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Mechanism of Action of Nitrosoureas

  • Chapter
Antineoplastic and Immunosuppressive Agents

Abstract

The material that is presented in this chapter is limited to that which relates directly or indirectly to the mechanism of action of the nitrosoureas. For a review of the results of experimental and clinical therapeutic trials with these agents, the reader is referred to other sections of this volume and to the review by Carter et al. (1972).

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References

  • Barranco, S.C., Humphrey, R.M.: The effects of 1,3-bis(2-chloroethyl)-l-nitrosourea on survival and cell progression in Chinese hamster cells. Cancer Res. 31, 191–195 (1971).

    PubMed  CAS  Google Scholar 

  • Berman, L.D., Hayes, J., Sibay, T.: The oncogenicity of the drug streptozotocin in the Chinese hamster. Proc. Amer. Ass. Cancer Res. 12, 86 (1971).

    Google Scholar 

  • Bhuyan, B.K.: The action of streptozotocin on mammalian cells. Cancer Res. 30, 2017–2023 (1970).

    PubMed  CAS  Google Scholar 

  • Bhuyan, B.K., Scheidt, L.G., Fraser, T. J.: Cell cycle specificity of several antitumor agents. Proc. Amer. Ass. Cancer Res. 11, 8 (1970).

    Google Scholar 

  • Bhuyan, B.K., Scheidt, L.G., Fraser, T.J.: Cell-cycle phase specificity of antitumor agents. Proc. Amer. Ass. Cancer Res. 12, 88 (1971).

    Google Scholar 

  • Bowdon, B. J., Wheeler, G.P.: Reaction of 1,3-bis(2-chloroethyl)-1 -nitrosourea (BCNU) with protein. Proc. Amer. Ass. Cancer Res. 12, 67 (1971).

    Google Scholar 

  • Bray, D.A., Devita, V.T., Adamson, R.H., Oliverio, V.T.: Effects of l-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU; NSC-79037) and its degradation products on progression of L1210 cells through the cell cycle. Cancer Chemother. Rep. 55, 215–220 (1971).

    CAS  Google Scholar 

  • Brown, W.E., Wold, F.: Alkyl isocyanates as active site-specific inhibitors of chymotrypsin and elastase. Science 174, 608–610 (1971).

    Article  PubMed  CAS  Google Scholar 

  • Bruce, W.R., Valeriote, F.A.: Normal and malignant stem cells and chemotherapy. In: The Proliferation and Spread of Neoplastic Cells, pp. 409–420. The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston. Baltimore: The Williams and Wilkins Company, 1968.

    Google Scholar 

  • Carter, S.K., Schabel, F.M.,Jr., Broder, L., Johnston, T.P.: BCNU and other nitro-soureas: a review. Advanc. Cancer Res., 16, 273–332 (1972).

    Google Scholar 

  • Chan, S.C., Leh, F.: The release of halide ions from some primary haloalkylamines. Austral. J. Chem. 19, 2271–2279 (1966).

    Article  CAS  Google Scholar 

  • Cheng, C. J., Fujimura, S., Grunberger, D., Weinstein, I. B.: Interaction of l-(2-chloro- ethyl)-3-cyclohexyl-l-nitrosourea (NSC 79037) with nucleic acids and proteins in vivo and in vitro. Cancer Res. 82, 22–27 (1972).

    Google Scholar 

  • Craddock, V. M.: Reaction of the carcinogen dimethylnitrosamine with proteins and with thiol compounds in the intact animal. Biochem. J. 94, 323–330 (1965).

    PubMed  CAS  Google Scholar 

  • Craddock, V.M.: Study of the methylation and lack of deamination of deoxyribonucleic acid by N-methyl-N′-nitro-N-nitrosoguanidine. Biochem. J. 111, 615–620 (1969).

    PubMed  CAS  Google Scholar 

  • DeVita, V.T., Denham, C., Davidson, J. D., Oliverio, V.T.: The physiological disposition of the carcinostatic 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) in man and animals. Clin. Pharmacol. Ther. 8, 566–577 (1967).

    PubMed  CAS  Google Scholar 

  • DiPaolo, J. A.: Teratogenic agents: mammalian test systems and chemicals. Ann. N. Y. Acad. Sci. 163, 801–812 (1969).

    Article  CAS  Google Scholar 

  • Druckrey, H., Preussmann, R., Ivankovic, S.: N-Nitroso compounds in organotropic and transplacental carcinogenesis. Ann. N.Y. Acad. Sci. 163, 676–695 (1969).

    Article  CAS  Google Scholar 

  • Druckrey, H., Preussmann, R., Ivankovic, S., Schmähl, D., Afkham, J., Blum, G., Mennel, H.D., Müller, M., Petropoulas, P., Schneider, H.: Organotrope carcinogene Wirkungen bei 64 verschiedenen N-Nitroso-Verbindungen an BD-Ratten. Z. Krebsforsch. 69, 103–201 (1967).

    Article  PubMed  CAS  Google Scholar 

  • Frei, J.Y.: Approach to transformation of mouse embryo cells by methylnitrosourea (MNUA). Proc. Amer. Ass. Cancer Res. 11, 27 (1970).

    Google Scholar 

  • Gale, G.R.: Effect of 1,3-bis(2-chloroethy 1)-1 -nitrosourea on Saccharomyces cerevisiae. Proc. Soc. exp. Biol. (N.Y.) 119, 1004–1010 (1965a).

    CAS  Google Scholar 

  • Gale, G.R.: Effect of l,3-bis-(2-chloroethyl)-l-nitrosourea on Ehrlich ascites tumor cells. Biochem. Pharmacol. 14, 1707–1712 (1965b).

    PubMed  CAS  Google Scholar 

  • Garrett, E.R.: Prediction of stability in pharmaceutical preparations. VII. The solution degradation of the antibiotic streptozotocin. J. Amer. Pharm. Ass., Sci. Ed. 49, 767–777 (1960).

    Google Scholar 

  • Garrett, E.R., Goto, S., Stubbins, J.F.: Kinetics of solvolysis of various N-alkyl-N-nitro-soureas in neutral and alkaline solutions. J. pharm. Sci. 54, 119 — 123 (1965).

    Article  PubMed  CAS  Google Scholar 

  • Gichner, T., Velemínský, J.: The mutagenic activity of 1-alkyl-1-nitrosoureas and 1-alkyl - 3-nitro-l-nitrosoguanidines. Mutation Res. 4, 207–212 (1967).

    Article  CAS  Google Scholar 

  • Gichner, T., Velemínský, J., Křepinský, J.: Strong mutagenic activity of streptozotocin—an antibiotic with an alkylnitroso group. Molec. gen. Genet. 102, 184–186 (1968).

    CAS  Google Scholar 

  • Gichner, T., Velemínský, J., Pokorný,V.: Comparison of the mutagenic activity of N- methylnitrosourea, N,N′-dimethylnitrosourea and N,N′,N′-trimethylnitrosourea. Arznei-mittel-Forsch. 19, 1053–1055 (1969).

    Google Scholar 

  • Givelber, H.M., DiPaolo, J.A.: Teratogenic effects of N-ethyl-N-nitrosourea in the Syrian hamster. Cancer Res. 29, 1151–1155 (1969).

    PubMed  CAS  Google Scholar 

  • Gorbacheva, L.B., Kukushkina, G. V.: Some aspects of the mechanism of action of 1-propyl - 1-nitrosourea. Biochem. Pharmacol. 19, 1561–1568 (1970).

    Article  PubMed  CAS  Google Scholar 

  • Graffi, A., Hoffman, F., Schütt, M.: N-Methyl-N-nitrosourea as a strong topical carcinogen when painted on skin of rodents. Nature (Lond.) 214, 611 (1967).

    Google Scholar 

  • Green, S.: The effect of 1,3-bis(2- chlor oethyl) -1 -nitrosourea on nicotinamide adenine dinucleotide glycohydrolase of mouse and rat neoplastic and normal tissues. Cancer Res. 26, 2481–2484 (1966).

    PubMed  CAS  Google Scholar 

  • Groth, D.P., D’Angelo, J.M., Vogler, W.R., Mingioli, E.S., Betz, B.: Selective metabolic effects of l,3-bis(2-chloroethyl)-l-nitrosourea upon de novo purine biosynthesis. Cancer Res. 81, 332–336 (1971).

    Google Scholar 

  • Henry, R.A.: The reaction of amines with N-methyl-N-nitroso-N′-nitroguanidine. J. Amer. chem. Soc. 72, 3287–3289 (1950).

    Google Scholar 

  • Herr, R.R., Jahnke, H.K., Argoudelis, A.D.: The structure of streptozotocin. J. Amer. chem. Soc. 89, 4808–4809 (1967).

    Article  CAS  Google Scholar 

  • Iriarte, P.V., Hananian, J., Cortner, J.A.: Central nervous system leukemia and solid tumors of childhood — Treatment with l,3-bis(2-chloroethy 1)-1 -nitrosourea (BCNU). Cancer (Philad.) 19, 1187–1194 (1966).

    Article  CAS  Google Scholar 

  • Jänish, W., Schreiber, D.: Experimentelle Hirngeschwülste bei Kaninchen nach Injektion von Methylnitrosoharnstoff. Naturwissenschaften 54, 171–172 (1967).

    Article  Google Scholar 

  • Jobst, K.: Teratogenous changes and tumors in rats following treatment with methylnitro- sourea (MNU). Neoplasma (Bratisl.) 14, 435–436 (1967).

    CAS  Google Scholar 

  • Johnston, T.P., McCaleb, G.S., Montgomery, J.A.: The synthesis of antineoplastic agents. XXXII. N-Nitrosoureas. I. J. med. Chem. 6, 669–681 (1963).

    Article  CAS  Google Scholar 

  • Johnston, T.P., McCaleb, G.S., Opliger, P.S., Laster, W.R., Montgomery, J.A.: Synthesis of potential anticancer agents. 38. N-Nitrosoureas. 4. Further synthesis and evaluation of haloethyl derivatives. J. med. Chem. 14, 600–614 (1971).

    Article  PubMed  CAS  Google Scholar 

  • Johnston, T. P., McCaleb, G. S., Opliger, P. S., Montgomery, J. A.: The synthesis of potential anticancer agents. XXXVI. N-Nitrosoureas. II. Haloalkyl derivatives. J. med. Chem. 9, 892–911 (1966).

    Article  PubMed  CAS  Google Scholar 

  • Johnston, T.P., Opliger, P.S.: The synthesis of potential anticancer agents. XXXVII. N- Nitrosoureas. III. l,5-Bis(2-chloroethyl)-l-nitrosobiuret and related derivatives of biurets, biureas, and carboxamides. J. med. Chem. 10, 675–681 (1967).

    Article  PubMed  CAS  Google Scholar 

  • Kann, H.E.,JR., Snyder, A.L., Kohn, K.W.: Effects of chemotherapeutic agents on RNA synthesis in LI210 cells. Proc. Amer. Ass. Cancer Res. 12, 59 (1971).

    Google Scholar 

  • Kao, F-T., Puck, T.T.: Genetics of somatic mammalian cells XII: mutagenesis by carcinogenic nitroso compounds. J. cell. Physiol. 78, 139–144 (1971).

    Article  PubMed  CAS  Google Scholar 

  • Kilgore, W.W., Morris, J. E., Greenberg, J.: Effect of diazoalkane-yielding compounds on strains of Escherichia coli resistant to l-methyl-3-nitro-l-nitrosoguanidine. Proc. Soc. exp. Biol. (N.Y.) 105, 469–473 (1960).

    CAS  Google Scholar 

  • Kleihues, P.: Blockierung der DNS-Synthese durch N-Methyl-N-Nitrosoharnstoff in vivo. Arzneimittel-Forsch. 19, 1041–1043 (1969).

    CAS  Google Scholar 

  • Kleihues, P., Patzschke, K.: Verteilung von N-[14C]Methyl-N-nitrosoharnstoff in der Ratte nach systemischer Applikation. Z. Krebsforsch. 75, 193–200 (1971).

    Article  PubMed  CAS  Google Scholar 

  • Kline, I., Woodman, R.J., Gang, M., Venditti, J.M.: Effectiveness of antileukemic agents in mice inoculated with leukemia L1210 variants resistant to 5-(3,3-dimethyl-l-triazeno)- imidazole-4-carboxamide (NSC-45388) or 5-[3,3-bis(2-chloroethyl)-l-triazeno]imidazole-4- carboxamide (NSC-82196). Cancer Chemother. Rept., Pt. 1, 55, 9–28 (1971).

    Google Scholar 

  • Kreybig, T. von: Die Wirkung einer carcinogenen Methyl-nitroso-Harnstoffdosis auf die Embryonalentwicklung der Ratte. Z. Krebsforsch. 67, 46–50 (1965).

    Article  Google Scholar 

  • Krüger, F. W., Ballweg, H., Maier-Borst, W.: Untersuchungen über die alkylierende Wirkung von 14C-Methylnitrosoharnstoff und 1-14C-Äthylnitrosoharnstoff. Experientia (Basel) 24, 592–593 (1968).

    Article  Google Scholar 

  • Krüger, F. W., Osswald, H., Walker, G., Schelten, E.: Untersuchungen zur Organotropie der alkylierenden Wirkung von Dimethylnitrosamin (DMNA) und Nitrosomethylharnstoff (NMH) in vivo. Z. Krebsforsch. 74, 434–447 (1970).

    Article  PubMed  Google Scholar 

  • Lawley, P. D.: Methylation of DNA by N-methyl-N-nitrosourethane and N-methyl-N- nitroso-N′-nitroguanidine. Nature (Lond.) 218, 580–581 (1968).

    Article  CAS  Google Scholar 

  • Lawley, P.D., Brookes, P., Magee, P.N., Craddock, V.M., Swann, P.F.: Methylated bases in liver nucleic acids from rats treated with dimethylnitrosamine. Biochim. biophys. Acta (Amst.) 157, 646–648 (1948).

    Google Scholar 

  • Lawley, P.D., Thatcher, C. J.: Methylation of deoxyribonucleic acid in cultured mammalian cells by N-methyl-N′-nitro-N-nitrosoguanidine. The influence of cellular thiol concentrations on the extent of methylation and the 6-oxygen atom of guanine as a site of methylation. Biochem. J. 116, 693–707 (1970).

    PubMed  CAS  Google Scholar 

  • Lee, K.Y., Lijinsky, W., Magee, P.N.: Methylation of ribonucleic acids of liver and other organs in different species treated with C14- and H3-dimethylnitrosamines in vivo. J. nat. Cancer Inst. 32, 65–76 (1964).

    PubMed  CAS  Google Scholar 

  • Levin, V. A., Shapiro, W.R., Clancy, T. P., Oliverio, V.T.: The uptake, distribution, and antitumor activity of l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea in the murine glioma. Cancer Res. 80, 2451–2455 (1970).

    Google Scholar 

  • Levins, P. L., Papanastassiou, Z.B.: A nuclear magnetic resonance study of the 2-halo-ethylamines. J. Amer. chem. Soc. 87, 826–831 (1965).

    Article  CAS  Google Scholar 

  • Lijinsky, W., Loo, J., Ross, A. E.: Mechanism of alkylation of nucleic acids by nitrosodimethyl- amine. Nature (Lond.) 218, 1174–1175 (1968).

    Article  CAS  Google Scholar 

  • Lingers, F., Haerlin, R., Süssmuth, R.: Mechanism of mutagenesis by N-methyl-N′-nitro-N-nitrosoguanidine (MNNG). Methylation of nucleic acids by N-trideuteromethyl-N′-nitro-N-nitrosoguanidine (D3-MNNG) in the presence of cysteine and in cells of Escherichia coli. FEBS Let. 13, 241–242 (1971).

    Google Scholar 

  • Lingers, F., Rau, J., Süssmuth, R.: Zum Wirkungsmechanismus von l-Nitroso-3-nitro- 1-methyl-guanidin bei der Mutationsauslösung. II. Produkte der Reaktion von 1-Nitroso- 3-nitro-l-methyl-guanidin mit Nucleobasen, Nucleosiden, Nucleosidphosphaten und Homopolyribonucleinsäuren. Z. Naturforsch. 23b, 1565–1570 (1968).

    Google Scholar 

  • Loo, T.L., Dion, R.L., Dixon, R.L., Rall, D.P.: The antitumor agent, 1,3-bis(2-chloroethyl)- 1-nitrosourea. J. pharm. Sci. 55, 492–497 (1966).

    Article  CAS  Google Scholar 

  • Loveless, A.: Possible relevance of O-6-alkylation of deoxyguanosine to the mutagenicity and carcinogenicity of nitrosamines and nitrosamides. Nature (Lond.) 223, 206–207 (1969).

    Article  CAS  Google Scholar 

  • Loveless, A., Hampton, C.L.: Inactivation and mutation of coliphage T2 by N-methyl- and N-ethyl-N-nitrosourea. Mutation Res. 7, 1–12 (1969).

    Article  PubMed  CAS  Google Scholar 

  • Magee, P.N.: In vivo reactions of nitroso compounds. Ann. N.Y. Acad. Sci. 163, 717–729 (1969).

    Google Scholar 

  • Magee, P.N., Farber, E.: Toxic liver injury and carcinogenesis — Methylation of rat-liver nucleic acids by dimethylnitrosamine in vivo. Biochem. J. 83, 114–124 (1962).

    PubMed  CAS  Google Scholar 

  • Magee, P.N., Hultin, T.: Toxic liver injury and carcinogenesis — Methylation of proteins of rat-liver slices by dimethylnitrosamine in vitro. Biochem. J. 83, 106–114 (1962).

    PubMed  CAS  Google Scholar 

  • Marquardt, H., Zimmermann, F.K., Schwaier, R.: Nitrosamide als mutagene Agentien. Naturwissenschaften 50, 625 (1963).

    Article  CAS  Google Scholar 

  • McCalla, D.R.: Reaction of N-methyl-N′-nitro-N-nitrosoguanidine and N-methyl-N-nitroso-p-toluenesulfonamide with DNA in vitro. Biochim. biophys. Acta (Amst.) 155, 114–120 (1968).

    CAS  Google Scholar 

  • McCalla, D.R., Reuvers, A.: Reaction of N-methyl-N′-nitro-N-nitrosoguanidine with protein: formation of nitroguanido derivatives. Canad. J. Biochem. 46, 1411–1415 (1968).

    Article  CAS  Google Scholar 

  • McKay, A.F., Wright, G.F.: Preparation and properties of N-methyl-N-nitroso-N′-nitro- guanidine. J. Amer. chem. Soc. 69, 3028–3030 (1947).

    Article  CAS  Google Scholar 

  • Mizuno, N.S., Humphrey, E.W.: Effect of combined therapy with cytosine arabinoside (NSC-63878) and l,3-bis(2-chloroethyl)-l-nitrosourea (NSC-409962) on sarcoma 180 and L 1210 in vivo. Cancer Chemother. Rep. 53, 215–221 (1969).

    PubMed  CAS  Google Scholar 

  • Montgomery, J. A., James, R., McCaleb, G.S., Johnston, T. P.: The modes of decomposition of l,3-bis(2-chloroethyl)-l-nitrosourea and related compounds. J. med. Chem. 10, 668–674 (1967).

    Article  PubMed  CAS  Google Scholar 

  • Nagao, M., Yokoshima, T., Hosoi, H., Sugimura, T.: Interaction of N-methyl-N′-nitro-N- nitrosoguanidine with ascites hepatoma cells in vitro. Biochim. biophys. Acta (Amst.) 192, 191–199 (1969).

    CAS  Google Scholar 

  • Oliverio, V.T., Vietzke, W.M., Williams, M.K., Adamson, R.H.: The absorption, distribution, excretion, and biotransformation of the carcinostatic l-(2-chloroethyl)-3-cyclo- hexyl-1-nitrosourea in animals. Cancer Res. 30, 1330–1337 (1970).

    PubMed  CAS  Google Scholar 

  • Pasternak, L.: Untersuchungen über die mutagene Wirkung verschiedener Nitrosamin- und Nitrosamid-Verbindungen. Arzneimittel-Forsch. 14, 802–804 (1964).

    CAS  Google Scholar 

  • Pittillo, R.F., Narkates, A.N., Burns, J.: Microbiological evaluation of 1,3-bis(2-chloro- ethyl)-l nitrosourea. Cancer Res. 24, 1222–1228 (1964).

    PubMed  CAS  Google Scholar 

  • Plant, J.E., Roberts, J. J.: A novel mechanism for the inhibition of DNA synthesis following methylation: the effect of N-methyl-N-nitrosourea on HeLa cells. Chem. biol. Interact. 3, 337–342 (1971a).

    Article  PubMed  CAS  Google Scholar 

  • Plant, J.E., Roberts, J.J.: Extension of the pre-DNA synthetic phase of the cell cycle as a consequence of DNA alkylation in Chinese hamster cells: a possible mechanism of DNA repair. Chem. biol. Interact. 3, 343–351 (1971b).

    Article  PubMed  CAS  Google Scholar 

  • Preussmann, R., Druckrey, H., Ivankovic, S., Hodenberg, A.V.: Chemical structure and carcinogenicity of aliphatic hydrazo, azo, and azoxy compounds and of triazenes, potential in vivo alkylating agents. Ann. N.Y. Acad. Sci. 163, 697–714 (1969a).

    Article  CAS  Google Scholar 

  • Preussmann, R., Hodenberg, A.V.: Mechanism of carcinogenesis with l-aryl-3,3-dialkyl- triazenes. II. In vitro alkylation of guanosine, RNA and DNA with aryl-monoalkyltriazenes to form 7-alkylguanine. Biochem. Pharmacol. 19, 1505–1508 (1970).

    Article  PubMed  CAS  Google Scholar 

  • Preussmann, R., Hodenberg, A. V., Hengy, H.: Mechanism of carcinogenesis with 1-aryl- 3,3-dialkyltriazenes. Enzymatic dealkylation by rat liver microsomal fraction in vitro. Biochem. Pharmacol. 18, 1–13 (1969b).

    Article  PubMed  CAS  Google Scholar 

  • Rice, J.M.: Transplacental carcinogenesis in mice by 1-ethyl-1-nitrosourea. Ann. N.Y. Acad. Sci. 163, 813–826 (1969).

    Article  CAS  Google Scholar 

  • Roberts, J.J., Pascoe, J.M., Plant, J.E., Sturrock, J.E., Crathorn, A.R.: 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. biol. Interact. 3, 29–47 (1971a).

    CAS  Google Scholar 

  • Roberts, J.J., Pascoe, J.M., Smith, B.A., Crathorn, A.R.: Quantitative aspects of the repair of alkylated DNA in cultured mammalian cells. II. Non-semiconservative DNA synthesis (“repair synthesis”) in HeLa and Chinese hamster cells following treatment with alkylating agents. Chem. biol. Interact. 3, 49–68 (1971b).

    Article  PubMed  CAS  Google Scholar 

  • Rosenkranz, H.S., Bitoon, M., Schmidt, R.M.: Biological and metabolic effects of nitroso- methylurea and nitrosomethylurethan. J. nat. Cancer Inst. 41, 1099–1109 (1968).

    PubMed  CAS  Google Scholar 

  • Rosenkranz, H.S., Carr, H.S.: Differences in the action of nitrosomethylurea and streptozotoein. Cancer Res. 30, 112–117 (1970).

    PubMed  CAS  Google Scholar 

  • Rosso, R., Donnelli, M.G., Innocenti, I.R.D., Garattini, S.: Chemotherapy of tumors transplanted intracerebrally. Europ. J. Cancer 3, 125–137 (1967).

    Article  CAS  Google Scholar 

  • Sanders, F.K., Burford, B.O.: Morphological conversion of cells in vitro by N-nitrosomethylurea. Nature (Lond.) 213, 1171 — 1173 (1967).

    Article  CAS  Google Scholar 

  • Schabel, F.M.,Jr.: BCNU, 1,3-bis(2-chloroethyl)-l-nitrosourea. Development, antitumor activity, and mechanism of action. In: Carter, S.K. (Ed.): Proceedings of the chemotherapy conference on the chemotherapy of solid tumors: an appraisal of 5-fluorouracil and BCNU, pp. 159–180. Bethesda, Maryland: Cancer Therapy Evaluation Branch, National Cancer Institute, 1970.

    Google Scholar 

  • Schabel, F.M.,Jr., Johnston, T.P., McCaleb,G.S., Montgomery, J.A., Laster, W.R., Skipper, H.E.: Experimental evaluation of potential anticancer agents. VIII. Effects of certain nitrosoureas on intracerebral L 1210 leukemia. Cancer Res. 23, 725–733 (1963).

    PubMed  CAS  Google Scholar 

  • Schabel, F.M.,Jr., Skipper, H.E., Trader, M.W., Wilcox, W.S.: Experimental evaluation of potential anticancer agents. XIX. Sensitivity of nondividing leukemic cell populations to certain classes of drugs in vivo. Cancer Chemother. Rept. 48, 17–30 (1965).

    CAS  Google Scholar 

  • Schein, P. S.: 1-Methyl-1-nitrosourea and dialkylnitrosamine depression of nicotinamide adenine dinucleotide. Cancer Res. 29, 1226–1232 (1969a).

    PubMed  CAS  Google Scholar 

  • Schein, P. S.: 1-Methyl-1-nitrosourea depression of brain nicotinamide adenine dinucleotide in the production of neurologic toxicity. Proc. Soc. exp. Biol. (N. Y.) 131, 517–520 (1969b).

    CAS  Google Scholar 

  • Schein, P. S., Loftus, S.: Streptozotocin: depression of mouse liver pyridine nucleotides. Cancer Res. 28, 1501–1506 (1968).

    PubMed  CAS  Google Scholar 

  • Schoental, R.: Methylation of nucleic acids by N [14C]-methyl-N-nitrosourethane in vitro and in vivo. Biochem. J. 102, 5 c–7 c (1967).

    Google Scholar 

  • Schoental, R., Rive, D. J.: Interaction of N-alkyl-N-nitrosourethanes with thiols. Biochem. J. 97, 466–474 (1965).

    PubMed  CAS  Google Scholar 

  • Schulz, U., McCalla, D.R.: Reactions of cysteine with N-methyl-N-nitroso-p-toluenesulfon- amide and N-methyl-N′-nitro-N-nitrosoguanidine. Canad. J. Chem. 47, 2021–2027(1969).

    Google Scholar 

  • Serebryanyi, A.M., Smotryaeva, M.A., Kruglyakova, K. E.: Methylation of DNA by N- nitroso-N-methylurea. Izv. Akad. Nauk SSSR, Ser. Biol. 607–608 (1969a).

    Google Scholar 

  • Serebryanyi, A.M., Smotryaeva, M.A., Kruglyakova, K.E., Kostyanovskii, R.G.: Carbamoylation of DNA by N-nitroso-N-methylurea. Dokl. Akad. Nauk SSSR. 185, 847–849 (1969b).

    CAS  Google Scholar 

  • Shapiro, W.R., Ausman, J.I., Rall, D.P.: Studies on the chemotherapy of experimental brain tumors: evaluation of l,3-bis(2-chloroethyl)-l-nitrosourea, cyclophosphamide, mithramycin, and methotrexate. Cancer Res. 30, 2401–2413 (1970).

    PubMed  CAS  Google Scholar 

  • Shirakawa, S., Frei, E. III,: Comparative effects of the antitumor agents 5-(dimethyltriazeno)- imidazole-4-carboxamide and l,3-bis(2-chloroethyl)-l-nitrosourea on cell cycle of L 1210 leukemia cells in vivo. Cancer Res. 30, 2173–2179 (1970).

    PubMed  CAS  Google Scholar 

  • Simpson-Herren, L., Skipper, H.E., Blow, J. G.: Kinetics of cell growth and death following treatment with l,3-bis(2-chloroethyl)-l-nitrosourea. Proc. Amer. Ass. Cancer Res. 7, 65 (1966).

    Google Scholar 

  • Singer, B., Fraenkel-Conrat, H.: Chemical modification of viral ribonucleic acid. VII. The action of methylating agents and nitrosoguanidine on polynucleotides including tobacco mosaic virus ribonucleic acid. Biochemistry 8, 3260–3266 (1969a).

    Article  PubMed  CAS  Google Scholar 

  • Singer, B., Fraenkel-Conrat, H.: Chemical modification of viral ribonucleic acid. VIII. The chemical and biological effects of methylating agents and nitrosoguanidine on tobacco mosaic virus. Biochemistry 8, 3266–3269 (1969b).

    Article  PubMed  CAS  Google Scholar 

  • Skibba, J.L., Johnson, R.O., Bryan, G.T.: Carcinogenicity and possible mode of action of 4 (5)-(3,3-dimethyl-l-triazeno) imidazole-5 (4)-carboxamide (NSC-45388, DIC). Proc. Amer. Ass. Cancer Res. 11, 73 (1970).

    Google Scholar 

  • Stark, G.R.: On the reversible reaction of cyanate with sulfhydryl groups and the determination of NH2-terminal cysteine and cystine in proteins. J. biol. Chem. 239, 1411–1414 (1964).

    PubMed  CAS  Google Scholar 

  • Stark, G.R.: Reactions of cyanate with functional groups of proteins. II. Formation, decomposition, and properties of N-carbamylimidazole. Biochemistry 4, 588–595 (1965 a).

    Google Scholar 

  • Stark, G.R.: Reactions of cyanate with functional groups of proteins. III. Reactions with amino and carboxyl groups. Biochemistry 4, 1030–1036 (1965b).

    Article  PubMed  CAS  Google Scholar 

  • Stark, G. R.: Reactions of cyanate with functional groups of proteins. IV. Inertness of aliphatic hydroxyl groups. Formation of carbamyl- and acylhydantoins. Biochemistry 4, 2363–2367 (1965 c).

    Google Scholar 

  • Swann, P.F.: The rate of breakdown of methyl methanesulphonate, dimethyl sulphate and N-methyl-N-nitrosourea in the rat. Biochem. J. 110, 49–52 (1968).

    PubMed  CAS  Google Scholar 

  • Swann, P.F., Magee, P.N.: Nitrosamine-induced carcinogenesis. The alkylation of nucleic acids of the rat by N-methyl-N-nitrosourea, dimethylnitrosamine, dimethyl sulphate and methyl methanesulphonate. Biochem. J. 110, 39–47 (1968).

    PubMed  CAS  Google Scholar 

  • Thatcher, C. J., Walker, I. G.: Sensitivity of confluent and cycling embryonic hamster cells to sulfur mustard, l,3-fos(2-chloroethyl)-l-nitrosourea, and actinomycin D. J. nat. Cancer Inst. 42, 363–368 (1969).

    PubMed  CAS  Google Scholar 

  • Thomas, C., Sierra, J. L.: Hirntumoren bei Ratten nach oraler Gabe von N-Nitroso-N-methyl-Harnstoff. Naturwissenschaften 54, 228 (1967).

    Article  PubMed  CAS  Google Scholar 

  • Thomas, C., Sierra, J. L.: Neurogene Tumoren bei Ratten nach intraperitonealer Applikation von N-Nitroso-N-methyl-Harnstoif. Naturwissenschaften 55, 183 (1968).

    Article  PubMed  CAS  Google Scholar 

  • Tsukagoshi, S., Kao, M.H., Goldin, A.: Effect of l,3-bis(2-chloroethyl)-l-nitrosourea (NSC- 409962) and cyclophosphamide (NSC-26271) on nicotinamide adenine dinucleotide glycohydrolase in normal and leukemic mouse tissues. Cancer Chemother. Rept. 52, 569–578 (1968).

    CAS  Google Scholar 

  • Vavra, J.J., DeBoer, C., Dietz, A., Hanka, L.J., Sokolski, W.T.: Streptozotocin, a new antibacterial antibiotic. Antibiot. Ann. 230–235 (1959—1960).

    Google Scholar 

  • Walker, M.D., Hurwitz, B.S.: BCNU (l,3-bis(2-chloroethyl)-l-nitrosourea; NSC-409962) in the treatment of malignant brain tumor — A preliminary report. Cancer Chemother. Rept. 54, 263–271 (1970).

    CAS  Google Scholar 

  • Walker, M.D., Rosenblum, M.L., Smith, K.A., Reynolds, A.F., Jr.: The treatment of brain tumor with l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNTJ). Proc. Amer. Ass. Cancer Res. 12, 51 (1971).

    Google Scholar 

  • Wheeler, G.P.: Studies related to the mechanisms of action of cytotoxic alkylating agents. A review. Cancer Res. 22, 651–688 (1962).

    PubMed  CAS  Google Scholar 

  • Wheeler, G. P., Bowdon, B.J.: Some effects of 1,3-BIS(2-chloroethyl)-L-nitrosourea upon the synthesis of protein and nucleic acids in vivo and in vitro. Cancer Res. 25, 1770–1778 (1965).

    PubMed  CAS  Google Scholar 

  • Wheeler, G.P., Bowdon, B.J.: Effects of l,3-fos(2-chloroethyl)-L-nitrosourea and related compounds upon the synthesis of DNA by cell-free systems. Cancer Res. 28, 52–59 (1968).

    PubMed  CAS  Google Scholar 

  • Wheeler, G.P., Bowdon, B. J.: Comparison of the effects of cysteine upon the decomposition of nitrosoureas and of l-methyl-3-nitro-l-nitrosoguanidine. Biochem. Pharmacol. 21, 265–267 (1972).

    Article  PubMed  CAS  Google Scholar 

  • Wheeler, G.P., Bowdon, B. J., Adamson, D. J., Vail, M.H.: Effects of 1,3-bis(2-chloroethyl)- 1-nitrosourea and some chemically related compounds upon the progression of cultured H.Ep.No. 2 cells through the cell cycle. Cancer Res. 30, 1817–1827 (1970).

    PubMed  CAS  Google Scholar 

  • Wheeler, G.P., Bowdon, B.J., Herren, T.C.: Distribution of C14 from C14-labeled 1,3-FOV (2-chloroethyl)-l-nitrosourea (NSC-409962) in tissues of mice and hamsters after intraperitoneal administration of the agent. Cancer Chemotherapy Repts. 42, 9–12 (1964).

    CAS  Google Scholar 

  • Wheeler, G. P., Chumley, S.: Alkylating activity of 1,3 -Bis(2 -chloroethy 1)-1 -nitrosourea and related compounds. J. med. Chem. 10, 259–261 (1967).

    Article  PubMed  CAS  Google Scholar 

  • Wilkoff, L.J., Dixon, G.J., Dulmadge, E.A., Schabel, F.M.,Jr.: Effect of 1,3-bis(2-chloro- ethyl)-l-nitrosourea (NSC-409962) and nitrogen mustard (NSC-762) on kinetic behavior of cultured L 1210 cells. Cancer Chemotherapy Repts. 51, 7–18 (1967).

    Google Scholar 

  • Wilson, C.B., Boldrey, E.B., Enot, K.J.: 1,3-bis(2-chloroethyl)-L-nitrosourea (NSC-409962) in the treatment of brain tumors. Cancer Chemotherapy Repts. 54, 273–281 (1970).

    CAS  Google Scholar 

  • Wunderlich, V., Schutt, M., Bottger, M., Graffi, A.: Preferential alkylation of mitochondrial deoxyribonucleic acid by N-methyl-N-nitrosourea. Biocem. J. 118, 99–109 (1970).

    CAS  Google Scholar 

  • Wyse. B.M., Dulin, W.E.: The effects of streptozotocin on glucose oxidation by isolated islets of Langerhans. Proc. Soc. exp. Biol. (N.Y.) 136, 70–72 (1971).

    CAS  Google Scholar 

  • Young, R.C., DeVita, V.T.: The effect of chemotherapy on the growth characteristics and cellular kinetics of leukemia L 1210. Cancer Res. 30, 1789–1794 (1970).

    PubMed  CAS  Google Scholar 

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  1. Glynn P. Wheeler
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Editors and Affiliations

  1. Department of Pharmacology, Yale University School of Medicine, 06510, New Haven, Connecticut, USA

    Alan C. Sartorelli (Professor) (Professor)

  2. Laboratory of Chemical Pharmacology, National Cancer Institute, National Institutes of Health, 20014, Bethesda, Maryland, USA

    David G. Johns M.D.

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© 1975 Springer-Verlag Berlin • Heidelberg

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Wheeler, G.P. (1975). Mechanism of Action of Nitrosoureas. In: Sartorelli, A.C., Johns, D.G. (eds) Antineoplastic and Immunosuppressive Agents. Handbuch der experimentellen Pharmakologie / Handbook of Experimental Pharmacology, vol 38 / 2. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-65806-8_6

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