Summary
Phorbol and six structurally related compounds representing the polyfunctional diterpenes of the tigliane, ingenane, and lathyrane types were tested for systemic promoting and leukemogenic activity in SWR mice. For systemic initiation soon after birth, 15 μg dimethylnitrosamine (DMN) was injected s.c. The diterpenes were administered i.p. either with or without prior systemic initiation with DMN. Systemic promotion was expressed for liver by induction of adenomas with all the diterpenes tested, some of them being more potent than phorbol. The relatively high dose of DMN used as initiator prevented an evaluation of promoting action in relation to lung carcinogenesis. The leukemogenic effect of phorbol in SWR mice was confirmed at three different dose levels. The other diterpenes tested had no significant leukemogenic activity. The leukemogenic action of phorbol was totally inhibited by prior DMN injection.
The lack of correlation between promoting action in skin, systemic promoting action in liver and leukemogenic action, among the diterpenes tested, is discussed.
Zusammenfassung
Phorbol und sechs strukturverwandte Substanzen, die die polyfunktionellen Diterpene des Tiglian-, Ingenan- und Lathyrantyps repräsentieren, wurden an SWR-Mäusen auf systemische promovierende und leukämogene Wirkung geprüft. Zur systemischen Initiation wurde kurz nach Geburt 15 μg Dimethylnitrosamin (DMN) s.c. injiziert. Die Diterpene wurden i.p. entweder mit oder ohne vorhergehende Initiation mit DMN gegeben. Systemische Promotion für Leber zeigten alle geprüften Diterpene mit der Entstehung von Adenomen. Einige der Diterpene erwiesen sich wirksamer als Phorbol. Die relativ hohe Dosis von DMN, die als Initiator verwendet wurde, machte eine Auswertung bezüglich promovierender Wirkung auf die Lunge unmöglich.
Die leukämogene Wirkung von Phorbol bei SWR Mäusen wurde für drei verschiedene Dosen bestätigt. Die übrigen Diterpene zeigten mit der jeweils geprüften Dosis keine signifikante leukämogene Wirkung. Die leukämogene Wirkung des Phorbols wurde durch vorausgehende DMN-Injektion vollständig verhindert.
Die fehlende Korrelation zwischen promovierender Wirkung an Haut, systemischer promovierender Wirkung an Leber und leukämogener Wirkung der getesteten Diterpene wird diskutiert.
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Abbreviations
- DMBA:
-
7,12-dimethylbenz[a]anthracene
- DMN:
-
dimethylnitrosamine
- PBS:
-
phosphate-buffered saline
- H-E:
-
hematoxylin-eosin
- tlc:
-
thin-layer chromatography
- TPA:
-
12-O-tetradecanoylphorbol-13-acetate
- PDD:
-
phorbol-12,13-didecanoate
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Supported, in part, by grants IIIB4-7291-MT 403a and 307-7291-MT-424 of the Bundesminister für Forschung und Technologie, Federal Republic of Germany, under a joint contract with the Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-6900 Heidelberg, Federal Republik of Germany
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Armuth, V., Berenblum, I., Adolf, W. et al. Systemic promoting action and leukemogenesis in SWR mice by phorbol and structurally related polyfunctional diterpenes. J Cancer Res Clin Oncol 95, 19–28 (1979). https://doi.org/10.1007/BF00411105
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DOI: https://doi.org/10.1007/BF00411105