The human DNA repair protein, O6-alkylguanine-DNA alkyltransferase is primarily responsible for the resistance exhibited by tumor cells to a number of chemotherapeutic drugs. This project focuses on design, synthesis and development of drugs that can inactivate this protein. The drugs are used as adjuvants to enhance the effectiveness of chemotherapeutic agents that modify the O6-position of DNA guanine residues.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
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Basic Sciences
United States
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Javanmard, Sahar; Loktionova, Natalia A; Fang, Qingming et al. (2007) Inactivation of O(6)-alkylguanine-DNA alkyltransferase by folate esters of O(6)-benzyl-2'-deoxyguanosine and of O(6)-[4-(hydroxymethyl)benzyl]guanine. J Med Chem 50:5193-201
Fishel, Melissa L; Rabik, Cara A; Bleibel, Wasim K et al. (2006) Role of GADD34 in modulation of cisplatin cytotoxicity. Biochem Pharmacol 71:239-47
Fishel, Melissa L; Gamcsik, Michael P; Delaney, Shannon M et al. (2005) Role of glutathione and nucleotide excision repair in modulation of cisplatin activity with O6-benzylguanine. Cancer Chemother Pharmacol 55:333-42
Fishel, Melissa L; Newell, David R; Griffin, Roger J et al. (2005) Effect of cell cycle inhibition on Cisplatin-induced cytotoxicity. J Pharmacol Exp Ther 312:206-13
Wei, Guangping; Loktionova, Natalia A; Pegg, Anthony E et al. (2005) Beta-glucuronidase-cleavable prodrugs of O6-benzylguanine and O6-benzyl-2'-deoxyguanosine. J Med Chem 48:256-61
Ewesuedo, R B; Wilson, L R; Friedman, H S et al. (2001) Inactivation of O6-alkylguanine-DNA alkyltransferase by 8-substituted O6-benzylguanine analogs in mice. Cancer Chemother Pharmacol 47:63-9
Pegg, A E; Goodtzova, K; Loktionova, N A et al. (2001) Inactivation of human O(6)-alkylguanine-DNA alkyltransferase by modified oligodeoxyribonucleotides containing O(6)-benzylguanine. J Pharmacol Exp Ther 296:958-65
Kokkinakis, D M; Bocangel, D B; Schold, S C et al. (2001) Thresholds of O6-alkylguanine-DNA alkyltransferase which confer significant resistance of human glial tumor xenografts to treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea or temozolomide. Clin Cancer Res 7:421-8