SENSITIVITY OF TUMORICIDAL FUNCTION IN MACROPHAGES FROM DIFFERENT ANATOMICAL SITES OF CANCER-PATIENTS TO MODULATION OF ARACHIDONIC-ACID METABOLISM

The sensitivity of cancer patient macrophages from different anatomica l sites to arachidonic acid metabolism was investigated in tumor cell cytotoxicity assays. Alveolar macrophages and peripheral blood monocyt es from 13 non-small cell lung cancer patients, peritoneal macrophages and peripheral blood monocytes from 13 ovarian cancer patients, and c omparable macrophages from control patients with nonmalignant lung or gynecological diseases were tested. Inhibitors of either the cyclooxyg enase pathway or the lipoxygenase pathway together with specific metab olites of each pathway were used to evaluate how these different macro phage populations are regulated by eicosanoids. In addition, metabolic studies were performed to compare directly the arachidonic acid metab olism of macrophages obtained from these different anatomical location s. The results demonstrate that the peripheral blood monocytes from lu ng cancer and ovarian cancer patients and the peritoneal macrophages f rom ovarian cancer patients are sensitive to cyclooxygenase inhibition ; this was not seen with comparable macrophages from the relevant cont rol patients. Sensitivity to modulation by cyclooxygenase inhibition c orrelated with increased cyclooxygenase metabolism and with the capaci ty of prostaglandin to mediate suppression of tumoricidal function in these populations of cancer patient macrophages. In contrast, alveolar macrophages from cancer patients were not sensitive to either cycloox ygenase inhibition or to prostaglandin-mediated suppression. No such d ifferential influences were revealed for the lipoxygenase pathway of a rachidonic acid metabolism in any macrophage population tested. Thus, eicosanoids, particularly those of the cyclooxygenase pathway can be a critical immunoregulatory feature of certain tumor microenvironments.