O6-benzylguanine enhances the sensitivity of a glioma xenograft with low O6-alkylguanine-DNA alkyltransferase activity to temozolomide and BCNU

Br J Cancer. 1996 May;73(9):1049-52. doi: 10.1038/bjc.1996.203.

Abstract

The effect of the O6-alkylguanine-DNA alkyltransferase (AGT) inhibitor, O6-benzylguanine (O6-BG), on the anti-tumour activity of 8-carbamoyl-3-methylimidazo [5,1-d]-1,2,3,5-tetrazine-4(3H)-one (temozolomide) or 1,3-bis(2-chloroethyl)-nitrosourea (BCNU) was evaluated in athymic mice bearing subcutaneous (s.c.) human glioma (U87MG) xenografts. The activity of AGT in U87MG xenografts was 4.3 +/- 1.5 fmol mg-1 protein (mean +/- s.d). These xenografts were inherently sensitive to treatment with alkylating compounds alone, with non-toxic doses of temozolomide (35 mg kg-1) or BCNU (10 mg kg-1) producing tumour growth delays of 23.3 and 11.8 days respectively. O6-BG (40 mg kg-1) did not inhibit tumour growth when administered alone, but was found to enhance significantly the anti-tumour activity of temozolomide or BCNU when administered 1 h before therapy (P < 0.002, Mann-Whitney test). AGT activity measured 24 h after the administration of 40 mg kg-1 O6-BG, was only 0.9 +/- 0.2 fmol mg-1 protein. These results are in contrast to previous studies in vitro with tumour cell lines of low AGT activity (< 15 fmol mg-1 protein), in which the cytotoxicity of temozolomide or BCNU was unaffected by AGT depletion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Astrocytoma
  • Body Weight / drug effects
  • Carmustine / therapeutic use*
  • Cell Division / drug effects
  • Cell Line
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / therapeutic use
  • Glioblastoma / drug therapy*
  • Glioblastoma / enzymology*
  • Glioblastoma / pathology
  • Guanine / analogs & derivatives*
  • Guanine / therapeutic use
  • Humans
  • Kinetics
  • Methyltransferases / metabolism*
  • Mice
  • Mice, Nude
  • O(6)-Methylguanine-DNA Methyltransferase
  • Temozolomide
  • Time Factors
  • Transplantation, Heterologous
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • O(6)-benzylguanine
  • Guanine
  • Dacarbazine
  • Methyltransferases
  • O(6)-Methylguanine-DNA Methyltransferase
  • Carmustine
  • Temozolomide