Cyclooxygenase-2 induction by paclitaxel, docetaxel, and taxane analogues in human monocytes and murine macrophages

Structure-activity relationships and their implications

Pamela Cassidy, Philip J. Moos, Robert C. Kelly, F. A. Fitzpatrick

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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, 6α-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.

Original languageEnglish (US)
Pages (from-to)846-855
Number of pages10
JournalClinical Cancer Research
Volume8
Issue number3
StatePublished - 2002
Externally publishedYes

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docetaxel
Cyclooxygenase 2
Structure-Activity Relationship
Paclitaxel
Monocytes
Macrophages
Taxoids
Proteins
Tubulin
Prostaglandin-Endoperoxide Synthases
Microtubules
taxane

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cyclooxygenase-2 induction by paclitaxel, docetaxel, and taxane analogues in human monocytes and murine macrophages : Structure-activity relationships and their implications. / Cassidy, Pamela; Moos, Philip J.; Kelly, Robert C.; Fitzpatrick, F. A.

In: Clinical Cancer Research, Vol. 8, No. 3, 2002, p. 846-855.

Research output: Contribution to journalArticle

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