O6-benzylguanine and its role in chemotherapy.
The presence of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT) in tumor cells is a significant source of resistance to chemotherapeutic alkylnitrosoureas and alkyltriazenes. O6-Benzylguanine provides a means to effectively inactivate the AGT protein and increase the chemotherapeutic effectiveness of chloroethylating and methylating agents in vitro and in human tumor xenograft models. Phase I clinical trials of the combination of O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea are ongoing. Efforts directed at overcoming potential enhanced hematopoietic toxicity and mutagenicity have included the use of gene therapy to express an alkyltransferase gene in the relevant marrow stem cells. Altered AGT proteins resistant to O6-benzylguanine generated from point mutations in the mammalian alkyltransferase gene have been expressed in animal models using retroviral transduction techniques. It is anticipated that the successful application of this approach in humans may provide a means to increase the therapeutic index of O6-benzylguanine and 1, 3-bis(2-chloroethyl)-1-nitrosourea.
Dolan
M E
ME
Department of Medicine, Committees on Clinical Pharmacology and Cancer Biology, University of Chicago, Chicago, Illinois 60637, USA.
Pegg
A E
AE
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002330:Carmustine / Q000627:therapeutic use; D004260:DNA Repair; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C064976:O(6)-benzylguanine; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine