1 The stimulation of ( 3H)-thymidine incorporation by lymphocytes in response to phorbol and seven other phorbol related compounds was investigated.
2 Lymphocytes from each of a small group of individuals were treated with the test compounds over wide concentration ranges.
3 All the tested compounds, including the most active, 12-0-tetradecanoylphorbol-13-acetate, were far less effective lymphocyte mitogens than the plant lectin phytohaemagglutinin.
4 Inter-individual differences were detected in the maximum response to the phorbols but not in their stimulating potency, as estimated by the concentration producing a half maximal response.
5 The rank order of the lymphocyte stimulating potency of the tested compounds was similar to the rank order of both tumour promoting activity and irritant potency in mouse skin.
6 Lymphocyte stimulation was paralleled equally well by these two mouse skin responses.
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References
1.
Slaga TJ, Sivak A. & Boutwell RKCocarcinogenesis, Vol. 2, Mechanisms of tumour Promotion and Cocarcinogenesis . New York: Raven Press, 1978.
2.
Bohrman JSIdentification and assessment of tumor-promoting and cocarcinogenic agents: State-of-the art in vitro methods. CRC Critical Reviews in Toxicology1983; 11: 121-67.
3.
Rohrschneider LR & Boutwell RKThe early stimulation of phospholipid metabolism by 12-0-tetradecanoyl-phorbol-13-acetate and its specificity for tumor promotion . Cancer Research1973; 33: 1945-52.
4.
Baird WM, Sedgwick JA & Boutwell RKEffects of phorbol and four diesters of phorbol on the incorporation of tritiated precursors into DNA, RNA and protein in mouse epidermis. Cancer Research1971; 31: 1434-9.
5.
Raick ANCell proliferation and promotion action in skin carcinogenesis. Cancer Research1974; 34: 920-6.
6.
Raick ANUltrastructural, and biochemical alterations produced by 12-0 tetradecanolphorbol-13-acetate on epidermis and their relevance to skin tumor promotion. Cancer Research1973; 33: 269-86.
7.
Baird WM& Boutwell RKTumor-promoting activity of phorbol and four diesters of phorbol in mouse skin. Cancer Research1971; 31: 1074-9.
8.
Abb J., Bayliss GJ & Deinhardt F.Lymphocyte activation by the tumor-promoting agent 12-0-tetradecanoylphorbol-13-acetate. (TPA). Journal of Immunology1979; 122: 1639-42.
9.
Wertz PW & Mueller GCRapid stimulation of phospholipid metabolism in bovine lymphocytes by tumor-promoting ester. Cancer Research1978; 38: 2900-4.
10.
Estensen RD , Hadden JW, Hadden EM, et al. Phorbol myistate acetate: Effects of a tumor promoter on intracellular cyclic-GMP in mouse fibroblasts and as a mitogen on human lymphocytes. In: Control of Proliferation in Animal Cells, eds B Clarkson & R Baserga , pp. 627-634. New York: Cold SpringHarbour Press, 1974.
11.
Skinnider LFThe effect of phorbol myristate acetate on human lymphocytes. An ultrastructural study. Experimental and Molecular Pathology, 1979; 31, 36-43.
12.
Solanki V. & Slaga TJSpecific binding of phorbol ester tumor promoters to intact primary epidermal cells from Sencar mice. Proceedings of the National Academy of Science USA, 1981; 78: 2549-53.
13.
Sando JJ, Hilfiker ML, Salomon DS & Farraar JJSpecific receptors for phorbol esters in lymphoid cell populations: Role in enhanced production of T-cell growth factor. Proceedings of the National Academy of Science USA1981; 78: 1189-93.
14.
Estensen RD, Drazich BF & Hadden JSPMA as a lymphocyte mitogen: Quantitation of effects in culture and relationship to binding and inhibition by analogs. In Carcinogenesis, volume 2. Mechanisms of Tumor Promotion and Cocarcinogenesis, eds TJ Slaga, A Sivak & RK Boutwell, pp. 379-388. New York: Raven Press, 1978.
15.
Verma AK & Boutwell RDVitamin A acid (retinoic acid) a potent inhibitor of 12-0-tetradecanoylphorbol-13-acetate-induced ornithine decarboxylase activity in mouse skin. Cancer Research1977; 37: 2196-201.
16.
Slaga TJ, Fisher SM, Viaje A., et al. Inhibition of tumor promotion by anti-inflammatory agents: An approach to the biochemical mechanism of promotion. In Carcinogenesis, volume 2. Mechanisms of tumor promotion and cocarcinogenesis, eds TJ Slaga, A Sivak & RK Boutwell, pp. 173-195. New York: Raven Press, 1978.
17.
Abb J. & Deinhardt F.The tumor promoter 12-0-tetradecanoylphorbol-13-acetate (TPA) induces the production of lymphocyte-activating factors (LAF) in human lymphocyte cultures . Archiv fiir Geschwulstforschung1980; 50: 331.
18.
Gordon D. & Nouri Ame.Comparison of the inhibition by glucocorticosteroids and cyclosporin A of mitogen-stimulated human lymphocyte proliferation. Clinical and Experimental Immunology1981; 44: 287-94.
19.
Thielmann HW & Hecker E.Beziehunger zwischen der struktur von phorbolderivaten und ihren entzundlichen und tumorpromovierenden eigenschaften. In: Fortschritte der Krebsforschung, volume 7, eds CG Schmidt & O Wetter , pp. 171-179. Stuttgart: Schattauer , 1969.
20.
Böyum A.Isolation of lymphocytes, granulocytes and macrophages. Scandinavian Journal of Immunology1976; 5: (suppl.) 9-15.
21.
Blumberg PMIn vitro studies on the mode of action of the phorbol esters, potent tumor promoters, part 2. CRC Critical Reviews in Toxicology1981; 9: 199-234.
22.
Ashman RFLymphocyte activation. In: Fundamental Immunology, ed. WE Paul, pp. 267-300. New York: Raven Press, 1984.
23.
Koretzy GA, Daniele RP & Nowell PCA phorbol ester (TPA) can replace macrophages in human lymphocyte cultures stimulated with a mitogen but not with an antigen. Journal of Immunology1982; 128: 1776-80.
24.
Hutchins D. & Steel CMPhytohaemagglutinin-induced proliferation of human T lymphocytes: differences between neonates and adults in accessory cell requirements. Clinical and Experimental Immunology1983; 52: 355-64.
25.
De Vries JE , Cavilles AP Jr, Bont WS & Mendelsohn J.The role of monocytes in human lymphocyte activation by mitogens. Journal of Immunology1979; 122: 1099-107.
26.
Touraine JL , Hadden JW, Touraine F., Hadden EM, Estensen R. & Good RAPhorbol myristate acetate: A mitogen selective for a T-lymphocyte subpopulation. Journal of ExperimentalMedicine1977; 145: 460-65.
27.
Penhale WJ, Farmer A., Maccuish AC & Irvine WJA rapid micro-method for the phytohaemagglutinin-induced human lymphocyte transformation test. Clinical and Experimental Immunology1974; 18: 155-67.
28.
Knight SCControl of lymphocyte stimulation in vitro: 'Help' and 'suppression' in the light of lymphoid population dynamics. Journal of Immunological Method1982; 50: R51-63.
29.
Stenzel KH, Schwartz R., Rubin AL & Novogrodsky A.Chemical inducers of differentiation in Freind leukemia cells inhibit lymphocyte mitogenesis. Nature1980; 285: 106-8.
30.
Hecker E.Isolation and characterisation of the cocarcinogenic principles from croton oil. In: Methods in Cancer Research, volume 6, ed. H Busch, pp. 439-484. New York: Academic Press, 1971.
31.
Hecker E.Structure-activity relationships in diterpene esters irritant and cocarcinogenic to mouse skin. In Carcinogenesis, volume 2, Mechanisms of Tumor Promotion and Carcinogenesis, eds TJ Slaga , A Sivak & RK Boutwell, pp. 11-48. New York: Raven Press , 1978.
32.
Lee L. & Weinstein IBUptake of the tumor-promoting agent 12-0-tetradecanoylphorbol-13-acetate by HeLa cells. Journal of Environmental Pathology Toxicology and Oncology1978; 1: 627-39.
33.
Edelman GM &Wang JLBinding and functional properties of concanavalin A and its derivatives. III. Interactions with indolacetic acid and other hydrophobic ligands. Journal Biological Chemistry1978 ; 253: 3016-22.x
34.
Hergenhahn M., Kusumoto S. & Hecker E.Diterpene esters from 'Euphorbium' and their irritant and cocarcinogenic activity. Experimentia1974; 30: 1438-40.
35.
Edwards M., Taylor SE, Evans FJ, Nouri Ame & Gordon D.Tumor-promoting and non-promoting pro-inflammatory phorbol esters as human lymphocyte mitogens. Journal of Pharmacy and Pharmacology1981; 33: 55P.
36.
Driedger PE & Blumberg PMSpecific binding of phorbol ester tumor promoters . Proceedings of the National Academy of Science USA1980; 77: 567-71.
37.
Nishizuka Y.The role of protein kinase C in cell surface signal transduction and tumor promotion. Nature1984; 308: 693-8.
38.
Diamond L., O'Brien TG & Baird WMTumor promoters and the mechanism of tumor promotion. Advanced Cancer Research1980; 32: 1-74.
39.
Schairer HUPhD Thesis. Heidelberg, FDR. University of Heidelberg, 1966, pp. 58-60.
