Leukotriene and 5-lipoxygenase inhibitor induced variations in thymidine uptake in a human glioma cell line cultured as monolayers or as multicellular spheroids.
Effects of exogenous leukotrienes and/or treatment with the 5-lipoxygenase inhibitor, AA-861, on the 3H-thymidine uptake were investigated in a human glioma cell line, U-343MGa, growing as monolayers or multicellular spheroids. The spheroids contained about four times more endogenous leukotrienes than the monolayers. Administration of 0.1 microM exogenous leukotriene D4 increased the 3H-thymidine uptake in the spheroids while it gave a decrease in the monolayers. Inhibition of 3H-thymidine uptake was induced in the spheroids by 10 microM AA-861 and this inhibition was only seen during the period at which central necrosis develops in the spheroids. This drug showed an inhibitory effect on monolayers one day after subculture but gave no measurable effect on the monolayers two days later. It seemed that AA-861 exerted an inhibitory action at culture conditions associated with "cellular stress" such as subculture (trypsinization) of monolayers and induction of necrosis in spheroids. Induction of "cellular stress" with heat or exposure to a Ca(2+)-ionophore also gave an inhibitory action of AA-861 and the inhibition could be counteracted by administration of exogenous B4 leukotrienes. The observed effects are probably related to the activation of the arachidonic acid cascade and indicate that leukotrienes in some way interact with "cellular stress" and induce acute changes in 3H-thymidine uptake. Further research is necessary to reveal the detailed molecular mechanisms.
Department of Neurology, Uppsala University, Sweden.
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Gáti
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Bergström
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Muhr
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Carlsson
D000970:Antineoplastic Agents / Q000633:toxicity*; D016227:Benzoquinones / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D046508:Culture Techniques / Q000379:methods; D004273:DNA, Neoplasm / Q000096:biosynthesis* / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005910:Glioma; D006801:Humans; D007975:Leukotriene B4 / Q000633:toxicity*; D017998:Leukotriene D4 / Q000633:toxicity*; D016859:Lipoxygenase Inhibitors / Q000633:toxicity*; D009336:Necrosis; D013936:Thymidine / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016227:Benzoquinones; D004273:DNA, Neoplasm; D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4; D017998:Leukotriene D4; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D013936:Thymidine