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Induction of epstein-barr virus early antigens by tumor promoters of the diterpene ester type in Raji cells and specific (receptor) binding as compared to irritant and promoting activities

  • Original Papers
  • Experimental Oncology
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Summary

Sixteen new diterpene esters (DTE) of the tigliane, ingenane, daphnane, and 1α-alkyldaphnane types were investigated in two in vitro assays: as inhibitors of specific binding of 3H-labeled 12-O-tetradecanoylphorbol 13-acetate (TPA) to protein kinase C in a receptor preparation from mouse brain, and as inducers of Epstein-Barr virus (EBV) early antigens in Raji cells. Inhibition of binding of [3H]TPA to the receptor preparation by tigliane and ingenane DTE correlates with irritant activity in vivo, while some daphnane and 1α-alkyldaphnane DTE inhibit binding of [3H]TPA in a less pronounced manner but still are very irritant. Tumor-promoting activity does not correlate consistently with the receptor-binding data. To test the hypothesis that early antigen induction in Raji cells by DTE is coupled to functional DTE receptors (protein kinase C), the latter were searched on these Raji cells by a ‘cold acetonefilter assay’ and shown to be present. The dependence of the early antigen induction rate on the concentration of the DTE tested was demonstrated. At a given concentration of DTE, differences in the induction rate between various DTE are seen. However, a clear quantiative correlation either between early antigen induction and receptor binding data in vitro, or early-antigen-inducing activity in vitro versus irritancy and tumor-promoting activity in vivo was not observed.

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Abbreviations

ANPA:

12-O-anthroylphorbol 13-acetate

DPH:

12-deoxyphorbol 13-hexadecanoate

DPT:

12-deoxyphorbol 13-tetradecanoate

EBV:

Epstein-Barr virus

HPA:

12-O-hexadecanoyl-phorbol 13-acetate

HPA-6α,7α-oxide:

12-O-hexadecanoyl-6α,7α-epoxyphorbol 13-acetate; I24, irritancy calculated from ID 5024

ID 5024 :

irritant dose 50 read 24 h after administration of compound

K da :

apparent dissociation constant

K ia :

apparent inhibition constant

PDD:

phorbol 12,13-didecanoate

R ta :

apparent total number of receptors

RPA:

12-O-retinoylphorbol 13-acetate

TPA:

12-O-tetradecanoylphorbol 13-acetate

3-TI:

3-O-tetradecanoylingenol

4α-PDD:

4α-phorbol 12,13-didecanoate

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Dedicated to Professor Dr. W. Kunz, Institute of Biochemistry, German Cancer Research Center, Heidelberg, on the occasion of his 65th birthday

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Kloz, U., Hergenhahn, M., Felhauer, M. et al. Induction of epstein-barr virus early antigens by tumor promoters of the diterpene ester type in Raji cells and specific (receptor) binding as compared to irritant and promoting activities. J Cancer Res Clin Oncol 115, 148–156 (1989). https://doi.org/10.1007/BF00397915

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  • DOI: https://doi.org/10.1007/BF00397915

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