Abstract
The DNA repair protein, O6-methylguanine DNA methyltransferase (MGMT), can confer resistance to guanine O6-alkylating agents. Therefore, inhibition of resistant MGMT protein is a practical approach to increase the anticancer effects of such alkylating agents. Numerous small molecule inhibitors were synthesized and exhibited potential MGMT inhibitory activities. Although they were nontoxic alone, they also inhibited MGMT in normal tissues, thereby enhancing the side effects of chemotherapy. Therefore, strategies for tumor-specific MGMT inhibition have been proposed, including local drug delivery and tumor-activated prodrugs. Over-expression of MGMT in hematopoietic stem cells to protect bone marrow from the toxic effects of chemotherapy is also a feasible selection. The future prospects and challenges of MGMT inhibitors in cancer chemotherapy were also discussed.
Graphical abstract
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Alkylation of DNA and its aftermath. Bioessays 17(6), 561–568 (1995).
- 2 . The induction and repair of DNA interstrand crosslinks and implications in cancer chemotherapy. Anticancer Agents Med. Chem. 16(2), 221–246 (2016).
- 3 The potential of combi-molecules with DNA-damaging function as anticancer agents. Future Med. Chem. 9(4), 403–435 (2017).
- 4 . Targeting O6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy. Cell. Mol. Life Sci. 67(21), 3663–3681 (2010). •• An excellent review that described the DNA alkylating agents widely used in clinic, expression of MGMT in different tissues, MGMT-mediated resistance and its potential inhibitors in clinical studies.
- 5 Investigations on the effect of O6-benzylguanine on the formation of dG-dC interstrand cross-links induced by chloroethylnitrosoureas in human glioma cells using stable isotope dilution high-performance liquid chromatography electrospray ionization tandem mass spectrometry. Chem. Res. Toxicol. 27(7), 1253–1262 (2014).
- 6 . DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett. 332(2), 237–248 (2013).
- 7 . The DNA damage response: implications for tumor responses to radiation and chemotherapy. Annu. Rev. Med. 66, 129–143 (2015).
- 8 . MGMT: its role in cancer aetiology and cancer therapeutics. Nat. Rev. Cancer 4(4), 296–307 (2004).
- 9 . A density functional theory investigation on the formation mechanisms of DNA interstrand crosslinks induced by chloroethylnitrosoureas. Int. J. Quantum Chem. 113(9), 1299–1306 (2013).
- 10 . Comparative theoretical investigation of the formation of DNA interstrand crosslinks induced by two kinds of N-nitroso compounds: nitrosoureas and nitrosamines. J. Phys. Org. Chem. 25(12), 1153–1167 (2012).
- 11 . Quantification of meCCNU-induced dG-dC crosslinks in oligonucleotide duplexes by liquid chromatography/electrospray ionization tandem mass spectrometry. Rapid Commun. Mass Spectrom. 25(14), 2027–2034 (2011).
- 12 Comparative investigation of the DNA inter-strand crosslinks induced by ACNU, BCNU, CCNU and FTMS using high-performance liquid chromatography–electrospray ionization tandem mass spectrometry. Int. J. Mass Spectrom. 368, 30–36 (2014).
- 13 . Multifaceted roles of alkyltransferase and related proteins in DNA repair, DNA damage, resistance to chemotherapy, and research tools. Chem. Res. Toxicol. 24(5), 618–639 (2011).
- 14 Retrospective study of the correlation between the DNA repair protein alkyltransferase and survival of brain tumor patients treated with carmustine. Cancer Res. 56(4), 783–788 (1996).
- 15 . Clinical relevance of MGMT in the treatment of cancer. J. Clin. Oncol. 20(9), 2388–2399 (2002).
- 16 . DNA alkylation products formed by 1-(2-chloroethyl)-1-nitrosourea as molecular dosimeters of therapeutic response. J. Neurooncol. 91(3), 257–264 (2009).
- 17 . DNA binding, nucleotide flipping, and the helix-turn-helix motif in base repair by O6-alkylguanine-DNA alkyltransferase and its implications for cancer chemotherapy. DNA Repair 6(8), 1100–1115 (2007).
- 18 . cDNA cloning and chromosomal assignment of the human O6-methylguanine-DNA methyltransferase – cDNA expression in Escherichia coli and gene expression in human cells. J. Biol. Chem. 265(16), 9563–9569 (1990).
- 19 . Expression and cloning of complementary-DNA for a human enzyme that repairs O6-methylguanine in DNA. J. Mol. Biol. 213(4), 739–747 (1990).
- 20 Isolation and structural characterization of a cDNA clone encoding the human DNA-repair protein for O6-alkylguanine. Proc. Natl Acad. Sci. USA 87(2), 686–690 (1990).
- 21 Active and alkylated human AGT structures: a novel zinc site, inhibitor and extrahelical base binding. EMBO J. 19(7), 1719–1730 (2000).
- 22 . Conserved structural motifs governing the stoichiometric repair of alkylated DNA by O6-alkylguanine-DNA alkyltransferase. Mutat. Res. 460(3–4), 151–163 (2000).
- 23 DNA binding and nucleotide flipping by the human DNA repair protein AGT. Nat. Struct. Mol. Biol. 11(8), 714–720 (2004). • A critical investigation on the crystal structure of MGMT and the mechanism of action of MGMT-mediated repair of O6-alkylguanines.
- 24 Ubiquitination-dependent proteolysis of O6-methylguanine-DNA methyltransferase in human and murine tumor cells following inactivation with O6-benzylguanine or 1,3-bis(2-chloroethyl)-1-nitrosourea. Biochemistry 35(4), 1328–1334 (1996).
- 25 . Degradation of the alkylated form of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase. Carcinogenesis 23(5), 823–830 (2002).
- 26 S-phase specific downregulation of human O6-methylguanine DNA methyltransferase (MGMT) and its serendipitous interactions with PCNA and p21cip1 proteins in glioma cells. Neoplasia 20(4), 305–323 (2018).
- 27 Degradation of BRCA2 in alkyltransferase-mediated DNA repair and its clinical implications. Cancer Res. 68(23), 9973–9981 (2008).
- 28 Inhibition of a specific DNA repair system and nitrosourea cytotoxicity in resistant human cancer cells. Cancer Commun. 1(1), 65–73 (1989).
- 29 Phase I study of streptozocin- and carmustine-sequenced administration in patients with advanced cancer. J. Natl Cancer Inst. 84(4), 256–261 (1992).
- 30 Modulation of O6-alkylguanine-DNA alkyltransferase-mediated carmustine resistance using streptozotocin – a Phase I trial. Cancer Res. 52(9), 2456–2459 (1992).
- 31 Carmustine and streptozocin in refractory melanoma: an attempt at modulation of O6-alkylguanine-DNA-alkyltransferase. Clin. Cancer Res. 2(7), 1129–1134 (1996).
- 32 . Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma. Br. J. Cancer 67(6), 1356–1360 (1993).
- 33 Sequential administration of temozolomide and fotemustine: depletion of O6-alkyguanineDNA alkyltransferase in blood lymphocytes and in tumours. Ann. Oncol. 10(7), 831–838 (1999).
- 34 . Effect of O6-methylguanine on DNA interstrand cross-link formation by chloroethylnitrosoureas and 2-chloroethyl(methylsulfonyl)methanesulfonate. Cancer Res. 48(13), 3603–3606 (1988).
- 35 . Depletion of mammalian O6-alkylguanine-DNA alkyltransferase activity by O6-benzylguanine provides a means to evaluate the role of this protein in protection against carcinogenic and therapeutic alkylating agents. Proc. Natl Acad. Sci. USA 87(14), 5368–5372 (1990). • An important study to evaluate the ability of O6-BG to deplete MGMT in vitro and in vivo and the effect of O6-BG to sensitize tumor cells to killing of guanine O6-alkylating agents.
- 36 . Reduction of O6-alkylguanine-DNA alkyltransferase activity in HeLa cells treated with O6-alkylguanines. Cancer Res. 45(12), 6413–6417 (1985).
- 37 Effect of O6-benzylguanine analogs on sensitivity of human tumor cells to the cytotoxic effects of alkylating-agents. Cancer Res. 51(13), 3367–3372 (1991).
- 38 O6-benzylguanine-mediated enhancement of chemotherapy. Mol. Cancer Ther. 1(11), 943–948 (2002).
- 39 Structural features of substituted purine derivatives compatible with depletion of human O6-alkylguanine-DNA alkyltransferase. J. Med. Chem. 35(23), 4486–4491 (1992).
- 40 Substituted O6-benzylguanine derivatives and their inactivation of human O-6-alkylguanine-DNA alkyltransferase. J. Med. Chem. 37(3), 342–347 (1994).
- 41 8-Substituted O6-benzylguanine, substituted 6(4)-(benzyloxy)pyrimidine, and related derivatives as inactivators of human O6-alkylguanine-DNA alkyltransferase. J. Med. Chem. 38(2), 359–365 (1995).
- 42 Inactivation of O6-alkylguanine-DNA alkyltransferase. 1. Novel O6-(hetarylmethyl)guanines having basic rings in the side chain. J. Med. Chem. 41(26), 5265–5271 (1998).
- 43 Resistance-modifying agents. 8. Inhibition of O6-alkylguanine-DNA alkyltransferase by O6-alkenyl-, O6-cycloalkenyl-, and O6-(2-oxoalkyl)guanines and potentiation of temozolomide cytotoxicity in vitro by O6-(1-cyclopentenylmethyl)guanine. J. Med. Chem. 43(22), 4071–4083 (2000).
- 44 Substitution of aminomethyl at the meta-position enhances the inactivation of O6-alkylguanine-DNA alkyltransferase by O6-benzylguanine. J. Med. Chem. 51(22), 7144–7153 (2008).
- 45 Identification of the structural features of guanine derivatives as MGMT inhibitors using 3D-QSAR modeling combined with molecular docking. Molecules 21(7), 823 (2016). • An interesting investigation that provided an insight into the understanding of the structure–activity relationship of guanine derivatives as MGMT inhibitors and gave useful information for designing novel MGMT inhibitors with desired activity.
- 46 Synthesis and antitumor activity evaluation of a novel combi-nitrosourea prodrug: designed to release a DNA cross-linking agent and an inhibitor of O6-alkylguanine-DNA alkyltransferase. Bioorg. Med. Chem. 24(9), 2097–2107 (2016).
- 47 Synthesis and antitumor activity evaluation of a novel combinitrosourea prodrug: BGCNU. ACS Med. Chem. Lett. 8(2), 174–178 (2017).
- 48 . Inhibition of human O6-alkylguanine-DNA alkyltransferase and potentiation of the cytotoxicity of chloroethylnitrosourea by 4(6)-(benzyloxy)-2,6(4)-diamino-5-(nitro or nitroso)pyrimidine derivatives and analogues. J. Med. Chem. 41(4), 503–508 (1998).
- 49 Topologies of complexes containing O6-alkylguanine-DNA alkyltransferase and DNA. J. Mol. Biol. 389(2), 248–263 (2009).
- 50 Towards more specific O6-methylguanine-DNA methyltransferase (MGMT) inactivators. Bioorg. Med. Chem. 19(5), 1658–1665 (2011).
- 51 Structure-based discovery of novel non-nucleosidic DNA alkyltransferase inhibitors: virtual screening and in vitro and in vivo activities. J. Chem. Inf. Model. 48(4), 844–854 (2008).
- 52 . 6-Carboxyfluorescein and structurally similar molecules inhibit DNA binding and repair by O6-alkylguanine DNA alkyltransferase. DNA Repair 10(12), 1193–1202 (2011).
- 53 Chemoproteomics-enabled discovery of a potent and selective inhibitor of the DNA repair protein MGMT. Angew. Chem. Int. Ed. Engl. 55(8), 2911–2915 (2016).
- 54 . Inhibition by nitric oxide of the repair protein, O6-methylguanine-DNA-methyltransferase. Carcinogenesis 15(3), 443–447 (1994).
- 55 Inactivation and degradation of O6-alkylguanine-DNA alkyltransferase after reaction with nitric oxide. Cancer Res. 62(11), 3037–3043 (2002).
- 56 . The NO-releasing aspirin inactivates and degrades human MGMT more efficiently than O6-benzylguanine and greatly sensitizes brain tumor cells to alkylating agents. Proc. Am. Assoc. Cancer Res. 54, 1094 (2013).
- 57 HIF-1α inhibition sensitizes pituitary adenoma cells to temozolomide by regulating MGMT expression. Oncol. Rep. 30(5), 2495–2501 (2013).
- 58 Disulfiram is a direct and potent inhibitor of human O6-methylguanine-DNA methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage. Carcinogenesis 35(3), 692–702 (2014). • An excellent investigation demonstrated that alcohol aversion drug, disulfiram, is a direct and potent inhibitor of resistant MGMT protein.
- 59 Disulfiram sensitizes pituitary adenoma cells to temozolomide by regulating O6-methylguanine-DNA methyltransferase expression. Mol. Med. Rep. 12(2), 2313–2322 (2015).
- 60 Oxidative cytotoxic agent withaferin A resensitizes temozolomide-resistant glioblastomas via MGMT depletion and induces apoptosis through Akt/mTOR pathway inhibitory modulation. Invest. New Drugs 32(4), 604–617 (2014).
- 61 New insights into estrogenic regulation of O6-methylguanine DNA-methyltransferase (MGMT) in human breast cancer cells: co-degradation of ER-α and MGMT proteins by fulvestrant or O6-benzylguanine indicates fresh avenues for therapy. J. Biomed. Res. 30(5), 393–410 (2016).
- 62 Inactivation of O6-methylguanine-DNA methyltransferase by glucose-conjugated inhibitors. Int. J. Cancer. 93(3), 373–379 (2001).
- 63 Modulation of mammalian O6-alkylguanine-DNA alkyltransferase in vivo by O6-benzylguanine and its effect on the sensitivity of a human glioma tumor to 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea. Cancer Commun. 2(11), 371–377 (1990).
- 64 Enhancement of nitrosourea activity in medulloblastoma and glioblastoma-multiforme. J. Natl Cancer Inst. 84(24), 1926–1931 (1992).
- 65 Treatment of subcutaneous and intracranial brain-tumor xenografts with O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Chemother. Pharmacol. 32(6), 471–476 (1993).
- 66 Sensitization of pancreatic tumor xenografts to carmustine and temozolomide by inactivation of their O6-methylguanine-DNA methyltransferase with O6-benzylguanine or O6-benzyl-2′-deoxyguanosine. Clin. Cancer Res. 9(10), 3801–3807 (2003).
- 67 Intraarterial O6-benzylguanine enables the specific therapy of nitrosourea-resistant intracranial human glioma xenografts in athymic rats with 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Chemother. Pharmacol. 39(4), 307–316 (1997).
- 68 . O6-Benzylguanine enhances the sensitivity of a glioma xenograft with low O6-alkylguanine-DNA alkyltransferase activity to temozolomide and BCNU. Br. J. Cancer. 73(9), 1049–1052 (1996).
- 69 O6-benzylguanine-mediated enhancement of nitrosourea activity in Mer− central nervous system tumor xenografts – implications for clinical trials. Cancer Chemother. Pharmacol. 45(6), 437–440 (2000).
- 70 O6-(4-bromothenyl)guanine improves the therapeutic index of temozolomide against A375M melanoma xenografts. Int. J. Cancer 85(2), 248–252 (2000).
- 71 Effect of O6-(4-bromothenyl)guanine on different temozolomide schedules in a human melanoma xenograft model. Int. J. Cancer. 100(5), 615–617 (2002).
- 72 O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts. Br. J. Cancer. 93(10), 1152–1156 (2005).
- 73 Phase I clinical and pharmacological study of O6-benzylguanine followed by carmustine in patients with advanced cancer. Clin. Cancer Res. 6(8), 3025–3031 (2000).
- 74 Determination of the optimal modulatory dose of O6-benzylguanine in patients with surgically resectable tumors. Clin. Cancer Res. 8(8), 2519–2523 (2002).
- 75 Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma. J. Clin. Oncol. 23(28), 7178–7187 (2005).
- 76 Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma. J. Clin. Oncol. 18(20), 3522–3528 (2000).
- 77 Phase I trial of O6-benzylguanine and BCNU in children with CNS tumors: a children's oncology group study. Pediatr. Blood Cancer 50(3), 549–553 (2008).
- 78 Lomeguatrib, a potent inhibitor of O6-alkylguanine-DNA-alkyltransferase: Phase I safety, pharmacodynamic, and pharmacokinetic trial and evaluation in combination with temozolomide in patients with advanced solid tumors. Clin. Cancer Res. 12(5), 1577–1584 (2006).
- 79 A Phase I study of extended dosing with lomeguatrib with temozolomide in patients with advanced melanoma. Br. J. Cancer 100(8), 1245–1249 (2009).
- 80 Inhibition of DNA repair with MGMT pseudosubstrates: Phase I study of lomeguatrib in combination with dacarbazine in patients with advanced melanoma and other solid tumours. Br. J. Cancer 105(6), 773–777 (2011).
- 81 Pharmacokinetics of O6-benzylguanine (NSC637037) and its metabolite, 8-oxo-O6-benzylguanine. J. Clin. Pharmacol. 43(8), 881–893 (2003).
- 82 . Role of cytochrome P450 isoenzymes in metabolism of O6-benzylguanine: implications for dacarbazine activation. Clin. Cancer Res. 7(12), 4239–4244 (2001).
- 83 . Debenzylation of O6-benzyl-8-oxoguanine in human liver: implications for O6-benzylguanine metabolism. Biochem. Pharmacol. 61(6), 721–726 (2001).
- 84 Phase II trial of carmustine plus O6-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma. J. Clin. Oncol. 20(9), 2277–2283 (2002).
- 85 Phase II trial of the O6-alkylguanine DNA alkyltransferase inhibitor O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea in advanced melanoma. Clin. Cancer Res. 11(21), 7861–7865 (2005).
- 86 A Phase II trial of O6-benzylguanine and carmustine in patients with advanced soft tissue sarcoma. Cancer Chemother. Pharmacol. 58(5), 634–639 (2006).
- 87 O6-benzylguanine and BCNU in multiple myeloma: a Phase II trial. Cancer Chemother. Pharmacol. 60(3), 415–421 (2007).
- 88 Phase II trial of temozolomide plus O6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma. J. Clin. Oncol. 27(8), 1262–1267 (2009).
- 89 A Phase II study of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a Pediatric Brain Tumor Consortium study. J. Neurooncol. 106(3), 643–649 (2012).
- 90 Randomized trial of the combination of lomeguatrib and temozolomide compared with temozolomide alone in chemotherapy naive patients with metastatic cutaneous melanoma. J. Clin. Oncol. 25(18), 2540–2545 (2007).
- 91 A Phase II trial of lomeguatrib and temozolomide in metastatic colorectal cancer. Br. J. Cancer 98(10), 1614–1618 (2008).
- 92 . Improvement of chemotherapy efficacy by inactivation of a DNA-repair pathway. Lancet Oncol. 4(1), 37–44 (2003).
- 93 . Hallmarks of cancer: the next generation. Cell 144(5), 646–674 (2011).
- 94 Monosaccharide-linked inhibitors of O6-methylguanine-DNA methyltransferase (MGMT): synthesis, molecular modeling, and structure–activity relationships. J. Med. Chem. 44(24), 4050–4061 (2001).
- 95 Inhibition of O6-methylguanine-DNA methyltransferase by glucose-conjugated inhibitors: comparison with nonconjugated inhibitors and effect on fotemustine and temozolomide-induced cell death. J. Pharmacol. Exp. Ther. 311(2), 585–593 (2004).
- 96 . Prodrugs in medicinal chemistry and enzyme prodrug therapies. Adv. Drug Deliv. Rev. 118, 65–77 (2017).
- 97 O6-alkylguanine-DNA alkyltransferase inactivation by ester prodrugs of O6-benzylguanine derivatives and their rate of hydrolysis by cellular esterases. Biochem. Pharmacol. 55(10), 1701–1709 (1998).
- 98 Folate-maytansinoids: target-selective drugs of low molecular weight. Int. J. Cancer 73(6), 859–864 (1997).
- 99 2-Amino-O4-benzylpteridine derivatives: potent inactivators of O6-alkylguanine-DNA alkyltransferase. J. Med. Chem. 47(15), 3887–3891 (2004).
- 100 Inactivation of O6-alkylguanine-DNA alkyltransferase by folate esters of O6-benzyl-2′-deoxyguanosine and of O6-[4-(hydroxymethyl)benzyl]guanine. J. Med. Chem. 50(21), 5193–5201 (2007).
- 101 β-Glucuronidase-responsive prodrugs for selective cancer chemotherapy: an update. Eur. J. Med. Chem. 74, 302–313 (2014).
- 102 β-glucuronidase-cleavable prodrugs of O6-benzylguanine and O6-benzyl-2′-deoxyguanosine. J. Med. Chem. 48(1), 256–261 (2005).
- 103 . Targeting hypoxia in cancer therapy. Nat. Rev. Cancer. 11(6), 393–410 (2011).
- 104 4-Nitrobenzyloxycarbonyl derivatives of O6-benzylguanine as hypoxia-activated prodrug inhibitors of O6-alkylguanine-dna alkyltransferase (AGT), which produces resistance to agents targeting the O6 position of DNA guanine. J. Med. Chem. 54(21), 7720–7728 (2011). •• A typical example of hypoxia-activated MGMT inhibitors with tumor targeting ability.
- 105 Design of a hypoxia-activated prodrug inhibitor of O6-alkylguanine-DNA alkyltransferase. Bioorg. Med. Chem. Lett. 22(19), 6242–6247 (2012).
- 106 A strategy for selective O6-alkylguanine-DNA alkyltransferase depletion under hypoxic conditions. Chem. Biol. Drug. Des. 80(2), 279–290 (2012).
- 107 Hypoxia-selective O6-alkylguanine-DNA alkyltransferase inhibitors: design, synthesis, and evaluation of 6-(benzyloxy)-2-(aryldiazenyl)-9H-purines as prodrugs of O6-benzylguanine. J. Med. Chem. 56(3), 1355–1359 (2013).
- 108 Recent advances in brain tumor therapy: local intracerebral drug delivery by polymers. Invest. New Drugs 22(1), 27–37 (2004).
- 109 . Advanced interstitial chemotherapy for treating malignant glioma. Expert Opin. Drug Del. 13(11), 1533–1544 (2016).
- 110 Phase I trial of polifeprosan 20 with carmustine implant plus continuous infusion of intravenous O6-benzylguanine in adults with recurrent malignant glioma: new approaches to brain tumor therapy CNS consortium trial. J. Clin. Oncol. 25(4), 399–404 (2007).
- 111 Phase II trial of Gliadel plus O6-benzylguanine in adults with recurrent glioblastoma multiforme. Clin. Cancer Res. 15(3), 1064–1068 (2009).
- 112 Phase I clinical trial of O6-benzylguanine and topical carmustine in the treatment of cutaneous T-cell lymphoma, Mycosis Fungoides Type. Arch. Dermatol. 148(5), 613–620 (2012).
- 113 Evaluation of O6-benzylguanine-potentiated topical carmustine for Mycosis Fungoides: a Phase I–II clinical trial. JAMA Dermatol. 153(5), 413–420 (2017).
- 114 Local intracerebral administration of O6-benzylguanine combined with systemic chemotherapy with temozolomide of a patient suffering from a recurrent glioblastoma. J. Neurooncol. 82(1), 85–89 (2007).
- 115 Protection of CHO cells by mutant forms of O6-alkylguanine-DNA alkyltransferase from killing by 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) plus O6-benzylguanine or O6-benzyl-8-oxoguanine. Biochem. Pharmacol. 58(2), 237–244 (1999).
- 116 Selection for G156A O6-methylguanine DNA methyltransferase gene-transduced hematopoietic progenitors and protection from lethality in mice treated with O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Res. 57(22), 5093–5099 (1997).
- 117 . Limiting numbers of G156A O6-methylguanine-DNA methyltransferase-transduced marrow progenitors repopulate nonmyeloablated mice after drug selection. Blood 95(10), 3078–3084 (2000).
- 118 Direct reversal of DNA damage by mutant methyltransferase protein protects mice against dose-intensified chemotherapy and leads to in vivo selection of hematopoietic stem cells. Cancer Res. 60(18), 5187–5195 (2000).
- 119 Hematoprotection and enrichment of transduced cells in vivo after gene transfer of MGMTP140K into hematopoietic stem cells. Cancer Gene Ther. 9(9), 737–746 (2002).
- 120 Stable differentiation and clonality of murine long-term hematopoiesis after extended reduced-intensity selection for MGMT P140K transgene expression. Blood 110(6), 1779–1787 (2007).
- 121 Mutations in human O6-alkylguanine-DNA alkyltransferase imparting resistance to O6-benzylguanine. Cancer Res. 54(23), 6221–6227 (1994).
- 122 . Isolation of human O6-alkylguanine-DNA alkyltransferase mutants highly resistant to inactivation by O6-benzylguanine. Cancer Res. 58(9), 1936–1945 (1998).
- 123 The P140K mutant of human O6-methylguanine-DNA-methyttransferase (MGMT) confers resistance in vitro and in vivo to temozolomide in combination with the novel MGMT inactivator O6-(4-bromothenyl)guanine. J. Gene Med. 8(1), 29–34 (2006).
- 124 Polyclonal chemoprotection against temozolomide in a large-animal model of drug resistance gene therapy. Blood 105(3), 997–1002 (2005).
- 125 Efficient and stable MGMT-mediated selection of long-term repopulating stem cells in nonhuman primates. J. Clin. Invest. 120(7), 2345–2354 (2010).
- 126 Chemoprotection of human hematopoietic stem cells by simultaneous lentiviral overexpression of multidrug resistance 1 and O6-methylguanine-DNA methyltransferase(P140K). Gene Ther. 17(3), 389–399 (2010).
- 127 F2A sequence linking MGMTP140K and MDR1 in a bicistronic lentiviral vector enables efficient chemoprotection of haematopoietic stem cells. Cancer Gene Ther. 19(11), 802–810 (2012).
- 128 Delta MGMT-transduced bone marrow infusion increases tolerance to O6-benzylguanine and 1,3-bis(2-chloroethy1)-1-nitrosourea and allows intensive therapy of 1,3-bis(2-chloroethyl)-1-nitrosourea-resistant human colon cancer xenografts. Hum Gene Ther. 10(6), 1021–1030 (1999).