Biopolym. Cell. 2001; 17(4):265-277.
Обзоры
Роль О6-алкилгуанин-ДНК алкилтрансферазы в репарации повреждений, индуцированных алкилирующими соединениями
1Лукаш Л. Л., 1Манько В. Г., 1Лыло В. В.
  1. Институт молекулярной биологии и генетики НАН Украины
    ул. Академика Заболотного, 150, Киев, Украина, 03680

Abstract

Обзор посвящен теоретическому изучению и практическому применению алкилтрансфераз, осуществляющих защиту клеток от цитотоксического и мутагенного воздействия алкилирующих соединений путем восстановления повреждений в ДНК

References

[1] Pegg AE. Alkylation and subsequent repair of DNA after exposure to dimethylnitrosoamine and carcinogenesis. Rev Biochem Toxicol. 1983; 5 (1): 83-133.
[2] Goodtzova K, Crone TM, Pegg AE. Activation of human O6-alkylguanine-DNA alkyltransferase by DNA. Biochemistry. 1994;33(28):8385-90.
[3] Lindahl T, Sedgwick B, Sekiguchi M, Nakabeppu Y. Regulation and expression of the adaptive response to alkylating agents. Annu Rev Biochem. 1988;57:133-57.
[4] Pegg AE, Byers TL. Repair of DNA containing O6-alkylguanine. FASEB J. 1992;6(6):2302-10.
[5] McCarthy TV, Lindahl T. Methyl phosphotriesters in alkylated DNA are repaired by the Ada regulatory protein of E. coli. Nucleic Acids Res. 1985;13(8):2683-98.
[6] Gorbacheva LB, Kukushkina. GV. Role of 0(6)-alkylguanine DNA alkyltransferase in the implementation of the antitumor activity of N-nitrosoureas (a review). Pharmaceutical Chemistry Journal. 1989. 4: 281-7.
[7] Potter PM, Wilkinson MC, Fitton J, Carr FJ, Brennand J, Cooper DP, Margison GP. Characterisation and nucleotide sequence of ogt, the O6-alkylguanine-DNA-alkyltransferase gene of E. coli. Nucleic Acids Res. 1987;15(22):9177-93.
[8] Wilkinson MC, Potter PM, Cawkwell L, Georgiadis P, Patel D, Swann PF, Margison GP. Purification of the E. coli ogt gene product to homogeneity and its rate of action on O6-methylguanine, O6-ethylguanine and O4-methylthymine in dodecadeoxyribonucleotides. Nucleic Acids Res. 1989;17(21):8475-84.
[9] Rebeck GW, Smith CM, Goad DL, Samson L. Characterization of the major DNA repair methyltransferase activity in unadapted Escherichia coli and identification of a similar activity in Salmonella typhimurium. J Bacteriol. 1989;171(9):4563-8.
[10] Kodama KI, Nakabeppu Y, Sekiguchi M. Cloning and expression of the Bacillus subtilis methyltransferase gene in Escherichia coli ada- cells. Mutat Res. 1989;218(2):153-63.
[11] Pegg AE, Dolan ME, Moschel RC. Structure, function, and inhibition of O6-alkylguanine-DNA alkyltransferase. Prog Nucleic Acid Res Mol Biol. 1995;51:167-223.
[12] Day RS 3rd, Ziolkowski CH, Scudiero DA, Meyer SA, Lubiniecki AS, Girardi AJ, Galloway SM, Bynum GD. Defective repair of alkylated DNA by human tumour and SV40-transformed human cell strains. Nature. 1980;288(5792):724-7.
[13] Yarosh DB. The role of O6-methylguanine-DNA methyltransferase in cell survival, mutagenesis and carcinogenesis. Mutat Res. 1985;145(1-2):1-16.
[14] Arita I, Tachibana A, Takebe H, Tatsumi K. Predominance of Mex+ cells in newly-established human lymphoblastoid cell lines. Carcinogenesis. 1989;10(11):2067-73.
[15] Green MH, Lowe JE, Petit-Fr?re C, Karran P, Hall J, Kataoka H. Properties of N-methyl-N-nitrosourea-resistant, Mex- derivatives of an SV40-immortalized human fibroblast cell line. Carcinogenesis. 1989;10(5):893-8.
[16] Karran P, Lindahl T, Griffin B. Adaptive response to alkylating agents involves alteration in situ of O6-methylguanine residues in DNA. Nature. 1979;280(5717):76-7.
[17] Brennand J, Margison GP. Reduction of the toxicity and mutagenicity of alkylating agents in mammalian cells harboring the Escherichia coli alkyltransferase gene. Proc Natl Acad Sci U S A. 1986;83(17):6292-6.
[18] Sklar R, Strauss B. Removal of O6-methylguanine from DNA of normal and xeroderma pigmentosum-derived lymphoblastoid lines. Nature. 1981;289(5796):417-20.
[19] Yarosh DB, Foote RS, Mitra S, Day RS 3rd. Repair of O6-methylguanine in DNA by demethylation is lacking in Mer- human tumor cell strains. Carcinogenesis. 1983;4(2):199-205.
[20] Yagi T, Yarosh DB, Day RS 3rd. Comparison of repair of O6-methylguanine produced by N-methyl-N'-nitro-N-nitrosoguanidine in mouse and human cells. Carcinogenesis. 1984;5(5):593-600.
[21] Yagi T, Day RS 3rd. Differential sensitivities of transformed and untransformed murine cell lines to DNA cross-linking agents relative to repair of O6-methylguanine. Mutat Res. 1987;184(3):223-7.
[22] Cohen A, Leung C. O6-methylguanine-DNA methyltransferase activity and sensitivity to N-methyl-N'-nitro-nitrosoguanidine during human T-lymphocyte differentiation. Carcinogenesis. 1986;7(11):1877-9.
[23] Goth R, Rajewsky MF. Persistence of O6-ethylguanine in rat-brain DNA: correlation with nervous system-specific carcinogenesis by ethylnitrosourea. Proc Natl Acad Sci U S A. 1974;71(3):639-43.
[24] Saffhill R, Margison GP, O'Connor PJ. Mechanisms of carcinogenesis induced by alkylating agents. Biochim Biophys Acta. 1985;823(2):111-45.
[25] Bertini R, Coccia P, Pagani P, Marinello C, Salmona M, D'Incalci M. Interferon inducers increase O6-alkylguanine-DNA alkyltransferase in the rat liver. Carcinogenesis. 1990;11(1):181-3.
[26] Frosina G, Laval F. The O6-methylguanine-DNA-methyltransferase activity of rat hepatoma cells is increased after a single exposure to alkylating agents. Carcinogenesis. 1987;8(1):91-5.
[27] Coccia P, Sen S, Erba E, Pagani P, Marinello C, D'Incalci M. O6-Alkylguanine-DNA alkyltransferase content in synchronised human cancer cells. Cancer Chemother Pharmacol. 1992;30(1):77-80.
[28] Jankun J, Maher VM, McCormick JJ. Malignant transformation of human fibroblasts correlates with increased activity of receptor-bound plasminogen activator. Cancer Res. 1991;51(4):1221-6.
[29] Chan CL, Wu Z, Eastman A, Bresnick E. Irradiation-induced expression of O6-methylguanine-DNA methyltransferase in mammalian cells. Cancer Res. 1992;52(7):1804-9.
[30] Wilson RE, Hoey B, Margison GP. Ionizing radiation induces O6-alkylguanine-DNA-alkyltransferase mRNA and activity in mouse tissues. Carcinogenesis. 1993;14(4):679-83.
[31] Fritz G, Kaina B. Stress factors affecting expression of O6-methylguanine-DNA methyltransferase mRNA in rat hepatoma cells. Biochim Biophys Acta. 1992;1171(1):35-40.
[32] Mitra G, Pauly GT, Kumar R, Pei GK, Hughes SH, Moschel RC, Barbacid M. Molecular analysis of O6-substituted guanine-induced mutagenesis of ras oncogenes. Proc Natl Acad Sci U S A. 1989;86(22):8650-4.
[33] Olsson M, Lindahl T. Repair of alkylated DNA in Escherichia coli. Methyl group transfer from O6-methylguanine to a protein cysteine residue. J Biol Chem. 1980;255(22):10569-71.
[34] Yarosh DB, Barnes D, Erickson LC. Transfection of DNA from a chloroethylnitrosourea-resistant tumor cell line (MER+) to a sensitive tumor cell line (MER-) results in a tumor cell line resistant to MNNG and CNU that has increased O-6-methylguanine-DNA methyltransferase levels and reduced levels of DNA interstrand crosslinking. Carcinogenesis. 1986;7(9):1603-6.
[35] Kyrtopoulos SA. O6-Alkylguanine-DNA alkyltransferase: influence on susceptibility to the genetic effects of alkylating agents. Toxicol Lett. 1998;102-103:53-7.
[36] Scicchitano DA, Pegg AE. Inhibition of O6-alkylguanine-DNA-alkyltransferase by metals. Mutat Res. 1987;192(3):207-10.
[37] Bhattacharyya D, Boulden AM, Foote RS, Mitra S. Effect of polyvalent metal ions on the reactivity of human O6-methylguanine-DNA methyltransferase. Carcinogenesis. 1988;9(4):683-5.
[38] Pegg AE. Mammalian O6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Res. 1990;50(19):6119-29.
[39] Spratt TE, Wu JD, Levy DE, Kanugula S, Pegg AE. Reaction and binding of oligodeoxynucleotides containing analogues of O6-methylguanine with wild-type and mutant human O6-alkylguanine-DNA alkyltransferase. Biochemistry. 1999;38(21):6801-6.
[40] Samson L. The suicidal DNA repair methyltransferases of microbes. Mol Microbiol. 1992;6(7):825-31.
[41] Graves RJ, Li BF, Swann PF. Repair of O6-methylguanine, O6-ethylguanine, O6-isopropylguanine and O4-methylthymine in synthetic oligodeoxynucleotides by Escherichia coli ada gene O6-alkylguanine-DNA-alkyltransferase. Carcinogenesis. 1989;10(4):661-6.
[42] Brent TP, Dolan ME, Fraenkel-Conrat H, Hall J, Karran P, Laval L, Margison GP, Montesano R, Pegg AE, Potter PM, et al. Repair of O-alkylpyrimidines in mammalian cells: a present consensus. Proc Natl Acad Sci U S A. 1988;85(6):1759-62.
[43] Sassanfar M, Dosanjh MK, Essigmann JM, Samson L. Relative efficiencies of the bacterial, yeast, and human DNA methyltransferases for the repair of O6-methylguanine and O4-methylthymine. Suggestive evidence for O4-methylthymine repair by eukaryotic methyltransferases. J Biol Chem. 1991;266(5):2767-71.
[44] Elder RH, Margison GP, Rafferty JA. Differential inactivation of mammalian and Escherichia coli O6-alkylguanine-DNA alkyltransferases by O6-benzylguanine. Biochem J. 1994;298 ( Pt 1):231-5.
[45] Dolan ME, Morimoto K, Pegg AE. Reduction of O6-alkylguanine-DNA alkyltransferase activity in HeLa cells treated with O6-alkylguanines. Cancer Res. 1985;45(12 Pt 1):6413-7.
[46] Karran P. Possible depletion of a DNA repair enzyme in human lymphoma cells by subversive repair. Proc Natl Acad Sci U S A. 1985;82(16):5285-9.
[47] Morimoto K, Dolan ME, Scicchitano D, Pegg AE. Repair of O6-propylguanine and O6-butylguanine in DNA by O6-alkylguanine-DNA alkyltransferases from rat liver and E. coli. Carcinogenesis. 1985;6(7):1027-31.
[48] Dolan ME, Moschel RC, Pegg AE. 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 U S A. 1990;87(14):5368-72.
[49] Wilkinson MC, Potter PM, Cawkwell L, Georgiadis P, Patel D, Swann PF, Margison GP. Purification of the E. coli ogt gene product to homogeneity and its rate of action on O6-methylguanine, O6-ethylguanine and O4-methylthymine in dodecadeoxyribonucleotides. Nucleic Acids Res. 1989;17(21):8475-84.
[50] Liem LK, Lim A, Li BF. Specificities of human, rat and E. coli O6-methylguanine-DNA methyltransferases towards the repair of O6-methyl and O6-ethylguanine in DNA. Nucleic Acids Res. 1994;22(9):1613-9.
[51] Peterson LA, Liu XK, Hecht SS. Pyridyloxobutyl DNA adducts inhibit the repair of O6-methylguanine. Cancer Res. 1993;53(12):2780-5.
[52] Mackay WJ, Han S, Samson LD. DNA alkylation repair limits spontaneous base substitution mutations in Escherichia coli. J Bacteriol. 1994;176(11):3224-30.
[53] Liem LK, Wong CW, Lim A, Li BF. Factors influencing the repair of the mutagenic lesion O6-methylguanine in DNA by human O6-methylguanine-DNA methyltransferase. J Mol Biol. 1993;231(4):950-9.
[54] Scicchitano D, Jones RA, Kuzmich S, Gaffney B, Lasko DD, Essigmann JM, Pegg AE. Repair of oligodeoxynucleotides containing O6-methylguanine by O6-alkylguanine-DNA-alkyltransferase. Carcinogenesis. 1986;7(8):1383-6.
[55] Dolan ME, Oplinger M, Pegg AE. Sequence specificity of guanine alkylation and repair. Carcinogenesis. 1988;9(11):2139-43.
[56] Topal MD. DNA repair, oncogenes and carcinogenesis. Carcinogenesis. 1988;9(5):691-6.
[57] Georgiadis P, Smith CA, Swann PF. Nitrosamine-induced cancer: selective repair and conformational differences between O6-methylguanine residues in different positions in and around codon 12 of rat H-ras. Cancer Res. 1991;51(21):5843-50.
[58] Wong CW, Tan NW, Li BF. Structure-related properties of the mutagenic lesion 6-O-methylguanine in DNA. J Mol Biol. 1992;228(4):1137-46.
[59] Bishop RE, Dunn LL, Pauly GT, Dolan ME, Moschel RC. The role of O6-alkylguanine-DNA alkyltransferase in protecting Rat4 cells against the mutagenic effects of O6-substituted guanine residues incorporated in codon 12 of the H-ras gene. Carcinogenesis. 1993;14(4):593-8.
[60] Thomale J, Hochleitner K, Rajewsky MF. Differential formation and repair of the mutagenic DNA alkylation product O6-ethylguanine in transcribed and nontranscribed genes of the rat. J Biol Chem. 1994;269(3):1681-6.
[61] Natarajan AT, Vermeulen S, Darroudi F, Valentine MB, Brent TP, Mitra S, Tano K. Chromosomal localization of human O6-methylguanine-DNA methyltransferase (MGMT) gene by in situ hybridization. Mutagenesis. 1992;7(1):83-5.
[62] Shiraishi A, Sakumi K, Nakatsu Y, Hayakawa H, Sekiguchi M. Isolation and characterization of cDNA and genomic sequences for mouse O6-methylguanine-DNA methyltransferase. Carcinogenesis. 1992;13(2):289-96.
[63] Nakatsu Y, Hattori K, Hayakawa H, Shimizu K, Sekiguchi M. Organization and expression of the human gene for O6-methylguanine-DNA methyltransferase. Mutat Res. 1993;293(2):119-32.
[64] Musarrat J, Wilson JA, Abou-Issa H, Wani AA. O(6)-alkylguanine DNA alkyltransferase activity levels in normal, benign and malignant human female breast. Biochem Biophys Res Commun. 1995;208(2):688-96.
[65] Belanich M, Pastor M, Randall T, Guerra D, Kibitel J, Alas L, Li B, Citron M, Wasserman P, White A, Eyre H, Jaeckle K, Schulman S, Rector D, Prados M, Coons S, Shapiro W, Yarosh D. Retrospective study of the correlation between the DNA repair protein alkyltransferase and survival of brain tumor patients treated with carmustine. Cancer Res. 1996;56(4):783-8.
[66] Baer JC, Freeman AA, Newlands ES, Watson AJ, Rafferty JA, Margison GP. Depletion of O6-alkylguanine-DNA alkyltransferase correlates with potentiation of temozolomide and CCNU toxicity in human tumour cells. Br J Cancer. 1993;67(6):1299-302.
[67] Mitchell RB, Dolan ME. Effect of temozolomide and dacarbazine on O6-alkylguanine-DNA alkyltransferase activity and sensitivity of human tumor cells and xenografts to 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Chemother Pharmacol. 1993;32(1):59-63.
[68] Harris LC, Margison GP. Expression in mammalian cells of the Escherichia coli O6 alkylguanine-DNA-alkyltransferase gene ogt reduces the toxicity of alkylnitrosoureas. Br J Cancer. 1993;67(6):1196-202.
[69] Erickson LC, Laurent G, Sharkey NA, Kohn KW. DNA cross-linking and monoadduct repair in nitrosourea-treated human tumour cells. Nature. 1980;288(5792):727-9.
[70] Brent TP, Houghton PJ, Houghton JA. O6-Alkylguanine-DNA alkyltransferase activity correlates with the therapeutic response of human rhabdomyosarcoma xenografts to 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea. Proc Natl Acad Sci U S A. 1985;82(9):2985-9.
[71] Aida T, Bodell WJ. Cellular resistance to chloroethylnitrosoureas, nitrogen mustard, and cis-diamminedichloroplatinum(II) in human glial-derived cell lines. Cancer Res. 1987;47(5):1361-6.
[72] Laval F, Laval J. Adaptive response in mammalian cells: crossreactivity of different pretreatments on cytotoxicity as contrasted to mutagenicity. Proc Natl Acad Sci U S A. 1984;81(4):1062-6.
[73] Myrnes B, Giercksky KE, Krokan H. Interindividual variation in the activity of O6-methyl guanine-DNA methyltransferase and uracil-DNA glycosylase in human organs. Carcinogenesis. 1983;4(12):1565-8.
[74] Ludlum DB. DNA alkylation by the haloethylnitrosoureas: nature of modifications produced and their enzymatic repair or removal. Mutat Res. 1990;233(1-2):117-26.
[75] Brent TP. Isolation and purification of O6-alkylguanine-DNA alkyltransferase from human leukemic cells. Prevention of chloroethylnitrosourea-induced cross-links by purified enzyme. Pharmacol Ther. 1985;31(1-2):121-40.
[76] Gonzaga PE, Potter PM, Niu TQ, Yu D, Ludlum DB, Rafferty JA, Margison GP, Brent TP. Identification of the cross-link between human O6-methylguanine-DNA methyltransferase and chloroethylnitrosourea-treated DNA. Cancer Res. 1992;52(21):6052-8.
[77] Mitchell RB, Moschel RC, Dolan ME. Effect of O6-benzylguanine on the sensitivity of human tumor xenografts to 1,3-bis(2-chloroethyl)-1-nitrosourea and on DNA interstrand cross-link formation. Cancer Res. 1992;52(5):1171-5.
[78] Erickson LC, Bradley MO, Ducore JM, Ewig RA, Kohn KW. DNA crosslinking and cytotoxicity in normal and transformed human cells treated with antitumor nitrosoureas. Proc Natl Acad Sci U S A. 1980;77(1):467-71.
[79] Singer B, Essigmann JM. Site-specific mutagenesis: retrospective and prospective. Carcinogenesis. 1991;12(6):949-55.
[80] Moschel RC, Hudgins WR, Dipple A. Reactivity effects on site selectivity in nucleoside aralkylation: a model for the factors influencing the sites of carcinogen-nucleic acid interactions. J Org Chem. 1986;51(22):4180–5.
[81] Loechler EL. A violation of the Swain-Scott principle, and not SN1 versus SN2 reaction mechanisms, explains why carcinogenic alkylating agents can form different proportions of adducts at oxygen versus nitrogen in DNA. Chem Res Toxicol. 1994;7(3):277-80.
[82] Jansen JG, de Groot AJ, van Teijlingen CM, Lohman PH, Mohn GR, Vrieling H, van Zeeland AA. Formation and persistence of DNA adducts in pouch skin fibroblasts and liver tissue of rats exposed in vivo to the monofunctional alkylating agents N-methyl-N-nitrosourea or N-ethyl-N-nitrosourea. Mutat Res. 1994;307(1):95-105.
[83] Singer B, Dosanjh MK. Site-directed mutagenesis for quantitation of base-base interactions at defined sites. Mutat Res. 1990;233(1-2):45-51.
[84] Tan HB, Swann PF, Chance EM. Kinetic analysis of the coding properties of O6-methylguanine in DNA: the crucial role of the conformation of the phosphodiester bond. Biochemistry. 1994;33(17):5335-46.
[85] Swann PF. Why do O6-alkylguanine and O4-alkylthymine miscode? The relationship between the structure of DNA containing O6-alkylguanine and O4-alkylthymine and the mutagenic properties of these bases. Mutat Res. 1990;233(1-2):81-94.
[86] Yang JL, Hsieh FP, Lee PC, Tseng HJ. Strand- and sequence-specific attenuation of N-methyl-N'-nitro-N-nitrosoguanidine-induced G.C to A.T transitions by expression of human 6-methylguanine-DNA methyltransferase in Chinese hamster ovary cells. Cancer Res. 1994;54(14):3857-63.
[87] Lukash LL, Boldt J, Pegg AE, Dolan ME, Maher VM, McCormick JJ. Effect of O6-alkylguanine-DNA alkyltransferase on the frequency and spectrum of mutations induced by N-methyl-N'-nitro-N-nitrosoguanidine in the HPRT gene of diploid human fibroblasts. Mutat Res. 1991;250(1-2):397-409.
[88] Rebeck GW, Samson L. Increased spontaneous mutation and alkylation sensitivity of Escherichia coli strains lacking the ogt O6-methylguanine DNA repair methyltransferase. J Bacteriol. 1991;173(6):2068-76.
[89] Rold?n-Arjona T, Luque-Romero FL, Ariza RR, Jurado J, Pueyo C. Influence of DNA repair by ada and ogt alkyltransferases on the mutational specificity of alkylating agents. Mol Carcinog. 1994;9(4):200-9.
[90] Aquilina G, Biondo R, Dogliotti E, Meuth M, Bignami M. Expression of the endogenous O6-methylguanine-DNA-methyltransferase protects Chinese hamster ovary cells from spontaneous G:C to A:T transitions. Cancer Res. 1992;52(23):6471-5.
[91] Sikpi MO, Waters LC, Kraemer KH, Preston RJ, Mitra S. N-methyl-N-nitrosourea-induced mutations in a shuttle plasmid replicated in human cells. Mol Carcinog. 1990;3(1):30-6.
[92] Dunn WC, Tano K, Horesovsky GJ, Preston RJ, Mitra S. The role of O6-alkylguanine in cell killing and mutagenesis in Chinese hamster ovary cells. Carcinogenesis. 1991;12(1):83-9.
[93] Moriwaki S, Yagi T, Nishigori C, Imamura S, Takebe H. Analysis of N-methyl-N-nitrosourea-induced mutations in a shuttle vector plasmid propagated in mouse O6-methylguanine-DNA methyltransferase-deficient cells in comparison with proficient cells. Cancer Res. 1991;51(23 Pt 1):6219-23.
[94] Palombo F, Kohfeldt E, Calcagnile A, Nehls P, Dogliotti E. N-methyl-N-nitrosourea-induced mutations in human cells. Effects of the transcriptional activity of the target gene. J Mol Biol. 1992;226(3):909.
[95] Cariello NF, Skopek TR. Analysis of mutations occurring at the human hprt locus. J Mol Biol. 1993;231(1):41-57.
[96] Yang JL, Lin JG, Hu MC, Wu CW. Mutagenicity and mutational spectrum of N-methyl-N'-nitro-N-nitrosoguanidine in the hprt gene in G1-S and late S phase of diploid human fibroblasts. Cancer Res. 1993;53(12):2865-73.
[97] Akagi T, Hiromatsu K, Iyehara-Ogawa H, Kimura H, Kato T. Specificity of mutations induced by N-methyl-N-nitrosourea in a cDNA of the hprt gene. Carcinogenesis. 1993;14(4):725-9.
[98] Jansen JG, Mohn GR, Vrieling H, van Teijlingen CM, Lohman PH, van Zeeland AA. Molecular analysis of hprt gene mutations in skin fibroblasts of rats exposed in vivo to N-methyl-N-nitrosourea or N-ethyl-N-nitrosourea. Cancer Res. 1994;54(9):2478-85.
[99] Benigni R, Palombo F, Dogliotti E. Multivariate statistical analysis of mutational spectra of alkylating agents. Mutat Res. 1992;267(1):77-88.
[100] Jiao J, Glickman BW, Anderson MW, Zielinska M. Mutational specificity of N-nitrosodimethylamine: comparison between in vivo and in vitro assays. Mutat Res. 1993;301(1):27-31.
[101] Ariza RR, Rold?n-Arjona T, Hera C, Pueyo C. A method for selection of forward mutations in supF gene carried by shuttle-vector plasmids. Carcinogenesis. 1993;14(2):303-5.
[102] Belinsky SA, Devereux TR, Maronpot RR, Stoner GD, Anderson MW. Relationship between the formation of promutagenic adducts and the activation of the K-ras protooncogene in lung tumors from A/J mice treated with nitrosamines. Cancer Res. 1989;49(19):5305-11.
[103] Wang Y, You M, Reynolds SH, Stoner GD, Anderson MW. Mutational activation of the cellular Harvey ras oncogene in rat esophageal papillomas induced by methylbenzylnitrosamine. Cancer Res. 1990;50(5):1591-5.
[104] Zarbl H, Sukumar S, Arthur AV, Martin-Zanca D, Barbacid M. Direct mutagenesis of Ha-ras-1 oncogenes by N-nitroso-N-methylurea during initiation of mammary carcinogenesis in rats. Nature. 1985 May 30-Jun 5;315(6018):382-5.
[105] Richardson FC, Richardson KK. Sequence-dependent formation of alkyl DNA adducts: a review of methods, results, and biological correlates. Mutat Res. 1990;233(1-2):127-38.
[106] Shoukry S, Anderson MW, Glickman BW. Use of fluorescently tagged DNA and an automated DNA sequencer for the comparison of the sequence selectivity of SN1 and SN2 alkylating agents. Carcinogenesis. 1993;14(1):155-7.
[107] Basic-Zaninovic T, Palombo F, Bignami M, Dogliotti E. Fidelity of replication of the leading and the lagging DNA strands opposite N-methyl-N-nitrosourea-induced DNA damage in human cells. Nucleic Acids Res. 1992;20(24):6543-8.
[108] Dosanjh MK, Galeros G, Goodman MF, Singer B. Kinetics of extension of O6-methylguanine paired with cytosine or thymine in defined oligonucleotide sequences. Biochemistry. 1991;30(49):11595-9.
[109] Harbach PR, Filipunas AL, Wang Y, Aaron CS. DNA sequence analysis of spontaneous and N-ethyl-N-nitrosourea-induced hprt mutations arising in vivo in cynomolgus monkey T-lymphocytes. Environ Mol Mutagen. 1992;20(2):96-105.
[110] Yang JL, Lee PC, Lin SR, Lin JG. Comparison of mutation spectra induced by N-ethyl-N-nitrosourea in the hprt gene of Mer+ and Mer- diploid human fibroblasts. Carcinogenesis. 1994;15(5):939-45.
[111] Bronstein SM, Cochrane JE, Craft TR, Swenberg JA, Skopek TR. Toxicity, mutagenicity, and mutational spectra of N-ethyl-N-nitrosourea in human cell lines with different DNA repair phenotypes. Cancer Res. 1991;51(19):5188-97.
[112] Abril N, Hera C, Alejandre E, Rafferty JA, Margison GP, Pueyo C. Effect of ogt expression on mutation induction by methyl-, ethyl- and propylmethanesulphonate in Escherichia coli K12 strains. Mol Gen Genet. 1994;242(6):744-8.
[113] Abril N, Rold?n-Arjona T, Prieto-Alamo MJ, van Zeeland AA, Pueyo C. Mutagenesis and DNA repair for alkylation damages in Escherichia coli K-12. Environ Mol Mutagen. 1992;19(4):288-96.
[114] Samson L, Thomale J, Rajewsky MF. Alternative pathways for the in vivo repair of O6-alkylguanine and O4-alkylthymine in Escherichia coli: the adaptive response and nucleotide excision repair. EMBO J. 1988;7(7):2261-7.
[115] Pourzand C, Cerutti P. Mutagenesis of H-ras codons 11 and 12 in human fibroblasts by N-ethyl-N-nitrosourea. Carcinogenesis. 1993;14(10):2193-6.
[116] Thomale J, Seiler F, M?ller MR, Seeber S, Rajewsky MF. Repair of O6-alkylguanines in the nuclear DNA of human lymphocytes and leukaemic cells: analysis at the single-cell level. Br J Cancer. 1994;69(4):698-705.
[117] Bronstein SM, Hooth MJ, Swenberg JA, Skopek TR. Modulation of ethylnitrosourea-induced toxicity and mutagenicity in human cells by O6-benzylguanine. Cancer Res. 1992;52(14):3851-6.
[118] Bronstein SM, Skopek TR, Swenberg JA. Efficient repair of O6-ethylguanine, but not O4-ethylthymine or O2-ethylthymine, is dependent upon O6-alkylguanine-DNA alkyltransferase and nucleotide excision repair activities in human cells. Cancer Res. 1992;52(7):2008-11.
[119] Goldmacher VS. Re: S. M. Bronstein et al. Efficient repair of O6-ethylguanine, but not O4-ethylthymine or O2-ethylthymine, is dependent upon O6-alkylguanine-DNA alkyltransferase and nucleotide excision repair activities in human cells. Cancer Res., 52: 2008-2011, 1992. Cancer Res. 1992;52(24):6983-5.
[120] Fong LY, Jensen DE, Magee PN. DNA methyl-adduct dosimetry and O6-alkylguanine-DNA alkyl transferase activity determinations in rat mammary carcinogenesis by procarbazine and N-methylnitrosourea. Carcinogenesis. 1990;11(3):411-7.
[121] Belinsky SA, Devereux TR, Anderson MW. Role of DNA methylation in the activation of proto-oncogenes and the induction of pulmonary neoplasia by nitrosamines. Mutat Res. 1990;233(1-2):105-16.
[122] Peterson LA, Hecht SS. O6-methylguanine is a critical determinant of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone tumorigenesis in A/J mouse lung. Cancer Res. 1991;51(20):5557-64.
[123] Fong LY, Bevill RF, Thurmon JC, Magee PN. DNA adduct dosimetry and DNA repair in rats and pigs given repeated doses of procarbazine under conditions of carcinogenicity and human cancer chemotherapy respectively. Carcinogenesis. 1992;13(11):2153-9.
[124] Loktionova NA, Beniashvili DSh, Sartania MS, Zabezhinski MA, Kazanova OI, Petrov AS, Likhachev AJ. Individual levels of activity of O6-alkylguanine-DNA alkyltransferase in monkey gastric mucosa during chronic exposure to a gastrocarcinogen N-ethyl-N'-nitro-N-nitrosoguanidine. Biochimie. 1993;75(9):821-4.
[125] Thomale J, Huh NH, Nehls P, Eberle G, Rajewsky MF. Repair of O6-ethylguanine in DNA protects rat 208F cells from tumorigenic conversion by N-ethyl-N-nitrosourea. Proc Natl Acad Sci U S A. 1990;87(24):9883-7.
[126] Gerson SL, Zaidi NH, Dumenco LL, Allay E, Fan CY, Liu L, O'Connor PJ. Alkyltransferase transgenic mice: probes of chemical carcinogenesis. Mutat Res. 1994;307(2):541-55.
[127] Lijinsky W, Pegg AE, Anver MR, Moschel RC. Effects of inhibition of O6-alkylguanine-DNA alkyltransferase in rats on carcinogenesis by methylnitrosourea and ethylnitrosourea. Jpn J Cancer Res. 1994;85(3):226-30.
[128] Liu L, Allay E, Dumenco LL, Gerson SL. Rapid repair of O6-methylguanine-DNA adducts protects transgenic mice from N-methylnitrosourea-induced thymic lymphomas. Cancer Res. 1994;54(17):4648-52.
[129] Zlotogorski C, Erickson LC. Pretreatment of normal human fibroblasts and human colon carcinoma cells with MNNG allows chloroethylnitrosourea to produce DNA interstrand crosslinks not observed in cells treated with chloroethylnitrosourea alone. Carcinogenesis. 1983;4(6):759-63.
[130] Zeller WJ, Berger MR, Henne T, Weber E. More than additive toxicity of the combination of 1-methyl-1-nitrosourea plus 1,3-bis(2-chloroethyl)-1-nitrosourea in the rat. Cancer Res. 1986;46(4 Pt 1):1714-6.
[131] Gerson SL. Modulation of human lymphocyte O6-alkylguanine-DNA alkyltransferase by streptozotocin in vivo. Cancer Res. 1989;49(11):3134-8.
[132] Meer L, Schold SC, Kleihues P. Inhibition of the hepatic O6-alkylguanine-DNA alkyltransferase in vivo by pretreatment with antineoplastic agents. Biochem Pharmacol. 1989;38(6):929-34.
[133] Yarosh DB, Hurst-Calderone S, Babich MA, Day RS 3rd. Inactivation of O6-methylguanine-DNA methyltransferase and sensitization of human tumor cells to killing by chloroethylnitrosourea by O6-methylguanine as a free base. Cancer Res. 1986;46(4 Pt 1):1663-8.
[134] Dolan ME, Corsico CD, Pegg AE. Exposure of HeLa cells to 0(6)-alkylguanines increases sensitivity to the cytotoxic effects of alkylating agents. Biochem Biophys Res Commun. 1985;132(1):178-85.
[135] Karran P, Williams SA. The cytotoxic and mutagenic effects of alkylating agents on human lymphoid cells are caused by different DNA lesions. Carcinogenesis. 1985;6(5):789-92.
[136] Pieper RO, Futscher BW, Dong Q, Erickson LC. Effects of streptozotocin/bis-chloroethylnitrosourea combination therapy on O6-methylguanine DNA methyltransferase activity and mRNA levels in HT-29 cells in vitro. Cancer Res. 1991;51(6):1581-5.
[137] Lee SM, Thatcher N, Margison GP. O6-alkylguanine-DNA alkyltransferase depletion and regeneration in human peripheral lymphocytes following dacarbazine and fotemustine. Cancer Res. 1991;51(2):619-23.
[138] Lee SM, Thatcher N, Crowther D, Margison GP. Inactivation of O6-alkylguanine-DNA alkyltransferase in human peripheral blood mononuclear cells by temozolomide. Br J Cancer. 1994;69(3):452-6.
[139] Mitchell RB, Dolan ME, Janisch L, Vogelzang NJ, Ratain MJ, Schilsky RL. Sequential therapy with dacarbazine and carmustine: a phase I study. Cancer Chemother Pharmacol. 1994;34(6):509-14.
[140] Panella TJ, Smith DC, Schold SC, Rogers MP, Winer EP, Fine RL, Crawford J, Herndon JE 2nd, Trump DL. Modulation of O6-alkylguanine-DNA alkyltransferase-mediated carmustine resistance using streptozotocin: a phase I trial. Cancer Res. 1992;52(9):2456-9.
[141] Micetich KC, Futscher B, Koch D, Fisher RI, Erickson LC. Phase I study of streptozocin- and carmustine-sequenced administration in patients with advanced cancer. J Natl Cancer Inst. 1992;84(4):256-60.
[142] Avril MF, Bonneterre J, Delaunay M, Grosshans E, Fumoleua P, Israel L, Bugat R, Namer M, Cupissol D, Kerbrat P, et al. Combination chemotherapy of dacarbazine and fotemustine in disseminated malignant melanoma. Experience of the French Study Group. Cancer Chemother Pharmacol. 1990;27(2):81-4.
[143] Marathi UK, Dolan ME, Erickson LC. Anti-neoplastic activity of sequenced administration of O6-benzylguanine, streptozotocin, and 1,3-bis(2-chloroethyl)-1-nitrosourea in vitro and in vivo. Biochem Pharmacol. 1994;48(11):2127-34.
[144] Dolan ME, Larkin GL, English HF, Pegg AE. Depletion of O6-alkylguanine-DNA alkyltransferase activity in mammalian tissues and human tumor xenografts in nude mice by treatment with O6-methylguanine. Cancer Chemother Pharmacol. 1989;25(2):103-8.
[145] Dolan ME, Mitchell RB, Mummert C, Moschel RC, Pegg AE. Effect of O6-benzylguanine analogues on sensitivity of human tumor cells to the cytotoxic effects of alkylating agents. Cancer Res. 1991;51(13):3367-72.
[146] Chen JM, Zhang YP, Sui JL, Moschel RC, Ikenaga M. Modulation of O6-methylguanine-DNA methyltransferase-mediated 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea resistance by O6-benzylguanine in vitro and in vivo. Anticancer Res. 1993;13(3):801-5.
[147] Chen JM, Zhang YP, Moschel RC, Ikenaga M. Depletion of O6-methylguanine-DNA methyltransferase and potentiation of 1,3-bis(2-chloroethyl)-1-nitrosourea antitumor activity by O6-benzylguanine in vitro. Carcinogenesis. 1993;14(5):1057-60.
[148] Marathi UK, Kroes RA, Dolan ME, Erickson LC. Prolonged depletion of O6-methylguanine DNA methyltransferase activity following exposure to O6-benzylguanine with or without streptozotocin enhances 1,3-bis(2-chloroethyl)-1-nitrosourea sensitivity in vitro. Cancer Res. 1993;53(18):4281-6.
[149] Marathi UK, Dolan ME, Erickson LC. Extended depletion of O6-methylguanine-DNA methyltransferase activity following O6-benzyl-2'-deoxyguanosine or O6-benzylguanine combined with streptozotocin treatment enhances 1,3-bis(2-chloroethyl)-1-nitrosourea cytotoxicity. Cancer Res. 1994;54(16):4371-5.
[150] M?ller MR, Thomale J, Lensing C, Rajewsky MF, Seeber S. Chemosensitisation of alkylating agents by pentoxifylline, O6-benzylguanine and ethacrynic acid in haematological malignancies. Anticancer Res. 1993;13(6A):2155-9.
[151] Gerson SL, Berger SJ, Varnes ME, Donovan C. Combined depletion of O6-alkylguanine-DNA alkyltransferase and glutathione to modulate nitrosourea resistance in breast cancer. Biochem Pharmacol. 1994;48(3):543-8.
[152] Sarkar A, Dolan ME, Gonzalez GG, Marton LJ, Pegg AE, Deen DF. The effects of O6-benzylguanine and hypoxia on the cytotoxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea in nitrosourea-resistant SF-763 cells. Cancer Chemother Pharmacol. 1993;32(6):477-81.
[153] Dolan ME, Pegg AE, Biser ND, Moschel RC, English HF. Effect of O6-benzylguanine on the response to 1,3-bis(2-chloroethyl)-1-nitrosourea in the Dunning R3327G model of prostatic cancer. Cancer Chemother Pharmacol. 1993;32(3):221-5.
[154] Friedman HS, Dolan ME, Moschel RC, Pegg AE, Felker GM, Rich J, Bigner DD, Schold SC Jr. Enhancement of nitrosourea activity in medulloblastoma and glioblastoma multiforme. J Natl Cancer Inst. 1992;84(24):1926-31.
[155] Friedman HS, Dolan ME, Moschel RC, Pegg AE, Felker GM, Rich J, Bigner DD, Schold SC Jr. Enhancement of nitrosourea activity in medulloblastoma and glioblastoma multiforme. Erratum in: J Natl Cancer Inst 1994;86(13):1027.
[156] Felker GM, Friedman HS, Dolan ME, Moschel RC, Schold C. Treatment of subcutaneous and intracranial brain tumor xenografts with O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Chemother Pharmacol. 1993;32(6):471-6.
[157] McElhinney RS, Donnelly DJ, McCormick JE, Kelly J, Watson AJ, Rafferty JA, Elder RH, Middleton MR, Willington MA, McMurry TB, Margison GP. Inactivation of O6-alkylguanine-DNA alkyltransferase. 1. Novel O6-(hetarylmethyl)guanines having basic rings in the side chain. J Med Chem. 1998;41(26):5265-71.