Synergistic efficacy of O6benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in a human colon cancer xenograft completely resistant to BCNU alone
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Cited by (103)
Chemoselection of allogeneic HSC after murine neonatal transplantation without myeloablation or post-transplant immunosuppression
2012, Molecular TherapyCitation Excerpt :The observation that transfer of the O6-alkylguanine-DNA alkyltransferase gene into mammalian cells decreased sensitivity to 1,3-bis(2-chloroethyl)nitrosourea (BCNU), a well-established HSC toxin, suggested that alkyltransferases such as MGMT could be used for in vivo chemoselection.8,9 Identification of O6-Benzylguanine (BG)10 as an inhibitor of endogenous MGMT, and the derivation of BG-resistant forms of MGMT (P140K and G156A)11,12 provided dramatic improvements in the durability of this in vivo chemoselection strategy. The MGMTP140K mutant repair enzyme exhibits 1,000-fold resistance to alkylators and nitrosoureas compared with the wild-type MGMT enzyme following treatment with BG.13,14,15
Long-term polyclonal and multilineage engraftment of methylguanine methyltransferase P140K gene-modified dog hematopoietic cells in primary and secondary recipients
2009, BloodCitation Excerpt :This was the first indication that MGMT might be a useful strategy for in vivo selection and chemoprotection. Subsequently, specific active site inhibitors of wild-type MGMT were developed, namely O6BG, which sensitized cells in a synergistic fashion when used in conjunction with BCNU.42,43 The development of specific mutants of MGMT that were resistant to O6BG44-49 further improved the positive selection of gene-modified cells relative to cells expressing the wild-type form of MGMT, and also reduced the mutagenesis rate.49
Should concomitant and adjuvant treatment with temozolomide be used as standard therapy in patients with anaplastic glioma?
2006, Critical Reviews in Oncology/HematologyExploiting the role of O<sup>6</sup>-methylguanine-DNA-methyltransferase (MGMT) in cancer therapy
2006, Current Opinion in PharmacologyInactivation of O<sup>6</sup>-alkylguanine DNA alkyltransferase as a means to enhance chemotherapy
2006, Cancer Treatment Reviews
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Recipient of an Edward Mallinckrodt Jr. Foundation Scholar Award.