Potentiation of BCNU anticancer activity by O6-benzylguanine: a study in vitro and in vivo.
O6-Alkylguanine-DNA alkyltransferase (O6-AGT), a constitutively expressed DNA repair protein, removes alkyl groups from the O6-position of guanine in DNA. Tumor cells with high O6-AGT activity are resistant to nitrosoureas and other agents that form toxic O6-alkyl adducts. We evaluated O6-benzylguanine (O6-BG) for its activity to inhibit O6-AGT and potentiate 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in O6-AGT-positive human gastric adenocarcinoma cell line, BGC-823 and its tumor xenograft. The sensitivity of BGC-823 cells to BCNU was increased by pretreatment for 2 hours with 1.5 to 6.0 microg/mL O6-benzylguanine. O6-benzylguanine (0.75-6.0 microg/mL) completely and rapidly suppressed the O6-AGT activity of cells for up to 12 hours. When given i.p. 2 hours before BCNU (25 mg/kg) to animals bearing s.c. tumors, O6-BG (90 mg/kg) produced a growth delay of 38.6 days in human gastric adenocarcinoma xenograft. Furthermore, O6-BG significantly inhibited the O6-AGT activity of tumor tissue and induced evident apoptosis. These results suggest that combination of O6-BG with BCNU may have a significant therapeutic effect in the treatment of mer + tumor.
Wan
Y
Y
Department of Clinical Pharmacology of Affiliated Hospital, Academy of Military Medical Sciences, Beijing, China.
Wu
D
D
Gao
H
H
Lu
H
H
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D002330:Carmustine / Q000008:administration & dosage / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007279:Injections, Subcutaneous; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013274:Stomach Neoplasms / Q000188:drug therapy; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C064976:O(6)-benzylguanine; D006147:Guanine; D019883:Alkyl and Aryl Transferases; C050956:DNA alkyltransferase; D002330:Carmustine