Cultured / drug effects

Substances

  • O(6)-benzylguanine
  • Streptozocin
  • Guanine
  • Methyltransferases
  • O(6)-Methylguanine-DNA Methyltransferase
  • Carmustine