BMC Cancer 2004, 4:49 http://www.biomedcentral.com/1471-2407/4/49 incubation. It is apoptosis that may mediate the cancer preventative action of tamoxifen [11,12]. Some tissue specific effects of tamoxifen and raloxifene, e.g. on endometrial cells of the uterus, may be related to COX activity. At the low cell densities used in the present studies, the PGI2 produced by the rat liver cells can be quantitatively determined. The effects of tamoxifen and LY117018 on the COX activity of the rat liver cells may be similar to their effects on other cells that express COX. Tamoxifen and LY117018 affect COX activity differently; only tamoxifen stimulates PGI2 production. AA, which regulates the production of lipoxygenase, COX and cytochrome P-450 epoxygenase products could impact many of the pharmacological actions of these two selec- tive estrogen receptor modulators. AA can be oxygenated by COX isoforms, lipoxygenases, and cytochrome P-450 epoxygenases and their products converted to the prostag- landins, leukotrienes, epoxyeicostetranoic acids [28] and AA to the oxidative stress-related isoprostanes [29]. In the COX pathway, enzymes convert PGH2 to the major phys- iologically active products, PGD2, PGE2, PGF2α, PGI2 and thromboxane A2 [28]. They, in turn, can be converted enzymatically and nonenzymatically to other biologically active compounds that possess different pharmacological properties. Often, only one major product is synthesized by the cell [8]. Thus, tissues can be affected differently by changes in COX activity. AA or its metabolites, would have different biological effects depending upon the genetic capabilities of the individual cell being affected. In addition to the spectrum of activities of the prostanoids, oxygenation of AA by 5-, 12- and 15-lipoxygenase and epoxygenases yield other products located in different cells and tissues [30,31]. Competing interests None declared. Author's contributions L.L. is the sole author and all of the experiments, with the exception of the western blots referred to as Levine L and Tashjian A (unpublished data), were conducted by L.L. Acknowledgements My thanks to Dr. Armen H. Tashjian, Jr., Department of Genetic and Com- plex Diseases, Harvard School of Public Health, for his continuing interest in these studies and Hilda B. Gjika for preparation of the manuscript. References 1. MacGregor JL, Jordan VC: Basic guide to the mechanisms of antiestrogen action. Pharmacol Rev 1998, 50:151-196. 2. Jordan VC, Morrow M: Tamoxifen, raloxifene, and the preven- tion of breast cancer. Endocr Rev 1999, 20:253-278. 3. Gottardis MM, Jordan VC: Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mam- mary carcinoma model. Cancer Res 1987, 47:4020-4024. 4. Levine L: Tamoxifen stimulates arachidonic acid release from rat liver cells by an estrogen receptor-independent, non- genomic mechanism. BMC Cancer 2003, 3:24. 5. Levine L: Stimulated release of arachidonic acid from rat liver cells by celecoxib and indomethacin. Prostaglandins Leukot Essent Fatty Acids 2001, 65:31-35. 6. Hong SL, Levine L: Inhibition of arachidonic acid release from cells as the biochemical action of anti-inflammatory corticosteroids. Proc Natl Acad Sci U S A 1976, 73:1730-1734. 7. Pong SS, Hong SL, Levine L: Prostaglandin production by meth- ylcholanthrene-transformed mouse BALB/3T3. Require- ment for protein synthesis. J Biol Chem 1977, 252:1408-1413. 8. Levine L, Alam I: Deacylation of cellular lipids and arachidonic acid metabolism. Prog Lipid Res 1981, 20:81-88. 9. Chan TA, Morin PJ, Vogelstein B, Kinzler KW: Mechanisms under- lying nonsteroidal antiinflammatory drug-mediated apoptosis. Proc Natl Acad Sci U S A 1998, 95:681-686. 10. Levine L: Measurement of arachidonic acid metabolites by radioimmunoassay. Manual of Clinical Laboratory Immunology. Washington DC: American Society for Microbiology 31986:685-691. 11. Gelmann EP: Tamoxifen induction of apoptosis in estrogen receptor-negative cancers: new tricks for an old dog? J Natl Cancer Inst 1996, 88:224-226. 12. Mandlekar S, Yu R, Tan TH, Kong AN: Activation of caspase-3 and c-Jun NH2-terminal kinase-1 signaling pathways in tamoxifen-induced apoptosis of human breast cancer cells. Cancer Res 2000, 60:5995-6000. 13. Dietze EC, Caldwell LE, Grupin SL, Mancini M, Seewaldt VL: Tamoxifen but not 4-hydroxytamoxifen initiates apoptosis in p53(-) normal human mammary epithelial cells by inducing mitochondrial depolarization. J Biol Chem 2001, 276:5384-5394. 14. Robertson DW, Katzenellenbogen JA, Long DJ, Rorke EA, Katzenel- lenbogen BS: Tamoxifen antiestrogens. A comparison of the activity, pharmacokinetics, and metabolic activation of the cis and trans isomers of tamoxifen. J Steroid Biochem 1982, 16:1-13. 15. Hollstein M, Sidransky D, Vogelstein B, Harris CC: p53 mutations in human cancers. Science 1991, 253:49-53. 16. Rockwell P, Yuan H, Magnusson R, Figueiredo-Pereira ME: Proteas- ome inhibition in neuronal cells induces a proinflammatory response manifested by upregulation of cyclooxygenase-2, its accumulation as ubiquitin conjugates, and production of the prostaglandin PGE(2). Arch Biochem Biophys 2000, 374:325-333. 17. Vane JR, Bakhle YS, Botting RM: Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 1998, 38:97-120. 18. Wakeling AE: Use of pure antioestrogens to elucidate the mode of action of oestrogens. Biochem Pharmacol 1995, 49:1545-1549. 19. Levine L: Stimulated release of arachidonic acid by agonists of the peroxisome proliferator-activated receptor and retinoic acid receptors. Prostaglandins Leukot Essent Fatty Acids 2001, 65:229-232. 20. Mokbel K: The evolving role of aromatase inhibitors in breast cancer. Int J Clin Oncol 2002, 7:279-283. 21. Whatley RE, Satoh K, Zimmerman GA, McIntyre TM, Prescott SM: Proliferation-dependent changes in release of arachidonic acid from endothelial cells. J Clin Invest 1994, 94:1889-1900. 22. Whiting KP, Restall CJ, Brain PF: Steroid hormone-induced effects on membrane fluidity and their potential roles in non- genomic mechanisms. Life Sci 2000, 67:743-757. 23. Levine L: Does the release of arachidonic acid from cells play a role in cancer chemoprevention? FASEB J 2003, 17:800-802. 24. Levine L: Lactacystin stimulates arachidonic acid metabolism in rat liver cells: effects of cell density on arachidonic acid release, PGI2 production and cyclooxygenase activity. Pros- taglandins Leukot Essent Fatty Acids 2000, 63:371-375. 25. Croxtall JD, Choudhury Q, White JO, Flower RJ: Tamoxifen inhib- its the release of arachidonic acid stimulated by thapsigargin in estrogen receptor-negative A549 cells. Biochim Biophys Acta 1997, 1349:275-284. 26. Zhang W, Couldwell WT, Song H, Takano T, Lin JH, Nedergaard M: Tamoxifen-induced enhancement of calcium signaling in gli- oma and MCF-7 breast cancer cells. Cancer Res 2000, 60:5395-5400. Page 7 of 8 (page number not for citation purposes)