Paclitaxel is a novel antineoplastic drug which has shown promise in the treatment of previously unresponsive breast, ovary, lung, and colon cancers. Paclitaxel is active at nanomolar concentrations and functions by binding to the amino-terminal region of the ␤-tubulin molecule, thereby promoting and stabilizing the formation of microtubules. However, the therapeutic effectiveness of paclitaxel exceeds that of microtubuledisrupting agents such as colchicine and vinca alkaloids, suggesting that paclitaxel may have multiple effects on cells. Recent studies in mice show that paclitaxel and bacterial lipopolysaccharide (LPS) can induce a broad range of shared bioactivities in macrophages, which includes the following: (i) induction of a series of cytokines, such as interleukin-1␣ (IL-1␣), IL-1␤, tumor necrosis factor alpha (TNF-␣), and IP-10 (1, 5, 15, 36-38); (ii) internalization of TNF-␣ receptors (14, 15); (iii) induction of a panel of immediate early genes; (iv) provision of a second signal for macrophage tumoricidal activity and nitric oxide production (25); and (v) induction of the phosphorylation of mitogen-activated protein kinases and activation of the autophosphorylation of lyn kinase (15,22,36,37). In addition, LPS-hyporesponsive C3H/HeJ mice do not respond to paclitaxel with the same pattern of phosphorylation and gene induction as other mice do, suggesting that paclitaxel and LPS may share a functionally important signaling transduction pathway (15,37).In contrast to its effect on mouse cells, the effect of paclitaxel on human macrophages/monocytes has been more difficult to demonstrate. However, paclitaxel activates IL-8 but not IL-1␣ or IL-1␤ or IL-6 transcription in a subset of human ovarian cancer cell lines and in freshly explanted ovarian cancer cells (32). Since ovarian cancer represents a primary type of tumor that is clinically responsive to paclitaxel, these findings may have significant clinical ramifications.IL-8 is a member of the superfamily of C-X-C chemokines (29), and it is a chemotactic factor for T cells, neutrophils, and basophils (41,47,59). IL-8 induction in tumors may be beneficial to the host in that immune cells are attracted to the tumor site. In fact a recent study by Hirose et al. shows that this is indeed the case (23). Alternatively, IL-8 also enhances angiogenesis and may enhance metastasis (51). Regardless of which role IL-8 plays in a clinical setting, understanding how paclitaxel activates the IL-8 gene can elucidate additional molecular targets of paclitaxel and provide an understanding which may lead to better antitumor therapies.The IL-8 gene is regulated at both the transcriptional and posttranscriptional levels. The former is primarily mediated by multiple cis elements, including a CCAAT box, a steroid-responsive element, an HNF-1 element, two IRF-1 elements, an AP-1 sequence, an AP-3 site, a C/EBP sequence, and an NF-B-NF-IL-6 overlapping sequence (30,40,42,46). Earlier, we demonstrated that paclitaxel can induce IL-8 gene expression in human ovarian cancer cells ...

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