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.