Abstract
Auerbach and Robson’s discovery (1942) that mustard gas is mutagenic was released after the close of the second World War (Auerbach and Robson, 1946, 1947) and quickly led to the finding that many simple alkylating agents are mutagenic. Some of these compounds were found to be useful in cancer chemotherapy because of their cytotoxic effect but, at the same time, were carcinogenic themselves, the ratio of therapeutic to carcinogenic activity varying mysteriously from compound to compound (see Whitelock, 1958). It was natural that the reactivity of these alkylating agents with cellular constituents should be investigated. The reactivity with protein was especially studied during the 1950’s because of the general biochemical importance of this class of compound. However, the gradual acceptance of the view that the genetic material is only DNA focused attention on alkylation of this substance. The reaction of alkylating agents with nucleic acid, particularly with DNA has therefore been extensively studied during the 1960’s and 1970’s for the theoretical reason that mutation must involve a change in DNA structure, rather than because of any direct demonstration that alkylation of DNA is uniquely important. Demonstration of the metabolic activation of hydrocarbon and other carcinogens to form electrophilic reagents with the reactivity characteristic of alkylating agents (Cramer et al., 1960; Miller et al., 1960) intensified the search for DNA adducts since this discovery made it likely that the initial reaction leading to carcinogenesis must be the formation of a covalently bound adduct, presumably to DNA.
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References
Auerbach, C., and Robson, J., 1946, Chemical production of mutations, Nature 157: 302.
Auerbach, C., and Robson, J., 1947, The production of mutation by chemical substances, Proc. Roy. Soc. Edn. B. 62: 271–283.
Bannon, P., and Verly, W., 1972, Alkylation of phosphates and stability of phosphate triesters in DNA, Eur. J. Biochem. 31: 103–111.
Brookes, P., and Lawley, P., 1961, The reaction of mono-and di-functional alkylating agents with nucleic acids, Biochem. J. 80: 496–503.
Cerdb-Olmedo, E., Hanawalt, P., and Guerola, N., 1968, Mutagenesis of the replication point by nitrosoguanidine: map and pattern of replication of the Escherichia coli chromosome, J. Mol. BioZ. 33: 705–719.
Clark, A., 1973, Recombination deficient mutants of E. coli and other bacteria, Annu. Rev. Genet. 7: 67–86.
Cleaver, J., 1970, DNA repair and radiation sensitivity in humans (Xeroderma pigmentosum) cells, Int. J. Radiat. BioZ. 18: 557–565.
Coyle, M., McMahon, M., and Strauss, B., 1971, Failure of alkylated HEp2 cells to replicate newly synthesized DNA, Mutat. Res. 12: 427–440.
Craddock, V., 1973, The pattern of methylated purines formed in DNA of intact and regenerating liver of rats treated with the carcinogen dimethylnitrosamine, Biochim. Biophys. Acta 312: 202–210.
Craddock, V., 1975, Effect of a single treatment with the alkylating carcinogens dimethylnitrosamine diethylnitrosamine and methyl methanesulfonate, on liver regenerating after partial hepatectomy. II. Alkylation of DNA and inhibition of DNA replication, Chem. BioZ. Interactions 10: 323–332.
Cramer, J., Miller, J., and Miller, E., 1960, N-hydroxylation: A new metabolic reaction observed in the rat with the carcinogen 2-acetyl aminofluorene, J. BioZ. Chem. 235: 885–888.
Davis, R., Simon, M., and Davidson, N., 1971, Electron microscope heteroduplex methods for mapping regions of base sequence homology in nucleic acids, Methods in Enzymology 21: 413–428.
Dipple, A., Brookes, P., Mackintosh, D., and Rayman, M., 1971, Reaction of 7-bromomethyl benz (a) anthracene with nucleic acids, polynucleotides and nucleosides, Biochemistry 10: 4323–4330.
Freese, E., 1971, Molecular mechanisms of mutations, Chemical Mutagens 1: 1–56.
Geiduschek, E.P., 1961, “Reversible” DNA, Proc. Nat. Acad. Sci. USA 47: 950–955.
Goth, R., and Rajewsky, M., 1974, Persistence of O6-ethylguanine in rat brain DNA; Correlation with nervous system-specific carcinogenesis by ethylnitrosourea, Proc. Nat. Acad. Sci. USA 71: 639–643.
Nadi, S., and Goldthwait, D., 1971, Endonuclease II of Escherichia coli degradation of partially depurinated deoxyribonucleic acid, Biochemistry 10: 4986–4994.
Hill, R., 1958, A radiation-sensitive mutant of Escherichia coli, Biochim. Biophys. Acta 30: 636–637.
Hince, T., and Neale, S., 1974, A comparison of the mutagenic action of the methyl and ethyl derivatives of nitrosamides and nitrosamidines on Escherichia coli, Mutat. Res. 24: 383–387.
Kato, K., and Strauss, B., 1974, Accumulation of an intermediate in DNA synthesis by HEp2 cells treated with methyl methanesulfonate, Proc. Nat. Acad. Sci. USA 71: 1969–1973.
Kleijer, W., Lohman, P., Mulder, M., and Bootsma, D., 1970, Repair of X-ray damage in DNA of cultivated cells from patients having Xeroderma pigmentosum, Mutat. Res. 9: 517–523.
Klimek, M., 1966, Thymine dimerization in L-strain mammalian cells after irradiation with ultraviolet light and the search for repair mechanisms, Photochem. Photobiol. 5: 603–607.
Lawley, P., 1973, Reaction of N-methyl-N-nitrosourea (MNUA) with 32P-labeled DNA: evidence for formation of phosphotriesters, Chem. Biol. Interactions 7: 127–130.
Lawley, P., 1974a, Some chemical aspects of dose-response relation- ships in alkylation mutagenesis, Mutat. Res. 23: 283–295.
Lawley, P., 1974b, Alkylation of nucleic acids and mutagenesis, in “Molecular and Environmental Aspects of Mutagenesis” (L. Prakash, F. Sherman, M. Miller, C. Lawrence, and H. Taber, eds.), pp. 1733, C. Thomas, Springfield.
Lawley, P., and Brookes, P., 1963, Further studies on the alkylation of nucleic acids and their constituent nucleotides, Biochem. J. 89: 127–138.
Lawley, P., and Orr, D., 1970, Specific excision of methylation products from DNA of Escherichia coli treated with N-methylN’-nitro-N-nitrosoguanidine, Chem. BioZ. Interactions 2: 154–157.
Lawley, P., and Shah, S., 1972, Reaction of alkylating mutagens and carcinogens with nucleic acids: detection and estimation of a small extent of methylation at 0–6 of guanine in DNA by methyl methanesulphonate in vitro, Chem. BioZ. Interactions 5: 286–288.
Lawley, P., and Shah, S., 1973, Methylation of DNA by 3H–14C-methyllabeled N-methyl-N-nitrosourea-evidence for transfer of the intact methyl group, Chem. Biol. Interactions 7: 115–120.
Lawley, P., and Thatcher, C., 1970, Methylation of deoxyribonucleic acid in cultured mammalian cells by N-methyl-N’-nitro-N-nitrosoguanidine, Biochem. J. 116: 693–707.
Lehmann, A., 1972, Post replication repair of DNA in ultraviolet-irradiated mammalian cells, J. Mol. Biol. 66: 319–337.
Lehmann, A., and Kirk-Bell, S., 1974, Effects of caffeine and theophylline on DNA synthesis in unirradiated and UV-irradiated mammalian cells, Mutat. Res. 26: 73–82.
Lieberman, M., and Dipple, A., 1972, Removal of bound carcinogen during DNA repair in non-dividing human lymphocytes, Cancer Res. 32: 1855–1860.
Lindahl, T., and Nyberg, B., 1972, Rate of depurination of native DNA, Biochemistry 11: 3610–3618.
Ljungquist, S., and Lindahl, T., 1974, A mammalian endonuclease specific for apurinic sites in double-stranded deoxyribonucleic acid. I. Purification and general properties, BioZ. Chem. 249: 1530–1535.
Loveless, A., 1969, Possible relevance of 0–6 alkylation of deoxyguanosine to mutagenicity of nitrosamines and nitrosamides, Nature 223: 206–208.
Magee, P., 1969, In vivo reactions of nitroso compounds, Annu. N.Y. Acad. Sci. 163: 717–729.
Maher, V., and McCormick, J., 1975, Effect of DNA repair on the cytotoxicity and on the frequency of mutations induced in normal human skin fibroblasts and in strains of Xeroderma pigmentosum by ultraviolet irradiation and by chemical carcinogens. Abstr. Int. Symp. “Protein and Other Adducts to DNA: Their Significance to Aging, Carcinogenesis and Radiation Biology,” Williamsburg, Virginia, May 2–6, 1975.
Meselson, M., and Radding, C., 1975, A general model for genetic recombination, Proc. Nat. Acad. Sci. USA 72: 385–361.
Miller, E., and Miller, J., 1969, Studies on the mechanism of activation of aromatic amine and amide carcinogens to ultimate carcinogenic electrophilic reactants, Annu. N.Y. Acad. Sci. 163: 731–750.
Miller, J., Cramer, J., and Miller, E., 1960, The N- and ring-hydroxylation of 2-acetylaminofluorene during carcinogenesis in the rat, Cancer Res. 20: 950–962.
Nicoll, J., Swann, P., and Pegg, A., 1975, Effect of dimethylnitrosamine on persistence of methylated guanines in rat liver and kidney DNA, Nature 254: 261–262.
O’Connor, P., Margison, G., and Craig, A., 1975, Phosphotriesters in rat liver deoxyribonucleic acid after the administration of the carcinogen N N-dimethylnitrosamine in vivo, Biochem. J. 145: 475–482.
Painter, R., 1974, DNA damage and repair in eukaryotic cells, Genetics 78: 139–148.
Prakash, L., and Strauss, B., 1970, Repair of alkylation damage: stability of methyl groups in Bacillus subtilis treated with methyl methanesulfonate, J. BacterioZ. 102: 760–766.
Radman, M., 1974, Phenomenology of an inducible mutagenic DNA repair pathway in Escherichia coli: SOS repair hypothesis, in “Molecular and Environmental Aspects of Mutagenesis” (L. Prakash, F. Sherman, M. Miller, C. Lawrence, and H. Taber, eds.), pp. 128–140, C. Thomas, Springfield.
Regan, J., and Setlow, R., 1974, Two forms of repair in the DNA of human cells damaged by chemical carcinogens and mutagens, Cancer Res. 34: 3318–3325.
Reiter, H., and Strauss, B., 1965, Repair of damage induced by a monofunctional alkylating agent in a transformable, ultraviolet-sensitive strain of Bacillus subtilis, J. Mol. Biol. 14: 179–194.
Robbins, J., Kraemer, K., Lutzner, M., Festoff, B., and Coon, H., 1974, Xeroderma pigmentosum. An inherited disease with skin sensitivity, multiple cutaneous neoplasms, and abnormal DNA repair, Annu. Intern. Med. 80: 221–248.
Roberts, J., Pascoe, J., Plant, J., Sturrock, J., and Crathorn, A., 1971, Quantitative aspects of the repair of alkylated DNA in cultured mammalian cells. I. The effect on HeLa and chinese hamster cell survival of alkylation of cellular macromolecules, Chem. BioZ. Interactions 3: 29–47.
Rupp, W., and Howard-Flanders, P., 1968, Discontinuities in the DNA synthesized in an excision-defective strain of E. coli following ultraviolet irradiation, J. Mol. BioZ. 31: 291–304.
Rupp, W., Wilde, C., Reno, D., and Howard-Flanders, P., 1971, Exchanges between DNA strands in ultraviolet irradiated E. colis J. Mol. Biol. 61: 25–44.
Scudiero, D., Henderson, E., Norin, A., and Strauss, B., 1975, The measurement of chemically-induced DNA repair synthesis in human cells by BND-cellulose chromatography, Mutat. Res. (in press).
Scudiero, D., and Strauss, B., 1974, Accumulation of single-stranded regions in DNA and the block to replication in a human cell line alkylated with methyl methanesulfonate, J. Mol. Biol. 83: 17–34.
Setlow, R.B., and Carrier, W., 1964, The disappearance of thymine dimers from DNA: an error-correcting mechanism, Proc. Nat. Acad. Sci. USA 51: 226–231.
Shooter, K., Howse, R., and Merrifield, R., 1974, Reaction of alkylating agents with bacteriophage R17: biological effects of phosphotriester formation, Biochem. J. 137: 313–317.
Stacey, K., Cobb, M., Cousens, S., and Alexander, P., 1958, The reactions of the “radiomimetic” alkylating agents with macromolecules in vitro, Annu. N.Y. Acad. Sci. 68: 682–701.
Strauss, B., 1974, Repair of DNA in mammalian cells, Life Sci. 15: 1685–1693.
Trosko, J., Chang, C., Yotti, L., and Chu, E.H.Y., 1975, Mutageni-city of cancer-promoting agents in cultured chinese hamster cells. Abstr. Int. Symp. “Protein and Other Adducts to DNA: Their Significance to Aging, Carcinogenesis and Radiation Biology,” Williamsburg, Virginia, May 2–6, 1975.
Venitt, S., and Tarmy, E., 1972, The selective excision of arylalkylated products from the DNA of Escherichia coli treated with the carcinogen 7-bromomethyl benz (a) anthracene, Biochim. Biophys. Acta 287: 38–51.
Whitelock, O., 1958, Comparative clinical and biological effects of alkylating agents, Annu. N.Y. Acad. Sci. 68: 657–1266.
Witkin, E., and George, D., 1973, Ultraviolet mutagenesis in poZA and uvrA poZA derivatives of Escherichia coli B/r: Evidence for an inducible error-prone repair system, Genetics Suppl. 73: 91–108.
Zimmerman, F., 1971, Genetic aspects of carcinogenesis, Biochem. Pharmacol. 20: 985–995.
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Strauss, B.S. (1976). Repair of DNA Adducts Produced by Alkylation. In: Smith, K.C. (eds) Aging, Carcinogenesis, and Radiation Biology. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-1662-7_16
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DOI: https://doi.org/10.1007/978-1-4757-1662-7_16
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