Quantitative dose response measurements of diethylnitrosamine-and dibenzylnitrosamine-induced DNA single-strand breaks plus alkali-labile bonds (SSB + ALB) (single-strand breaks, apurinic/apyrimidinic sites, and phosphotriesters) were performed on samples of 100,000 nuclei from Sprague-Dawley rats. Twenty-four hours after diethylnitrosamine injection, there were no SSB + ALB in brain (nontarget), SSB + ALB in kidney (target), and SSB + ALB in liver (target only after partial hepatectomy, tumor promoters, or chronic administration). Seven days after diethylnitrosamine injection, liver SSB + ALB had declined. The noncarcinogenic diethylnitrosamine analog, dibenzylnitrosamine, induced no SSB + ALB at 6 hours or 7 days postinjection. Induction of DNA damage, therefore, correlates well with target organ specificity of tumorigenesis when specificity is broadened to include those organs that exhibit tumors only when DNA damage is followed by additional treatments.
References
1.
1. Druckrey, H., Steinhoff, D., Preussmann, R., and Ivankovic, S. (1963). Krebserzeugung durch einmalige dosis von methylnitroso-harnstoff and verscheidenen dialkylnitrosaminen. Naturwissenschaften50, 735.
2.
2. Druckrey, H., Steinhoff, D., Preussmann, R., and Ivankovic, S. (1964). Erzeugung von krebs durch eine einmalige dosis von methylnitroso-harnstoff und verscheidenen dialkylnitrosaminen an Ratten. A. Krebsforsch66, 1–10.
3.
3. Thomas, C., and Schmahl, D. (1964). Zur Morphologie der Nierentumoren bei der Ratte. Z. Krebsforsch66, 127–137.,
4.
4. Druckrey, H., Preussman, R., Vankovic, S., and Schmahl, D. (1967). Organotrope carcinogene wirkungen bei 65 verscheidenen N-nitroso-verbindungen an BD-Ratten. Z. Krebsforsch69, 103–201.
5.
5. Magee, P. N., and Barnes, J. M. (1967). Carcinogenic nitroso compounds. Cancer Res.10, 163–246.
6.
6. Swann, P. F., and Magee, P. N. (1971). Nitrosamine-induced carcinogenesis. Biochem. J.125, 841–847.
7.
7. Craddock, V. M. (1975). Effect of a single treatment with the alkylating carcinogens dimethylnitrosamine, diethylnitrosamine, and methyl methanesulphonate on liver regenerating after partial hepatectomy. I. Test for induction of liver carcinomas. Chem. Biol. Interact.10, 313–321.
8.
8. Weisburger, J. H., Madison, R. M., Ward, J. M., Viguera, C., and Weisburger, E. K. (1975). Modification of diethylnitrosamine liver carcinogenesis with phenobarbital but not with immunosuppression. J. Natl. Cancer Inst.54, 1185–1188.
9.
9. Pitot, H. C., Barsness, L., Goldsworthy, T., and Kitagawa, T. (1978). Biochemical characterization of stages of heptocarcinogenesis after a single dose of diethylnitrosamine. Nature271, 456–458.
10.
10. Pound, A. W., and McGUIRE, L. J. (1978). Repeated partial hepatectomy as a promoting stimulus for carcinogenic response of liver to nitrosamines in rats. Br. J. Cancer37, 585–594.
11.
11. Damjanov, I., Cox, R., Sarma, D. S. R., and Farber, E. (1973). Patterns of damage and repair of liver DNA induced by carcinogenic methylating agents in vivo. Cancer Res.33, 2122–2128.
12.
12. Farber, E., and Sarma, D. S. R. (1974). DNA damage and repair during carcinogenesis. In: Control Processes in Neoplasia. Mehlman, M. A., and Hanson, R. W. eds. New York: Academic Press, pp. 173–185.
13.
13. Goth, R., and Rajewsky, M. F. (1974). Persistence of O6-ethylguanine in rat-brain DNA: Correlation with nervous system-specific carcinogenesis by ethylnitrosourea. Proc. Natl. Acad. Sci. USA71, 639–643.
14.
14. Kanagalingam, K., and Balis, M. E. (1975). In vivo repair of rat intestinal DNA damage by alkylating agents. Cancer36, 2364–2372.
15.
15. Laishes, B. A., Koropatnick, D. J., and Stich, H. F. (1975). Organ-specific DNA damage induced in mice by the organotropic carcinogens 4-nitroquinoline-I-oxide and dimethylnitrosamine. Proc. Soc. Exp. Biol. Med.149, 978–982.
16.
16. Petzold, G. L., and Swenberg, J. A. (1978). Detection of DNA damage induced in vivo following exposure of rats to carcinogens. Cancer Res.38, 1589–1594.
17.
17. Cleaver, J. E., Thomas, G. H., and Burki, H. J. (1972). Biological damage from intranuclear tritium: DNA strand breaks and their repair. Science177, 996–998.
18.
18. Ehmann, U. K., Williams, J. R., Nagle, W. A., Brown, J. A., Belli, J. A., and Lett, J. T. (1975). Peturbations in cell cycle progression from radioactive DNA precursors. Nature258, 633–636.
19.
19. Marz, R., Zylka, J. M., Plagemann, P. G. W., Erbe, J., Howard, R., and Sheppard, J. R. (1977) G2 + M arrest of cultured mammalian cells after incorporation of tritium-labeled nucleosides. J. Cell. Physiol.90, 1–8.
20.
20. Brash, D. E., and Hart, R. W. (1978). DNA damage and repair in vivo. J. Environ. Path. Toxicol.2, 79–114.
21.
21. Brash, D. E., and Hart, R. W. (1982). Biopsy measurement of DNA damage and repair in vivo: Single-strand breaks, alkali-labile bonds, and endonuclease-sensitive sites. Radiat. Res.91, 169–180.
22.
22. Brash, D. E., and Hart, R. W. (1983). Fluorescent dye labeling to measure DNA damage in non-radio-labeled cells. In: DNA Repair: A Manual of Research Procedures. Friedberg, E. C., and Hanawalt, P. C. eds. New York: Marcel Dekker. Vol 2, pp. 173–183.
23.
23. Floot, B. G. J., Philippus, E. J., Hart, A. A. M., and Den Engelse, L. (1979). Persistence and accumulation of (potential) single-strand breaks in liver DNA of rats treated with diethylnitrosamine or dimethylnitrosamine: Correlation with hepatocarcinogenicity. Chem. Biol. Interact.25, 229–242.
24.
24. Heyting, C., Huigen, A., and Den Engelse, L. (1980). Repair of ethylnitrosourea-induced DNA damage in the newborn rat. I. Alkali-labile lesions and in situ breaks. Carcinogenesis1, 769–778.
25.
25. Walker, I. G. (1981). Alkaline sucrose sedimentation analysis as an indicator of repair capability of xeroderma pigmentosum fibroblasts for 4-nitroquinoline-1-oxide damage. Carcinogenesis2, 691–695.
26.
26. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans: Some Nitroso Compounds (1978). 17, 83–124.
27.
27. Pensabene, J. W., Fiddler, W., Dooley, C. J., Doerr, R. C., and Wasserman, A. E. (1972). Spectral and gas chromatographic characteristics of some N-nitrosamines. J. Agr. Food Chem.20, 274–277.
28.
28. Dean, C. J., Ormerod, M. G., Serianni, R. W., and Alexander, P. (1969). DNA strand breakage in cells irradiated with x-rays. Nature222, 1042–1044.
29.
29: Charlesby, A. (1954). Molecular weight changes in the degradation of long-chain polymers. Proc. R. Soc. London [A]224, 120–128.
30.
30. Heath, D. F. (1962). The decomposition and toxicity of dialkylnitrosamines in rats. Biochem. J.85, 72–91.
31.
31. Sosnowski, S. A., Rajalakshmi, S., and Sarma, D. S. R. (1976). Protection by dimethylsulfoxide of strand breaks in hepatic DNA induced by dimethylnitrosamine. Chem. Biol. Interact.15, 101–104.
32.
32. Craddock, V. M., and Frei, J. V. (1974). Induction of liver cell adenomata in the rat by a single treatment with N-methyl-N-nitrosourea given at various times after partial hepatectomy. Br. J. Cancer30, 503–511.
