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Journal of Cancer Research and Clinical Oncology

, Volume 115, Issue 4, pp 309–328 | Cite as

Experimental investigations into the carcinogenic effect of antitumor and immunosuppressive agents

  • N. Brock
  • B. Schneider
  • J. Stekar
  • J. Pohl
Guest Editorial

Summary

In a comprehensive experimental study on rats, the carcinogenicity of various therapeutically important antitumor drugs was investigated. The influences of strain, sex, dose and time of administration were systematically varied. The tested compounds showed remarkable differences in their carcinogenic potential. These differences were particularly obvious, not only when the total tumor rate was analyzed, but also when the distribution of tumor rates to the various localizations was considered (tumor spectrum). Three classes of carcinogenic substances were identified: (1) Substances showing a specific carcinogenicity: they lead to tumorogenesis primarily in organs or organ systems that, in the untreated control animals, remain virtually tumor-free for life. One example of such a substance is chlormethine. (2) Substances with nonspecific carcinogenicity: they lead to an increase in tumors in organs that are also stricken in the control animals, however, to a clearly reduced extent. Oxazaphosphorine carcinogenicity is typical for this class. (3) Substances of mixed-type carcinogenicity: this group shows non-specific carcinogenicity, as well as a carcinogenic action with marked organ specificity. One example of this class is procarbazine.

The antimetabolites tested were shown to be practically non-carcinogenic.

Characteristic differences occurred between the two rat strains used in the investigation, Sprague-Dawley and BD II, with regard to the spontaneous tumor spectrum and the organ-related extent of carcinogenicity under the influence of the substances tested. In an experiment involving short-term application (up to 17% LD50, five times i.v. at 14-day intervals), the carcinogenic effects were substantially lower than in an experiment involving long-term application (up to 7% LD50, once a week for 52 weeks, i.v.), although the strain- and substancespecific characteristics in both experiments were rather similar.

Key words

Carcinogenicity Cytostatics Alkylating Drugs Antimetabolites Lifetable analysis Tumor spectrum distribution analysis Hierarchical cluster analysis 

Abbreviations used

CTL

controls

CMT

chlormethine

PRO

procarbizine

CPA

cyclophosphamide

IFO

ifosfamide

TRO

trofosfamide

SUF

sufosfamide

MTX

methotrexate

5-FU

5-fluorouracil

AZA

azathioprine

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References

  1. BMDP Statistical Software, 1981 edn. Programm BMDP1L (Life tables and survival function), University of California PressGoogle Scholar
  2. Brock N (1983) Oxazaphosphorine cytostatics: structure-activity relationships, selectivity and metabolism, regional detoxification. In: Reinhoudt DN, Connors TA, Pinedo HM, van de Poll KW (eds) Structure-activity relationships of anti-tumor agents. Martinus Nijhoff, The Hague, Boston, London pp 239–267Google Scholar
  3. Brock N, Schneider B (1971) Zur Frage der carcinogenen Wirkung von Krebs-Chemotherapeutika und chemischen Immunsuppressiva. Arzneimittelforschung (Drug Res) 21:435–443Google Scholar
  4. Druckrey H (1956) Krebserzeugende Eigenschaften bei Arzneimitteln. Muench Med Wochenschr 98:295–297Google Scholar
  5. Druckrey H (1973) Specific carcinogenic and teratogenic effects of “indirect” alkylating methyl and ethyl compounds, and their depeudency on stages of ontogenic developments. Xenobiotica 3:271–303Google Scholar
  6. Druckrey H (1975) Chemical carcinogenesis on N-nitroso derivatives. GANN Monogr Cancer Res 17:107–132Google Scholar
  7. Druckrey H, Preussmann R, Ivankovic S, Schmähl D (1967) Organotrope carcinogene Wirkungen bei 65 verschiedenen N-Nitroso-Verbindungen an BD-Ratten. Z Krebsforsch 69:103–201PubMedGoogle Scholar
  8. McKnight B, Crowley J (1984) Tests for differences in tumor incidence based on animal carcinogenesis experiments. J Am Statist Assoc 79:639–648Google Scholar
  9. Pelfrene A, Garcia H (1976) Chemically induced esthesioneuroblastomas in Rats. Z Krebsforsch 86:113–119CrossRefGoogle Scholar
  10. Schellong G, Hörnig I, Brämswig J, Bökkerink JPM, Steinhoff A, Ludwig R, Niethammer D, Reiter A, v. Lengerke HJ, Heinecke H, Schwarze E-W, Pötter R, Müller RP, Wannenmacher M (1988) Zur Bedeutung des Procarbazins in der Chemotherapie des Morbus Hodgkin — Ein Berich der kooperativen Therapiestudie DAL-HD-85. Klin Pädiatr 200:205–213Google Scholar
  11. Schmähl D (1967) Karzinogene Wirkung von Cyclophosphamid und Triazichon bei Ratten. Dtsch Med Wochenschr 92:1150–1152Google Scholar
  12. Schmähl D, Habs M (1979) Carcinogenic action of low-dose cyclophosphamide given orally to Sprague-Dawley rats in a lifetime experiment. Int J Cancer 23:706–712PubMedGoogle Scholar
  13. Schmähl D, Habs M (1982) Cancer after the use of alkylating and non-alkylating cytotoxic agents in animals. Cancer Surv 1:585–597Google Scholar
  14. Schmähl D, Kaldor JM (1986) Carcinogenicity of alkylating cytostatic drugs, IARC Scientific publication, LyonGoogle Scholar
  15. Schmähl D, Osswald H (1970) Experimentelle Untersuchungen über carcinogene Wirkungen von Krebs-Chemotherapeutica und Immunsuppressiva. Arzneimittelforschung (Drug Res) 20:1461–1467Google Scholar
  16. Schneider B (1972) Mathematische Modelle für den Einfluß konkurriender Risiken bei Langzeitstudien. Arzneimittelforschung (Drug Res) 22:1680–1685Google Scholar
  17. Thomas C (1965) Zur Morphologie der Nasenhöhlentumoren bei der Ratte. Z Krebsforsch 67:1–10PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • N. Brock
    • 1
  • B. Schneider
    • 2
  • J. Stekar
    • 1
  • J. Pohl
    • 1
  1. 1.Department of Experimental Cancer ResearchASTA Pharma AGBielefeldFederal Republic of Germany
  2. 2.Institute for BiometryMedical UniversityHannover 61Federal Republic of Germany

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