ENHANCEMENT OF MACROPHAGE-INDUCED CYTO-TOXICITY BY PHORBOL ESTER TUMOR PROMOTERS

  • 1 January 1981
    • journal article
    • research article
    • Vol. 41  (11) , 4523-4528
Abstract
The potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) markedly enhanced the ability of mouse peritoneal macrophages to inhibit the growth of L5178Y [lymphoma] tumor cells as measured by growth in agar. Three populations of macrophages (resident, divinylether maleic anhydride copolymer and thioglycollate-recruited) were used. In general TPA reduced both the cocultivation time and the number of macrophages required to induce cytotoxicity in all 3 macrophage types. With divinylether maleic anhydride copolymer macrophages, TPA enhanced cytotoxicity in dose-dependent manner in the concentration range 1.7 to 170 nM at macrophage: tumor cell ratios of 10:1 and 1:1. For reasons that were not apparent inhibition of cytotoxicity was found at higher cell ratios. With thioglycollate-elicited and resident macrophages TPA (170 nM) enhanced cytotoxicity at all ratios tested. Even 1:1 ratios of macrophages:tumor cells, which were not cytotoxic alone, inhibited cell viability by 50-60% in the presence of TPA. A correlation was found between the biological activity of related macrocyclic diterpenes and their ability to enhance macrophage-mediated cytotoxicity. Mezerein and phorbol didecanoate enhanced macrophage cytotoxicity, the biologically inactive analogs phorbol, 4-O-methyl-12-O-tetradecanoylphorbol-13-acetate and 4-.alpha.-phorbol-12,13-didecanoate were without effect in this assay. Cytotoxicity towards untransformed BALB/c/3T3 cells was also demonstrated using a liquid cloning assay. These target cells were much less sensitive to growth inhibition by the macrophages than were the L5178Y cells. A 50% decrease in survival occurred only after 48 h incubation and required macrophage: target cell ratios of 100:1. The addition of 170 nM TPA led to a dramatic enhancement of cytotoxicity in these cells at macrophage:target cell ratios of 10:1 and 1:1. The results observed with the phorbol esters in the present studies are compatible with other evidence that these compounds can modulate a variety of macrophage functions.

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