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Enhancement of carcinogen-induced mutations or recombinations by 12-O-tetradecanoyl-phorbol-13-acetate in the mammalian spot test

  • Original Papers
  • Experimental Oncology
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Summary

The mammalian spot test is suitable for detecting gene mutations and reciprocal recombinations. When given alone 12-O-tetradecanoyl-phorbol-13-acetate (TPA) did not have any statistically significant effect upon these genetic alterations. In combination with ethylnitrosourea (ENU) however TPA enhanced the effect of the mutagen/carcinogen. The effective dose range of TPA + ENU was very small, i.e., between 2x0.2 and 2x0.33 mg/kg, but the effect was very strong as shown by the steep slope of the dose-effect curve.

The results agree with the hypothesis that the mode of action of cocarcinogens and tumor promoters is a genetic one and that recombination plays an important role in this process.

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References

  • Benedict WF (1986) Characterizations of the retinoblastoma gene. In: Hollaender A, Hartmann P, Shankel D (eds) Mechanism of antimutagenesis and anticarcinogenesis (in press)

  • Benedict WF, Murphree AL, Banerjee A, Spina CA, Sparkes MC, Sparkes RS (1983) Patient with 13 chromosome deletion: evidence that the retinoblastoma gene is a recessive cancer gene. Science 219:973–975

    PubMed  Google Scholar 

  • Cavanee WK, Dryja TP, Phillips RA, Benedict WF, Godbort R, Gallie BL, Murphree AL, Strong LC, White RL (1983) Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305:779–784

    PubMed  Google Scholar 

  • Cerni C (1984) The transformation of a rat cell line induced by tumor promoter occurs without affecting sister chromatid exchange. Oncology 41:357–362

    PubMed  Google Scholar 

  • Connell JR, Duncan SJ (1981) The effect of nonphorbol promoters as compared with phorbol myristate acetate on sister chromatid exchange induction in cultured Chinese hamster cells. Cancer Lett 11:351–356

    Article  PubMed  Google Scholar 

  • Dewdney RS, Soper CJ (1984) A mutagenesis-enhancing activity of 12-O-tetradecanoylphorbol 13-acetate detected in Chinese hamster ovary cells. Mutat Res 129:119–127

    PubMed  Google Scholar 

  • Dzarlieva RT, Fusenig NE (1982) Tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate enhances sister chromatid exchanges and numerical and structural chromosome aberrations in primary mouse epidermal cell cultures. Cancer Lett 16:7–17

    Article  PubMed  Google Scholar 

  • Emerit I, Cerutti P (1982) The tumor promoter phorbol 12-myristate 13-acetate induces chromosomal aberrations in human lymphocytes via indirect action. UCLA Symp Mol Cell Biol, Iss Mech Chem Carcinog 2:495–497

    Google Scholar 

  • Fahrig R (1975) A mammalian spot test: Induction of genetic alterations in pigment cells of mouse embryos with X-rays and chemical mutagens. Mol Gen Genet 138:309–314

    Article  Google Scholar 

  • Fahrig R (1976) The effect of dose and time on the induction of genetic alterations in Saccharomyces cerevisiae by amino acridines in the presence and absence of visible light irradiation in comparison with the dose-effect curves of mutagens with other types of action. Mol Gen Genet 144:131–140

    PubMed  Google Scholar 

  • Fahrig R (1978) The mammalian spot test, a sensitive in vivo method for the detection of genetic alterations in somatic cells of mice. In: Holländer A, de Serres FJ (eds) Chemical mutagens: principles and methods for their detection. New York, Plenum, 151–176

    Google Scholar 

  • Fahrig R (1979) Evidence that induction and suppression of mutations and recombinations by chemical mutagens in S. cerevisiae during mitosis are jointly correlated. Mol Gen Genet 169:125–139

    Google Scholar 

  • Fahrig R (1984) Genetic mode of action of cocarcinogens and tumor promoters in yeast and mice. Mol Gen Genet 194:7–14

    PubMed  Google Scholar 

  • Fahrig R, Neuhäuser-Klaus A (1985) Similar pigmentation characteristics in the specific locus and the mammalian spot test: A way to distinguish between induced mutation and recombination. J Hered 76:421–426

    PubMed  Google Scholar 

  • Fujiwara Y, Kano Y, Tatsumi M (1980) Effects of a tumor promoter and an antipromoter on spontaneous and UV-induced 6-thioguanine-resistant mutations and sister chromatid exchanges in V79 Chinese hamster cells. Mutat Res 71:243–251

    PubMed  Google Scholar 

  • Gentil A, Renault G, Margot A (1980) The effect of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate on UV-induced and N-methyl-N-nitro-N-nitrosoguanidine induced sister chromatid exchanges in mammalian cells. Int J Cancer 26:517–521

    PubMed  Google Scholar 

  • Harris H, Miller OJ, Klein G, Worst P, Tachibana T (1968) Tumor suppression on malignancy by cell fusion. Nature 223:363–368

    Google Scholar 

  • Hecker E (1968) Cocarcinogenic principles from the seed of Croton tiglium and from other Euphorbiaceae. Cancer Res 28:2338–2349

    PubMed  Google Scholar 

  • Hsueh JL, Chen HH, Huang CC (1981) Effect of tumor promoter 12-O-tetradecanoyl-phorbol 13-acetate on induction of sister chromatid exchanges in Chinese hamster V79 cells treated with mutagens. Mutat Res 81:387–94

    PubMed  Google Scholar 

  • Kinsella AR (1981) Investigation of the effects of the phorbol ester TPA on carcinogen-induced forward mutagenesis to 6-thioguanine-resistance in V79 Chinese hamster cells. Carcinogenesis 2:43–47

    PubMed  Google Scholar 

  • Kinsella AR, Radman M (1978) Tumor promoter induced sister chromatid exchanges: relevance to mechanisms of carcinogenesis. Proc Natl Acad Sci USA 75:6149–6153

    PubMed  Google Scholar 

  • Knudsen I, Pedersen H, Thorling EB (1984) Modifiers of carcinogenesis. Acta Pharmacol Toxicol 55: Supplement II

  • Lankas GR, Baxter CS, Christian RJ (1977) Effect of tumor promoting agents on mutation frequencies in cultured V79 hamster cells. Mutat Res 45:153–156

    PubMed  Google Scholar 

  • Lasne C, Cole J, Arlett CF (1980) Tumor promoter TPA does not affect mutation to ouabain resistance in L5178Y mouse lymphoma cells. Carcinogenesis 1:627–631

    PubMed  Google Scholar 

  • Lin FL, Sternberg N (1984) Homologous recombination between overlapping thymidine kinase gene fragments stably inserted into a mouse cell genome. Mol Cell Biol 4:852–861

    PubMed  Google Scholar 

  • Little JB, Nagasawa H, Kennedy AR (1979) DNA repair and malignant transformation: Effect of X-irradiation, 12-O-tetradecanoyl-phorbol-13-acetate, and protease inhibitors in transformation and sister-chromatid exchanges in mouse 10T 1/2 cells. Radiat Res 79:241–255

    PubMed  Google Scholar 

  • Loveday KS, Latt SA (1979) The effect of a tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate, on sister chromatid exchange formation in cultured Chinese hamster cells. Mutat Res 67:343–348

    PubMed  Google Scholar 

  • Miller RC, Geard CR, Osmak RS, Rutledge-Freeman M, Ong A, Mason H, Napholz A, Perez N, Harisiadis L, Borek C (1981) Modification of sister chromatid exchanges in radiation-induced transformation in rodent cells by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate and two retinoids. Cancer Res 41:655–659

    PubMed  Google Scholar 

  • Nagasawa H, Little JB (1979) Effect of tumor promoters, protease inhibitors, and repair processes on X-ray-induced sister chromatid exchanges in mouse cells. Proc Natl Acad Sci USA 76:1943–1947

    PubMed  Google Scholar 

  • Nagasawa H, Little JB (1981) Factors influencing the induction of sister chromatid exchanges in mammalian cells by 12-O-tetradecanoyl-phorbol-13-acetate. Carcinogenesis 2:601–608

    PubMed  Google Scholar 

  • Nagasawa H, Fornace D, Little JB (1983) Induction of sister chromatid exchanges by DNA-damaging agents and 12-O-tetradecanoylphorbol-13-acetate (TPA) in synchronous Chinese hamster ovary (CHO) cells. Mutat Res 107:315–327

    PubMed  Google Scholar 

  • Ohno S (1974) Aneuploidy as a possible means employed by malignant cells to express recessive phenotypes. In: German I (ed) Chromosomes and cancer. Wiley, New York, pp 7–94

    Google Scholar 

  • Popescu NC, Amsbaugh SC, Dipaolo JA (1980) Enhancement of N-methyl-N′-nitro-N-nitrosoguanidine transformation of Syrian hamster cells by a phorbol diester is independent of sister chromatid exchanges and chromosome aberrations. Proc Natl Acad Sci USA 77:7282–7286

    PubMed  Google Scholar 

  • Popescu NC, Amsbaugh SC, Larramendy ML, Dipaolo JA (1982) 12-O-tetradecanoyl-phorbol-13-acetate and its relationship to sister chromatid exchange induction in Syrian and Chinese hamster cells. Environ Mutagen 4:73–82

    PubMed  Google Scholar 

  • Ray-Chaudhuri R, Currens M, Iype PT (1982) Enhancement of sisters chromatid exchanges by tumor promoters. Br J Cancer 45:769–777

    PubMed  Google Scholar 

  • Russell LB, Major MH (1957) Radiation-induced presumed somatic mutations in the house mouse. Genetics 42:161–175

    Google Scholar 

  • Schwartz JL, Banda MJ, Wolff S (1982) 12-O-Tetradecanoylphorbol 13-acetate (TPA) induces sister chromatid exchanges and delays in cell progression in Chinese hamster ovary and human cell lines. Mutat Res 92:393–409

    PubMed  Google Scholar 

  • Stanbridge EJ (1976) Suppression of malignancy in human cells. Nature 260:17–20

    PubMed  Google Scholar 

  • Thompson LH, Baker RM, Carrano AV, Brookman KW (1980) Failure of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate to enhance sister chromatid exchange, mitotic segregation, or expression of mutations in Chinese hamster cells. Cancer Res 40:3245–3251

    PubMed  Google Scholar 

  • Trosko JE, Chang CC, Yotti LP, Chu EHY (1977) Effect of phorbol myristate acetate on the recovery of spontaneous and ultraviolet light-induced 6-thioguanine- and ouabain-resistant Chinese hamster cells. Cancer Res 37:188–193

    PubMed  Google Scholar 

  • Yamasaki H (1984) Tumor promotion-mechanisms and implication to risk estimation. Acta Pharmacol Toxicol 55:89–106

    Google Scholar 

  • Zimmermann FK, von Borstel RC, von Halle ES, Parry JM, Siebert D, Zetterberg G, Barale R, Loprieno N (1984) Testing of chemicals for genetic activity with Saccharomyces cerevisiae: a report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutat Res 133:199–244

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Fraunhofer-Institut für Toxikologie und Aerosolforschung, Nikolai-Fuchs-Straße 1, D-3000, Hannover 61, Federal Republic of Germany

    Rudolf Fahrig

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  1. Rudolf Fahrig
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Dedicated to Professor Dr. Erich Hecker on the occasion of his 60th birthday.

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Fahrig, R. Enhancement of carcinogen-induced mutations or recombinations by 12-O-tetradecanoyl-phorbol-13-acetate in the mammalian spot test. J Cancer Res Clin Oncol 113, 61–66 (1987). https://doi.org/10.1007/BF00389968

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  • DOI: https://doi.org/10.1007/BF00389968

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