Abstract
The susceptibilities of Nagase analbuminemic rats (NAR) and control Sprague‐Dawley rats (SDR) to N‐ethyl‐N‐nitrosourea (ENU) were compared. In Experiment I, the rats were given daily subcutaneous injections of 10 mg/kg of ENU for a week from 4 weeks of age. In Experiment II, mother rats were given a single subcutaneous injection of 60 mg/kg of ENU on day 17 of pregnancy and tumor development in their offspring was examined. In Experiment I, the incidence of neurogenic tumors was slightly, but not significantly, higher in NAR than in control rats. In Experiment II, the incidence of total tumors including neurogenic tumors was significantly higher in NAR (40/43, 93.0%) than in SDR (13/61, 21.3%). NAR showed particularly high susceptibility to induction of nenrogenic tumors (34/43, 79.1%) and renal tumors (15/43, 34.9%). In an attempt to elucidate the underlying mechanisms of the increased susceptibility of NAR to ENU, O6‐ethylguanine, a major premutagenic ethylated DNA adduct, was quantitated in fetal brain DNA of NAR and SDR after a pulse exposure to 60 mg/kg ENU. No significant difference in the initial formation or subsequent repair of O6‐ethylguanine was observed in the two strains, indicating that abnormality at some later stage(s) of chemical carcinogenesis may lead to the increased susceptibility of NAR to induction of neurogenic tumors.
Keywords: Key words, Analbuminemic rats, N‐Ethyl‐N‐nitrosourea, Transplacental administration, Neurogenic tumor
Full Text
The Full Text of this article is available as a PDF (600.7 KB).
REFERENCES
- 1. ) Nagase , S. , Shimamune , K. and Shumiya , S.Albumin‐deficient rat mutant . Science , 205 , 590 – 591 ( 1979. ). [DOI] [PubMed] [Google Scholar]
- 2. ) Rothshild , M. A. , Oratz , M. and Schreiber , S. S.Albumin synthesis. I and II. N. Engl. J. Med. , 286 , 748 – 757 , 816 – 821 ( 1972. ). [DOI] [PubMed] [Google Scholar]
- 3. ) Weisiger , R. , Gollan , J. and Ockner , R.Receptor for albumin on the liver cell surface may mediate uptake of fatty acids and other albumin‐bound substances . Science , 211 , 1048 – 1050 ( 1981. ). [DOI] [PubMed] [Google Scholar]
- 4. ) Nagase , S. , Shumiya , S. , Emori , T. and Tanaka , H.High incidence of renal tumors induced by N‐dimethylnitrosamine in analbuminemic rats . Gann , 74 , 317 – 318 ( 1983. ). [PubMed] [Google Scholar]
- 5. ) Sugiyama , K. , Nagase , S. , Maekawa , A. , Onodera , H. and Hayashi , Y.High susceptibility of analbuminemic rats to gastric tumor induction by N‐methy‐N′‐nitro‐N‐nitrosoguanidine . Jpn. J. Cancer Res. , 77 , 219 – 221 ( 1986. ). [PubMed] [Google Scholar]
- 6. ) Kakizoe , T. , Komatsu , H. , Honma , Y. , Niijima , T. , Kawachi , T. , Sugimura , T. and Nagase , S.High susceptibility of analbuminemic rats to induced bladder cancer . Br. J. Cancer , 45 , 474 – 476 ( 1982. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. ) Takahashi , M. , Shumiya , S. , Maekawa , A. , Hayashi , Y. and Nagase , S.High susceptibility of an analbuminemic congenic strain of rats with an F344 genetic background to induced bladder cancer and its possible mechanism . Jpn. J. Cancer Res. , 79 , 705 – 709 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. ) Druckrey , H. , Ivankovic , S. and Preussmann , R.Teratogenic and carcinogenic effects in the offspring after single injection of ethylnitrosourea to pregnant rats . Nature , 210 , 1378 – 1379 ( 1966. ). [DOI] [PubMed] [Google Scholar]
- 9. ) Ivankovic , S. and Druckrey , H.Transplacentare Erzeugung maligner Tumoren des Nervensystems. I. Äthylnitrosoharnstoff (ÄNH) an BD IX‐Ratten . Z Krebsforsch. , 71 , 320 — 360 ( 1968. ). [PubMed] [Google Scholar]
- 10. ) Ivankovic , S. , Druckrey , H. and Preussmann , R.Erzeugung neurogener Tumoren bei den Nachkommen nach einmaliger Injektion von Äthylnitrosoharnstoff an schwangere Ratten . Naturwissenschaften , 53 , 410 ( 1966. ). [DOI] [PubMed] [Google Scholar]
- 11. ) Beranek , D. T. , Weis , C. C. and Swenson , D. H.A comprehensive quantitative analysis of methylated and ethylated DNA using high pressure liquid chromatography . Carcinogenesis , 1 , 595 – 605 ( 1980. ). [DOI] [PubMed] [Google Scholar]
- 12. ) Pegg , A. E.Methylation of the Opposition of guanine in DNA is the most likely initiating event in carcinogenesis by methylating agents . Cancer Invest , 2 , 223 – 231 ( 1984. ). [DOI] [PubMed] [Google Scholar]
- 13. ) Thomale , J. , Huh , N. , Nehls , P. , Eberle , G. and Rajewsky , M. F.Repair of O6‐ethylguanine in DNA protects rat 208F cells from tumorigenic conversion by N‐ethyl‐N‐nitrosourea . Proc. Natl. Acad. Sci. USA , 87 , 9883 – 9887 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. ) Goth , R. and Rajewsky , M. F.Persistence of O6‐ethylguanine in rat‐brain DNA: correlation with nervous system‐specific carcinogenesis by ethylnitrosourea . Proc. Natl. Acad. Sci. USA , 71 , 639 – 643 ( 1974. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. ) Maniatis , T. , Fritsch , E. F. and Sambrook , J. “ Molecular Cloning: A Laboratory Manual ” ( 1982. ). Cold Spring Harbor Laboratory; , Cold Spring Harbor, New York . [Google Scholar]
- 16. ) Muller , R. and Rajewsky , M. F.Immunological quantification by high affinity antibodies of O'‐ethyldeoxy‐guanosine in DNA exposed to N‐ethyl‐N‐nitrosourea . Cancer Res. , 40 , 887 – 896 ( 1980. ). [PubMed] [Google Scholar]
- 17. ) Huh , N. and Rajewsky , M. F.Enzymatic elimination of O6‐ethylguanine and stability of O4‐ethylthymine in the DNA of malignant neural cell lines exposed to N‐ethyl‐N‐nitrosourea in culture . Carcinogenesis , 7 , 435 – 439 ( 1986. ). [DOI] [PubMed] [Google Scholar]
- 18. ) Rajewsky , M. F. , Muller , R. , Adamkiewicz , J. and Drosdziok , W.Immunological detection and quantification of DNA components structurally modified by alkylating carcinogens (ethylnitrosourea) . In “ Carcinogenesis: Fundamental Mechanisms and Environmental Effects ,” ed. Pullman B. , P. O. P. Ts' o and Gelboin H. , pp. 207 – 218 ( 1980. ). D. Reidel Publishing Company; , Boston . [Google Scholar]
- 19. ) Adamkiewicz , J. , Eberle , G. , Huh , N. , Nehls , P. and Rajewsky , M. F.Quantitation and visualization of alkyldeoxynucleosides in the DNA of mammalian cells by monoclonal antibodies . Environ. Health Perspect , 62 , 49 – 56 ( 1985. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. ) Muller , R. and Rajewsky , M. F.Enzymatic removal of O6‐ethylguanine versus stability of O4‐ethylthymine in the DNA of rat tissues exposed to the carcinogen ethylnitrosourea: possible interference of guanine O6‐alkylation with 5‐cytosine methylation in the DNA of replicating target cells . Z. Naturforsch. , 38c , 1023 – 1029 ( 1983. ). [DOI] [PubMed] [Google Scholar]
- 21. ) Maekawa , A. and Mitsumori , K.Spontaneous occurrence and chemical induction of neurogenic tumors in rats — influence of host factors and specificity of chemical structure . Crit. Rev. Toxicol , 20 , 287 – 310 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 22. ) Esumi , H. , Takahashi , Y. , Sato , S. , Nagase , S. and Sugimura , T.A seven‐base‐pair deletion in an intron of the analbuminemic rats . Proc. Nad. Acad, Set. USA , 80 , 95 – 99 ( 1983. ). [DOI] [PMC free article] [PubMed] [Google Scholar]