Repair of O6-(2-chloroethyl)guanine mediates the biological effects of chloroethylnitrosoureas.

Chloroethylnitrosoureas (CENUs) are alkylating and crosslinking agents used for the treatment of human cancer; they are both mutagenic and carcinogenic. We compared the levels of induction of sister chromatid exchanges (SCEs) and the cytotoxicity of nitrosoureas that alkylate only with CENUs. CENUs are 200-fold more cytotoxic and induce SCEs with 45-fold greater efficiency than agents that do not crosslink; therefore, crosslinking is probably the most important molecular event that leads to cell death and induction of SCEs. The biological and biochemical properties of both human and rat brain tumor cells that are sensitive or resistant to the cytotoxic effects of CENUs have been investigated. CENUs induce SCEs in both sensitive and resistant cells, but to induce similar levels of SCEs, resistant cells must be treated with a 5- to 14-fold higher concentration of CENUs than are used to treat sensitive cells. Resistant cells have a higher cellular level of O6-methylguanine-DNA methyl transferase, increased repair of O6-methylguanine, and 50% fewer DNA interstrand crosslinks formed than do sensitive cells treated with the same concentration of CENU. Based on these findings, we propose that cellular resistance to the cytotoxic effects of CENUs is mediated by O6-methylguanine-DNA methyltransferase and that DNA repair may also modify the mutagenic and carcinogenic properties of CENUs.

[1]  G. F. Otto.  Chemotherapeutic agents , 2018, Reactions Weekly.

[2]  W. Morgan,et al.  Reduced level of DNA cross-links and sister chromatid exchanges in 1,3-bis(2-chloroethyl)-1-nitrosourea-resistant rat brain tumor cells. , 1984, Cancer research.

[3]  T. Brent.  Suppression of cross-link formation in chloroethylnitrosourea-treated DNA by an activity in extracts of human leukemic lymphoblasts. , 1984, Cancer research.

[4]  W. Bodell,et al.  Tumor cell resistance. , 1984, Progress in experimental tumor research.

[5]  A. Harris,et al.  Cross-linking of DNA induced by chloroethylnitrosourea is presented by O6-methylguanine-DNA methyltransferase. , 1983, Nucleic acids research.

[6]  J. Sagi,et al.  Escherichia coli polymerase I can use O2-methyldeoxythymidine or O4-methyldeoxythymidine in place of deoxythymidine in primed poly(dA-dT).poly(dA-dT) synthesis. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[7]  K. Kohn,et al.  Quenching of DNA:platinum(II) monoadducts as a possible mechanism of resistance to cis-diamminedichloroplatinum(II) in L1210 cells. , 1983, Cancer research.

[8]  W. Tong,et al.  Mechanism of action of the nitrosoureas--V. Formation of O6-(2-fluoroethyl)guanine and its probable role in the crosslinking of deoxyribonucleic acid. , 1983, Biochemical pharmacology.

[9]  A. Harris,et al.  O6-Methylguanine-DNA methyltransferase of human lymphoid cells: structural and kinetic properties and absence in repair-deficient cells. , 1983, Cancer research.

[10]  R. S. Foote,et al.  Purification and properties of O6-methylguanine-DNA transmethylase from rat liver. , 1983, The Journal of biological chemistry.

[11]  P. Tofilon,et al.  Nitrosourea-induced sister chromatid exchanges and correlation to cell survival in 9L rat brain tumor cells. , 1983, Cancer research.

[12]  G. Goldenberg,et al.  Membrane transport, sulfhydryl levels and DNA cross-linking in Chinese hamster ovary cell mutants sensitive and resistant to melphalan. , 1983, Biochemical pharmacology.

[13]  L. Erickson,et al.  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. , 1983, Carcinogenesis.

[14]  R. S. Foote,et al.  Repair of O6-methylguanine in DNA by demethylation is lacking in Mer- human tumor cell strains. , 1983, Carcinogenesis.

[15]  K. Kohn,et al.  Modifications of DNA by different haloethylnitrosoureas. , 1982, Cancer research.

[16]  R. Kodell,et al.  Alkylation-induced sister-chromatid exchanges correlate with reduced cell survival, not mutations. , 1982, Mutation research.

[17]  J. Swenberg,et al.  Cell specificity in hepatocarcinogenesis: preferential accumulation of O6-methylguanine in target cell DNA during continuous exposure to rats to 1,2-dimethylhydrazine. , 1982, Cancer research.

[18]  L. Thompson,et al.  Defective removal of DNA cross-links in a repair-deficient mutant of Chinese hamster cells. , 1982, Cancer research.

[19]  W. Tong,et al.  Formation of the cross-link 1-[N3-deoxycytidyl),2-[N1-deoxyguanosinyl]ethane in DNA treated with N,N'-bis(2-chloroethyl)-N-nitrosourea. , 1982, Cancer research.

[20]  V. Craddock,et al.  Nature of the constitutive and induced mammalian O6-methylguanine DNA repair enzyme. , 1982, Biochemical and biophysical research communications.

[21]  B. Fox,et al.  Repair of DNA interstrand crosslinks after busulphan. A possible mode of resistance. , 1982, Cancer chemotherapy and pharmacology.

[22]  J. M. Bogden,et al.  A system in mouse liver for the repair of O6-methylguanine lesions in methylated DNA , 1981, Nucleic Acids Res..

[23]  W. Tong,et al.  Formation of the cross-linked base, diguanylethane, in DNA treated with N,N'-bis(2-chloroethyl)-N-nitrosourea. , 1981, Cancer research.

[24]  A. Prestayko.  Nitrosoureas : current status and new developments , 1981 .

[25]  S. Latt.  Sister chromatid exchange formation. , 1981, Annual review of genetics.

[26]  R. Sklar,et al.  Limited capacity for the removal of O6-methylguanine and its regeneration in a human lymphoma line. , 1981, Carcinogenesis.

[27]  W. Bodell,et al.  Tissue-dependent enzyme-mediated repair or removal of O-ethyl pyrimidines and ethyl purines in carcinogen-treated rats. , 1981, Carcinogenesis.

[28]  K. Kohn,et al.  DNA cross-linking and monoadduct repair in nitrosourea-treated human tumour cells , 1980, Nature.

[29]  D. Scudiero,et al.  Defective repair of alkylated DNA by human tumour and SV40-transformed human cell strains , 1980, Nature.

[30]  W. Tong,et al.  Mechanism of action of the nitrosoureas--IV. Reactions of bis-chloroethyl nitrosourea and chloroethyl cyclohexyl nitrosourea with deoxyribonucleic acid. , 1980, Biochemical pharmacology.

[31]  K. Kohn,et al.  Mutagenicity and cytotoxicity of various nitrosoureas in V-79 Chinese hamster cells. , 1980, Cancer research.

[32]  P. Perry.  Chemical Mutagens and Sister-Chromatid Exchange , 1980 .

[33]  G. Eisenbrand,et al.  Carcinogenic activity in Sprague-Dawley rats of 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-gluco-pyranose (chlorozotocin). , 1979, Cancer letters.

[34]  P. Schein,et al.  Chlorozotocin. Mechanism of reduced bone marrow toxicity in mice. , 1979, The Journal of clinical investigation.

[35]  J. Cleaver,et al.  Evidence for removal at different rates of O-ethyl pyrimidines and ethylphosphotriesters in two human fibroblast cell lines. , 1979, Nucleic acids research.

[36]  B. Singer.  N-nitroso alkylating agents: formation and persistence of alkyl derivatives in mammalian nucleic acids as contributing factors in carcinogenesis. , 1979, Journal of the National Cancer Institute.

[37]  J. Lown,,et al.  Nitrosourea-induced DNA single-strand breaks. , 1979, Biochemical pharmacology.

[38]  D. Brown,et al.  Comparison of mutagenicity, antitumor activity, and chemical properties of selected nitrosoureas and nitrosoamides. , 1979, Cancer research.

[39]  R. Saffhill,et al.  DNA synthesis with methylated poly(dC-dG) templates. Evidence for a competitive nature to miscoding by O(6)-methylguanine. , 1979, Biochimica et biophysica acta.

[40]  J. Cleaver,et al.  Oxygens in DNA are main targets for ethylnitrosourea in normal and xeroderma pigmentosum fibroblasts and fetal rat brain cells , 1978, Nature.

[41]  T. Hoshino,et al.  Development of a clonogenic cell assay for human brain tumors , 1978, Cancer.

[42]  H. Fraenkel-conrat,et al.  Preparation and template activities of polynucleotides containing O2- and O4-alkyluridine. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[43]  S. Vogl.  Acute leukemia complicating treatment of glioblastoma multiforme , 1978, Cancer.

[44]  E. Weisburger.  Bioassay program for carcinogenic hazards of cancer chemotherapeutic agents , 1977, Cancer.

[45]  K. Kohn.  Interstrand cross-linking of DNA by 1,3-bis(2-chloroethyl)-1-nitrosourea and other 1-(2-haloethyl)-1-nitrosoureas. , 1977, Cancer research.

[46]  A. Pegg,et al.  Formation and metabolism of alkylated nucleosides: possible role in carcinogenesis by nitroso compounds and alkylating agents. , 1977, Advances in cancer research.

[47]  R. Cohen,et al.  Acute nonlymphocytic leukemia associated with nitrosourea chemotherapy: report of two cases. , 1976, Cancer treatment reports.

[48]  Montgomery Ja.  Chemistry and structure-activity studies of the nitrosoureas. , 1976 .

[49]  J. Montgomery.  Chemistry and structure-activity studies of the nitrosoureas. , 1976, Cancer treatment reports.

[50]  R Montesano,et al.  Mutagenic and carcinogenic N-nitroso compounds: possible environmental hazards. , 1976, Mutation research.

[51]  S. Wolff,et al.  New Giemsa method for the differential staining of sister chromatids , 1974, Nature.

[52]  M. Rajewsky,et al.  Persistence of O6-ethylguanine in rat-brain DNA: correlation with nervous system-specific carcinogenesis by ethylnitrosourea. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[53]  A. Pound.  Chemical Mutagens: Principles and Methods for their Detection , 1974 .

[54]  C. Wilson,et al.  Development of an animal brain tumor model and its response to therapy with 1,3-bis(2-chloroethyl)-1-nitrosourea. , 1973, Cancer research.

[55]  F. Schabel,et al.  1,3-bis(2-chloroethyl)-1-nitrosourea (bcnu) and other nitrosoureas in cancer treatment: a review. , 1972, Advances in cancer research.

[56]  S. Epstein,et al.  Chemical Mutagenesis , 1971, Nature.

[57]  M. Walker,et al.  BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea; NSC-409962) in the treatment of malignant brain tumor--a preliminary report. , 1970, Cancer chemotherapy reports.

[58]  H. Skipper,et al.  Experimental evaluation of potential anticancer agents VIII. Effects of certain nitrosoureas on intracerebral L1210 leukemia. , 1963, Cancer research.