The studies described herein were undertaken with the objective of determining the effect of modulation of
arachidonic acid metabolism on proliferation of rat mammary
tumor cells in culture. The TMT-081 rat mammary tumor cell line was shown to metabolize [14C]
arachidonic acid to
thromboxane B2,
PGE2,
PGF2 alpha, and 12- and/or
15-HETE. Furthermore, synthesis of these
eicosanoids was physiologically significant since each metabolite stimulated
DNA synthesis. Both
cyclooxygenase and
lipoxygenase inhibitors suppressed cell growth and modulated
eicosanoid synthesis in a concentration-dependent manner. Thin layer chromatography showed that the production of
cyclooxygenase metabolites (
thromboxane B2,
PGE2 and
PGF2 alpha) by TMT-081 cells was inhibited by
indomethacin,
ibuprofen,
BW755C and
timegadine. The
lipoxygenase inhibitor NDGA was also shown to inhibit
thromboxane B2 synthesis, but increased
PGE2 and
PGF2 alpha syntheses;
esculetin, a
lipoxygenase inhibitor in other systems, increased all the
cyclooxygenase products. The production of the
lipoxygenase products 12- and/or
15-HETE was inhibited by NDGA, increased by
indomethacin and
ibuprofen, but not affected by
esculetin,
BW755C and
timegadine in this cell line. Changes in
eicosanoid profile were observed before
drug-induced inhibition of cell growth suggesting that the balance of the various
eicosanoids may be a critical determinant of cell proliferation. However, since
drug-induced effects on
arachidonic acid profile occurred at concentrations lower than that necessary for inhibition of cell growth, the effects of these inhibitors on other biochemical pathways affecting cell growth cannot be ruled out.