Amplification of Carcinogenesis by Non-Carcinogens — Diterpene Type Promoters and Models of Environmental Exposure

  • E. Hecker
Conference paper
Part of the The Jerusalem Symposia on Quantum Chemistry and Biochemistry book series (JSQC, volume 13)

Summary

In the last 15 years the cocarcinogens of the polyfunctional di- terpene ester type originating from plants were established molecularly and biologically as non-carcinogenic amplifiers of carcinogenesis. Thus the long suspected concept of amplification of carcinogenesis by non- carcinogens was finally verified. In addition the new principle of “cryptic” cocarcinogens was detected in the form of higher esters of diterpenes. Besides for investigations in molecular cytology and molecular mechanisms of carcinogenesis, cocarcinogens of this type may be used in models of environmental exposure to investigate the role of cocarcinogens in general as possible carcinogenic risk factors of the human environment. Three model situations are devised and investigated: (i) Several polyfunctional diterpenes were detected to be present in roots of Croton flavens L. and identified as highly active irritants and cocarcinogens of the promoter type. The utilization of parts of this plant according to local habits may be suspected therefore to be responsible for the unusually high incidence of esophageal cancer on Curacao, (ii) Many but not all species of the Euphorbiaceae and Thyme- laeaceae families utilized as ornamentals were shown to contain irritant and cocarcinogenic diterpene esters. Provided intensive contacts are avoided with skin and/or by ingestion of plant parts, it is concluded that most likely an actual carcinogenic risk does not exist by maintenance of single species. However, it is called for epidemiological investigations of a possible risk in persons involved professionally in raising and handling of mass cultures of species of Euphorbiaceae and Thymelaeaceae containing irritants, (iii) It was shown that nectar collected by honey bees from certain species of Euphorbiaceae may contain irritant polyfunctional diterpenes of the promoter type. - The actual new findings i - iii suggest that in the etiology of human tumors besides solitary carcinogens, the classical first order carcinogenic risk factors, diterpene ester type co-carcinogens of the promoter type - non-carcinogenic amplifiers of carcinogenesis - may contribute. As compared to solitary carcinogens cocarcinogens of whatever type may be classified as second order carcinogenic risk factors.

Keywords

Mouse Skin Carcinogenic Risk Parent Alcohol Prototype Process Skin Irritant 
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References

  1. Armuth V, Berenblum I, Adolf W, Opferkuch HJ, Schmidt R, Hecker E (1979) J Cancer Res Clin Oncol 95; 19–28.CrossRefGoogle Scholar
  2. Bauer KH (1928) Mutationstheorie der Geschwulstentstehung, Springer Verlag, BerlinGoogle Scholar
  3. Bauer KH (1963) Das Krebsproblem, 2. Aufl., Springer, Berlin Göttinngen HeidelbergGoogle Scholar
  4. Berenblum I (1941a) Cancer Res. 1; 44–48Google Scholar
  5. Berenblum I (1941b) Cancer Res. 1; 807–814Google Scholar
  6. Berenblum I, Shubik P (1947) Brit J Cancer, 1; 383–391CrossRefGoogle Scholar
  7. Boutwell RK (1964) Progr. exp. Tumor Res. 4; 207–250Google Scholar
  8. Boutwell RK (1974) CRC Critical Reviews in Toxicology 2; 419–443CrossRefGoogle Scholar
  9. Butenandt A (1949) Verhandlungen der Dt. Ges. f. innere Med., 55. Kongreß, Wiesbaden, 342–364Google Scholar
  10. Butenandt A (1950) Dt. Med. Wochenschrift 75; 5–7CrossRefGoogle Scholar
  11. Dontenwill W (1966) Hdb. der experimentellen Pharmakologie, Bd. XV1/13; Springer, Berlin Heidelberg New York, 74–204Google Scholar
  12. Druckrey H, Küpfmüller K (1948) Dosis und Wirkung, Editio Cantor KG, Aulendorf/Württ.Google Scholar
  13. Druckrey H (1967) In: Truhaut R (ed.) Potential Carcinogenic Hazards from Drugs, UICC Monographs Series Vol 7; Springer, Berlin Heidelberg New York, 60–77Google Scholar
  14. van Duuren BL, Blazej T, Goldschmidt BM, Katz C, Melchione S, Sivak A (1971) J. Nat. Cancer Inst. 46; 1039–1044Google Scholar
  15. van Duuren BL, Katz C, Goldschmidt 3M (1973) J. Nat. Cancer Inst. 51; 703–705Google Scholar
  16. O’Gara RW, Lee C, Morton JF (1971) J. Nat. Cancer Inst. 46; 1131–1137Google Scholar
  17. Goertller K, Löhrke H (1976a) Virchows Arch. A Path. Anat and Histol. 376; 117–132CrossRefGoogle Scholar
  18. Goerttler K and Löhrke H (1976b) Exp.Path., 12; 336–341Google Scholar
  19. Goerttler K, Löhrke H, Schweizer J, Hesse B (1979) Cancer Res. 39; 1293–1297Google Scholar
  20. Goerttler K, Löhrke H, Schweizer J, Hesse B (1980a) Cancer Res. 40; 155–161Google Scholar
  21. Goerttler K, Löhrke H, Schweizer J, Hesse B (1980b) Virchows Arch. A Path. Anat. and Histol. 385; 181–186CrossRefGoogle Scholar
  22. Hecker E (1971) In: Busch H (ed.) Methods in Cancer Research, Vol. 6; 439–484, Academic Press, New York LondonGoogle Scholar
  23. Hecker E (1972) Z. Krebsforsch. 78; 99–122CrossRefGoogle Scholar
  24. Hecker E (1976a) Internat. J. Cancer 18; 122–129 (b) Z. Krebsforsch. 86; 219–230. (c) GANN 67; 471–481. (d) Bull. World Health Organ. 54; 1–10CrossRefGoogle Scholar
  25. Hecker E (1976e) Pure and Applied Chem. 49; 1423CrossRefGoogle Scholar
  26. Hecker E (1978a) Cocarcinogenesis in occupational cancer. Symp. No. 26, XII. Internat. Cancer Congress, Buenos Aires, Oct. 5–11, In: Adv. in Med. Oncology, Research and Education, Vol. 3. EpidemiologyGoogle Scholar
  27. Hecker E (1979) In: Miller EC, Miller JA, Hirono T, Sugimura T, Takayama S (eds.) Naturally occuring carcinogens — mutagens and modulators of carcinogenesis. Japan Scientific Societies Press, Tokyo, 263–286Google Scholar
  28. Hecker E, Schmidt R (1974) Chem.Org.Nat.Prod. 31; 377–467Google Scholar
  29. Hecker E, Weber J (1977) 7th Internat. Symposium on the Biological Characterization of Human Tumors, Budapest, 13–15 April Abstracts p. 52; see also Experientia (Basel) 34; 679–682 (1978)Google Scholar
  30. Hecker E, Friesel H, Marquardt H, Schmidt R, Siebert D. (1978) Symposium No. 2, XII. Internat. Cancer Congress, Buenos Aires, Oct. 5–11; Adv. in Med. Oncology, Research and Education, Vol.1, Carcinogenesis, Margison GP (ed.) 1979, Pergamon Press Oxford and Newas Krebsproblem, 2. Auf1., Springer, Berlin Gottingen HeidelbergGoogle Scholar
  31. Hecker E (1979) In: Miller EC, Miller JA, Hirono T, Sugimura T, Takayama S (eds.) Naturally occuring carcinogens — mutagens and modulators of carcinogenesis. Japan Scientific Societies Press, Tokyo, 263–286Google Scholar
  32. Hecker E, Schmidt R (1974) Chem.Org.Nat.Prod. 31; 377–467Google Scholar
  33. Hecker E, Weber J (1977) 7th Internat. Symposium on the Biological Characterization of Human Tumors, Budapest, 13–15 April Abstracts p. 52; see also Experientia (Basel) 34; 679–682 (1978)Google Scholar
  34. Hecker E, Friesel H, Marquardt H, Schmidt R, Siebert D. (1978) Symposium No. 2, XII. Internat. Cancer Congress, Buenos Aires, Oct. 5–11; Adv. in Med. Oncology, Research and Education, Vol.1, Carcinogenesis, Margison GP (ed.) 1979, Pergamon Press Oxford and New York, 207–212; J.Cancer Res. Clin. Oncology, in pressGoogle Scholar
  35. Hecker E, Adolf W, Opferkuch HJ, Ott HH, Weber G (1979a) Internat. Symposium on Environmental Carcinogenesis, Bombay, Dec. 9–11, Aostracts p 29. Proceedings J. Cancer Res. Clin. Oncology, in pressGoogle Scholar
  36. Hecker E, Pyerin W, Friesel H, Oberender H. Schmidt R (1979b) Internat. Symposium on Environmental Carcinogenesis, Bombay, Dec. 9–11. Abstracts 2728; Proceedings J. Cancer Res. Clin. Oncol., in pressGoogle Scholar
  37. Higginson J (1978), UICC Bulletin Cancer 16; 67Google Scholar
  38. Kaufmann C, Müller HA, Butenandt A und Friedrich-Freska H (1949) Z. Krebs forsch. 56; 482–542CrossRefGoogle Scholar
  39. Kunz W, Appel KE, Rickart R, Schwarz M, Stöckle G (1978) In: Reitnier H, Bolt HM, Bannasch P, Popper H (eds.) Primary Liver Tumors, Press Ltd, Lancaster UK, 261–283Google Scholar
  40. Kunz W, Appel KE, Jones GRN, Rickart R. Schwarz M, Stöckle G (in press) Arch. Toxicol, supplement, Proceedings of the European Society of Toxicol.Google Scholar
  41. Likhachey AY (1968) Vopr. Onkol. 14; 114–124Google Scholar
  42. Lutz D, Hecker E (1979) VII. Internat. Symposium on the Biological Characterization of Human Tumors, May 8–11, Book of AbstractsGoogle Scholar
  43. Morton JF (1971) Econ. Bot. 25; 457–463CrossRefGoogle Scholar
  44. Mottram JC (1944) J. Path. Bacterid. 56; 181–187CrossRefGoogle Scholar
  45. Ott HH, Hecker E (1980) Japanese-German Workshop on Chemical, Viral and Environmental Carcinogenesis, Deutsches Krebsforschungszentrum Heidelberg May 20–23Google Scholar
  46. Pound AW, Bell Jr (1962) Brit. J. Cancer 16; 690–695CrossRefGoogle Scholar
  47. Princess Takamatsu Cancer Research Fund (1979) 9th Internat. Symposium: Naturally occuring carcinogens — mutagens and modulators of carcinogenesis, Jan. 23–25, Tokyo, Japan; Proceedings see loc. cit. Hecker 1979Google Scholar
  48. Roe FJC, Carter RJ, Mitschley BCV, Peto R, Hecker E (1972) Int. J. Cancer 9; 264–273CrossRefGoogle Scholar
  49. Schmähl D (1976) (Experimental Results) Oncology 33:73Google Scholar
  50. Schweizer J, Marks F (1977) Cancer Res. 37; 4195–4201Google Scholar
  51. Shear MJ (1938) Amer. J. Cancer 33; 499–537, dort S. 532Google Scholar
  52. Shinozuka H, Ritchie AC (1967) Int. J. Cancer 2; 77–84CrossRefGoogle Scholar
  53. Sivak A (1979) Biochem. Biophys. Acta 560; 67–89Google Scholar
  54. Slaga TJ, Sivak A, Boutwell RK (eds.) (1978) Carcinogenesis Vol. 2, Mechanism of Tumor Promotion and Cocarcinogenesis, Raven Press, New YorkGoogle Scholar
  55. Soper CB, Evans FB (1977) Cancer Res. 37; 2487–2491Google Scholar
  56. Sugimura T, Kawachi T, Nakayasu N, Matsukura N, Takayama S (1978) Symposium Biological Effects of Phorbol Esters in Cell Culture Systems, Cold Spring Harbour Laboratory, May 11–14, Abstracts of Papers 30Google Scholar
  57. Süss R, Kreibich G, Kinzel V (1972) Europ. J. Cancer 8; 299–304CrossRefGoogle Scholar
  58. Tomatis L, Agathe C, Bartsch H, Huff I, Montesano T, Saracci R, Walker E, Wilbourn I (1978) Cancer Res. 38; 8775–885Google Scholar
  59. Traut M, Kreibich G und Hecker E (1971) In: Lettre H and Wagner G (eds.) Aktuelle Probleme der Cancerologie III, Springer Berlin Heidelberg New York, 91–96Google Scholar
  60. UICC, International Symposium “Carcinogens of Plant Origin” (1968), National Institutes of Health, Bethesda, Maryland, USA, see Cancer Res. 28; 2233–2396; see also IARC Monograph series “Evaluation of Carcinogenic Risk of Chemicals to Man,” Vol. 10, Internat. Agency for Research on Cancer, Lyon, 1976Google Scholar
  61. Upadhyay RR, Eslampanah S, Daudi A (1979) IV. Asian Cancer Conference, ec. 4–8, Bombay, Abstracts 15Google Scholar
  62. Upton AC (1978) National Cancer Program (USA), Special Communication: Cancer and estrogen use, May 22Google Scholar
  63. Weber J (1976) Dissertation, Univ. HeidelbergGoogle Scholar
  64. Weinstein B, Troll W (1977) Cancer Res. 37; 3461–3463Google Scholar
  65. Weinstein 3, Troll W (1978) (eds.) Symposium Biological Effects of Phorbol Esters in Cell Culture Systems, Cold Spring Harbour Laboratory, May 11–14, Abstracts of PapersGoogle Scholar
  66. WHO Chronicle (1977) 31; IARC: past and present developments, 239–245, see p 243Google Scholar
  67. WHO Scientific Group (1978) Steroid contraception and the risk of neoplasia. WHO Technical Report Series No. 619Google Scholar
  68. Yamagiwa K, Ichikawa K (1914) GANN, Tokyo, 8; 11–15; see: Collected Papers on Artificial Production of Cancer by Prof. K. Yamagiwa (1965) 1–9. Maruzen Comp. Ltd. Tokyo, JapanGoogle Scholar
  69. Zur Hausen H, O’Neill FB, Freese UK and Hecker E (1978) Nature 272; 373–374CrossRefGoogle Scholar
  70. Zur Hausen H, Bornkamm GW, Schmidt R und Hecker E (1979) Proc. Ntl. Acad. Sei. (USA) 76; 782–785CrossRefGoogle Scholar

Copyright information

© D. Reidel Publishing Company 1980

Authors and Affiliations

  • E. Hecker
    • 1
  1. 1.Deutsches KrebsforschungszentrumInstitut für BiochemieHeidelberg 1Federal Republic of Germany

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