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Plasminogen activator induction and platelet aggregation by phorbol and some of its derivatives: Correlation with skin irritancy and tumor-promoting activity

Induktion von Plasminogen-Aktivator und Blutplättchen-Aggregation durch Phorbol und einige seiner Derivate: Korrelation mit hautirritierender und tumorpromovierender Wirkung

  • Original Papers
  • Experimental Oncology
  • Published:
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Zusammenfassung

Phorbol und acht seiner Derivate wurden auf ihre Fähigkeit untersucht, die Synthese von Plasminogen-Aktivator in Zellkulturen von Hühnerembryo-Fibroblasten zu stimulieren und die Aggregation von Blutplättchen zu induzieren und auf ihre tumorpromovierende und hautirritierende Wirkung getestet. Die Erhöhung der Plasminogen-Aktivator Aktivität durch Phorbolderivate korreliert gut mit ihren irritierenden und promovierenden Eigenschaften. Im Test auf Blutplättchen-Aggregation ist die Korrelation nicht eindeutig: Sie gilt für starke Promotoren (wie TPA), die auch hochwirksame Induktoren der Aggregation sind, sowie für schwache Promotoren (wie PDA), die nur gering oder nicht induzieren; Ausnahmen sind PDD und PDB: PDD, ein starker Promoter, ist nur schwach wirksam, PDB, ein schwacher Promotor, ist dagegen das am stärksten aggregationsstimulierende Derivat.

Summary

Phorbol and eight of its derivatives were investigated for their ability to stimulate the synthesis of the enzyme plasminogen activator in cultured chick embryo fibroblasts and to aggregate human blood platelets and have been assayed for tumor, promoting and skin, irritant activities. Over a range of concentrations, elevation in the levels of plasminogen activator activity induced by phorbol derivatives correlates well with their promoting and irritant properties. In the platelet aggregation assay however, the parallelism between the activities measured in different biological assays was less complete. While strong promoters, such as TPA, are potent aggregating agents, and weak promoters, such as PDA, are poor or ineffective inducers of aggregation, two derivatives, PDD and PDB, deviate from this general result. Platelets must be exposed to PDD in relatively high concentrations before they will aggregate, and PDB was found to be the most potent aggregating agent of all the derivatives tested.

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Abbreviations

TPA:

12-O-tetradecanoylphorbol-13-acetate

PDD:

phorbol-12,13-didecanoate

TPA-β-oxide:

12-O-tetradecanoylphorbol-13-acetate-6β,7β-oxide

PDB:

phorbol-12,13-dibenzoate

PDA:

phorbol-12,13-diacetate

4-OMe-TPA:

4-O-methyl-12-O-tetradecanoylphorbol-13-acetate

1,2-dihydro-TPA-β-oxide:

1,2-dihydro-12-O-tetradecanoylphorbol-13-acetate-6β,7β-oxide

4α-PDD:

4α-phorbol-12,13-didecanoate

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Authors and Affiliations

  1. Department of Pharmacological Sciences, State University of New York at Stony Brook, 11794, Stony Brook, NY, USA

    P. J. Brynes

  2. Deutsches Krebsforschungszentrum, Institut für Biochemie, Im Neuenheimer Feld 280, D-6900, Heidelberg 1, Federal Republic of Germany

    R. Schmidt & E. Hecker

Authors
  1. P. J. Brynes
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  2. R. Schmidt
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  3. E. Hecker
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Additional information

This work was supported by a Grant-in-Aid from the American Heart Association and with funds contributed in part by the Suffolk Heart Association (Grant 78 747), the National Cancer Institute (Grants CA08290 and CA00118), and the American Cancer Society (Grant PDT1)

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Brynes, P.J., Schmidt, R. & Hecker, E. Plasminogen activator induction and platelet aggregation by phorbol and some of its derivatives: Correlation with skin irritancy and tumor-promoting activity. J Cancer Res Clin Oncol 97, 257–266 (1980). https://doi.org/10.1007/BF00405777

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