O6-benzylguanine enhances the sensitivity of a glioma xenograft with low O6-alkylguanine-DNA alkyltransferase activity to temozolomide and BCNU.
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.
Wedge
S R
SR
Department of Medical Oncology, Charing Cross Hospital, London, UK.
Newlands
E S
ES
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001254:Astrocytoma; D001835:Body Weight / Q000187:drug effects; D002330:Carmustine / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007700:Kinetics; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide; D013997:Time Factors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C064976:O(6)-benzylguanine; D006147:Guanine; D003606:Dacarbazine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine; D000077204:Temozolomide