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O6-benzylguanine
and its role in chemotherapy
Dolan ME, Pegg AE
Department
of Medicine, Committees on Clinical Pharmacology and Cancer Biology, University
of Chicago, Chicago, Illinois 60637, USA
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.
PMID:
9815757 [PubMed - indexed for MEDLINE]
Source:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9815757&dopt=Abstract
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