PHOSPHOLIPASE A(2) INHIBITORS REGULATE THE PROLIFERATION OF NORMAL UTERINE CELLS

The effects of inhibitors of phospholipase A(2), cyclooxygenase, lipox ygenase and cytochrome P450 activity on the proliferation of normal ra t uterine stromal cells (U-III) were studied. At non-cytotoxic doses, inhibitors of cyclooxygenase, lipoxygenase and cytochrome P450 activit y had no effect; U-III cells did not lose their ability to synthesize and secrete arachidonic acid metabolites, mainly prostaglandin I-2 and prostaglandin E(2), after successive passages. Inhibition of prostagl andin production did not affect their proliferation. In contrast, phos pholipase A, inhibitors significantly reduced U-III cell proliferation in a reversible and dose-dependent manner. Aristolochic acid was the most potent inhibitor with an IC50 of 0.3 mu mol/l on day 7 of culture . Moreover, low doses of arachidonic acid stimulated U-III cell prolif eration. Thus, the proliferation of normal uterine stromal cells appea rs to be independent of arachidonic acid oxygenated metabolites, contr ary to what is observed in tumor cells, but requires an intact phospho lipase A(2) pathway.