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Biological assays for irritant tumor-initiating and -promoting activities

I. Kinetics of the irritant response in relation to the initiation-promoting activity of polyfunctional diterpenes representing tigliane and some daphnane types

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  • Experimental Oncology
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Summary

The kinetics of the irritant response on the mouse ear [erythema measured quantitatively by the irritant dose 50 (ID50)] and its relation to the initiation-promoting activity on the back skin of NMRI mice of some polyfunctional diterpene esters were investigated: (1) A very rapid and transient erythema response is associated with low or absent promoting activity (2) an early and more persistent erythema response in most cases is associated with moderate-to-high promoting activity, and (3) a relatively late onset but persistence up to at least 24 h of the erythema response is associated with high promoting activity. These results may indicate a relationship between the kinetics of the erythema response and the initiation-promoting activity of diterpene esters. The comparatively low promoting activity of esters carrying polyunsaturated acyl functions may indicate that importance of pharmacological parameters such as biovailability and stability in the biological system, drug-receptor interaction, and “intrinsic activity” of the diterpene esters.

Zusammenfassung

Die Kinetik der irritierenden Wirkung von einigen polyfunktionellen Diterpenestern auf dem Mausohr [Erythem-Auslösung, quantitativ gemessen als irritierende Dosis 50 (ID50)], und ihre Beziehung zur initiationspromovierenden Aktivität auf der Rückenhaut der NMRI-Maus wurde untersucht: 1) Ein sehr schnell einsetzendes, aber rasch abklingendes Erythem ist mit schwacher oder fehlender Promoter-Wirkung verbunden. 2) Ester, die ein schnell einsetzendes, aber langsam abklingendes Erythem verurschen, zeigen in den meisten Fällen mäßige bis starke initiationspromovierende Wirkung und 3) relativ spät einsetzende, aber anhaltende Erythem-Wirkung (bis mindestens 24 h) ist mit hoher promovierender Aktivität verbunden.

Diese Ergebnisse weisen auf eine Beziehung zwischen der Kinetik der irritierenden Wirkung und der initiationspromovierenden Aktivität der Diterpenester hin. Die verhältnismäßig geringe promovierende Aktivität von Estern mit mehrfach ungesättigten Acylresten könnte auf den Einfluß von pharmakologischen Parametern wie Bioverfügbarkeit und Stabilität im biologischen System, Wirkstoff-Rezeptor-Wechselwirkung und “intrinsic activity” der Diterpeneser hinweisen.

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Abbreviations

ID50 :

irritant dose 50

tlc:

thin layer chromatography

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Authors and Affiliations

  1. Institut für Biochemie, Deutsches Krebsforschungszentrum, D-6900, Heidelberg, Germany

    M. Hergenhahn, G. Fürstenberger, H. J. Opferkuch, W. Adolf, H. Mack & E. Hecker

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  1. M. Hergenhahn
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  2. G. Fürstenberger
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  3. H. J. Opferkuch
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  4. W. Adolf
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  5. H. Mack
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  6. E. Hecker
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Dedicated to Andrej D. Sacharov

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Hergenhahn, M., Fürstenberger, G., Opferkuch, H.J. et al. Biological assays for irritant tumor-initiating and -promoting activities. J Cancer Res Clin Oncol 104, 31–39 (1982). https://doi.org/10.1007/BF00402051

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  • DOI: https://doi.org/10.1007/BF00402051

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