Cyclooxygenase-2 induction by paclitaxel, docetaxel, and taxane analogues in human monocytes and murine macrophages: structure-activity relationships and their implications.
Paclitaxel and docetaxel can induce pro-inflammatory proteins, typified by cyclooxygenase-2 (prostaglandin H synthase). In some circumstances, this phenomenon may be relevant to the immunomodulatory actions and the adverse effects associated with paclitaxel or docetaxel. Accordingly, we compared a panel of sixteen taxanes, including paclitaxel and docetaxel, for their ability to induce cyclooxygenase-2 in a murine macrophage cell line (RAW 264.7) and in human peripheral blood monocytes. We discovered that the structure-activity relationships governing the induction of cyclooxygenase-2 protein differ markedly between the two species. Of 14 analogues evaluated, only 2 had activity comparable with paclitaxel in RAW 264.7 cells. In contrast, docetaxel and 12 of 14 analogues had activity comparable with paclitaxel in human monocytes. Our results enabled us to predict and subsequently affirm that the major human hepatic metabolite, 6alpha-hydroxypaclitaxel, would induce cyclooxygenase-2 in human cells but not in murine cells. Our structure-activity data and our experiments with combinations of taxanes suggest a provisional model for cyclooxygenase-2 induction. This model suggests that binding at a high-affinity site on tubulin and stabilization of microtubules is necessary, but not sufficient, for cyclooxygenase-2 induction. Binding at a second, lower-affinity receptor site is also necessary. However, our structure activity data are not fully compatible with two candidate proteins currently proposed as the low-affinity receptor.
Cassidy
Pamela B
PB
Department of Medicinal Chemistry, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112-5550, USA.
Moos
Philip J
PJ
Kelly
Robert C
RC
Fitzpatrick
F A
FA
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001667:Binding, Competitive; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2; D000077143:Docetaxel; D004790:Enzyme Induction; D006801:Humans; D007124:Immunoenzyme Techniques; D007527:Isoenzymes / Q000096:biosynthesis*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology; D008565:Membrane Proteins; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011956:Receptors, Cell Surface / Q000378:metabolism; D013329:Structure-Activity Relationship; D043823:Taxoids; D014404:Tubulin / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D001952:Bridged-Ring Compounds; D007527:Isoenzymes; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D043823:Taxoids; D014404:Tubulin; D000077143:Docetaxel; C080625:taxane; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017239:Paclitaxel