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Metabolism of Arachidonic Acid in Human Lung Cancer Cell Lines¹

Laboratory of Experimental Therapeutics and Metabolism, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20892

The metabolism of arachidonic acid (AA) was studied in two pulmonary bronchioloalveolar-carcinoma cell lines (NCI-H322 and NCI-H358) and two small cell lung carcinoma cell lines (NCI-H69 and NCI-H128). Exogenous AA was metabolized only in the NCI-H322 and NCI-H358 cells. There was no detectable metabolism of AA in NCI-H69 or NCI-H128 cells, either in the presence or the absence of the calcium ionophore A23187. The major metabolite of AA isolated from both NCI-H322 and NCI-H358 cells was prostaglandin E₂ (PGE₂). Prostaglandin endoperoxide synthase activities, expressed as immunoreactive PGE₂ (pmol/min/mg protein), were 10.3 ± 0.28 (SD) and 4.8 ± 0.48 in NCI-H358 and NCI-H322 cells, respectively. The rate of production of PGE₂ by both NCI-H358 and NCI-H322 cells was linear up to 10 min. Production of PGE₂ in both cell lines was dependent upon substrate concentration and was maximal above 17 µM AA. Moreover, PGE₂ did not undergo further metabolism by either the NCI-H358 or the NCI-H322 cells. Aspirin (0.1 mM), a cyclooxygenase inhibitor, decreased PGE₂ production by 77 and 60% in NCI-H358 and NCI-H322 cells, respectively. In the presence of exogenous AA the calcium ionophore, A23187 (20 µM), stimulated PGE₂ production in NCI-H322 cells by almost 2-fold, although it did not affect PGE₂ production in the NCI-H358 cells. In contrast, A23187 stimulated the endogenous production of PGE₂ in both NCI-H322 and NCI-H358 cells by 4- and 9-fold respectively. In addition, both the NCI-H358 and NCI-H322 cell lines were susceptible to the cytotoxic effects of the anticancer agent mitoxantrone in both a time and concentration dependent manner. In contrast, the two cell lines lacking detectable prostaglandin synthesis activity, NCI-H69 and NCI-H128 were unaffected by treatment with mitoxantrone. These results illustrate that there are major differences in the abilities of human lung cancer cell lines to biosynthesize and release PGE₂. It is conceivable that such differences might have exploitable diagnostic and/or therapeutic implications.

¹ This work was presented in part at the 76th Annual Meeting of the American Association for Cancer Research, 1985 (52).

² Present address: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712.

³ To whom requests for reprints should be addressed, at Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Landow Building, Room 5A21, Bethesda, MD 20892.

Received 3/10/86. Revised 5/28/86. Revised 10/22/86. Revised 3/23/87. Accepted 3/30/87.

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