The immunopharmacology of paclitaxel (Taxol®), docetaxel (Taxotere®), and related agents

doi:10.1016/j.intimp.2003.08.007

International Immunopharmacology

Volume 3, Issues 13–14, December 2003, Pages 1699-1714

https://doi.org/10.1016/j.intimp.2003.08.007 Get rights and content

Abstract

Paclitaxel (Taxol®) and docetaxel (Taxotere®) are among the most unique, and successful, chemotherapeutic agents used for the treatment of breast and ovarian cancer. Both agents have anti-mitotic properties derived from binding to tubulin and excessive stabilization of microtubules. Their anti-neoplastic effects derive from this mechanism. Distinct from their effects on microtubule stabilization, paclitaxel, docetaxel, and related taxanes display immunopharmacological traits. In this review, we discuss their induction of pro-inflammatory genes and proteins; the current hypotheses on the molecular mechanism for this induction, especially its relationship to the lipopolysaccharide (LPS) signaling pathway. We also discuss the structure–activity relationships (SAR) that govern gene induction, especially the striking differences between the SAR for murine and human cells in vitro. Lastly, we discuss the immunopharmacological traits of paclitaxel and docetaxel in terms of their relevance to human clinical pharmacology and toxicology and their activity in animal models of autoimmune disorders.

Introduction

Thirty years ago, Wani et al. [1] isolated an anti-tumor agent from the bark of Pacific yew trees and established its chemical structure—the novel diterpene taxol. Twenty years ago, Horwitz et al. [2], [3] discovered the distinctive mechanism of action of taxol stabilization of microtubules. During the past decade, Taxol® and the related semi-synthetic compound, Taxotere®, have achieved prominence in clinical oncology for their efficacy against a range of solid tumors, including tumors refractory to many other anti-neoplastic agents [4], [5], [6], [7]. For consistency in this review, we will use the generic names paclitaxel and docetaxel when referring to Taxol® and Taxotere®, respectively. Fig. 1 depicts their chemical structures.

Microtubule stabilization within neoplastic cells confers the clinical benefits from paclitaxel or docetaxel in oncology [8]. Both agents bind avidly to the β subunit of tubulin in microtubules with a dissociation constant K_d≈10 nM and a stoichiometry of one taxane molecule per one αβ subunit of tubulin [9], [10], [11], [12]. Taxanes shift the dynamic equilibrium between disassembly D assembly of microtubules in favor of their assembly, and thereby cause mitotic arrest or apoptosis. Separate from their effects on microtubule stabilization, paclitaxel, docetaxel, and related taxanes display a rich and interesting set of immunopharmacological traits that are the focus of this review. In Section 2, we discuss the induction of pro-inflammatory genes and proteins by paclitaxel or docetaxel; the current hypotheses on the molecular mechanism for this induction; the structure–activity relationships (SAR) that govern gene induction, especially the striking differences between the SAR for murine and human cells in vitro. In Section 3, we discuss the immunopharmacological traits of paclitaxel and docetaxel in terms of their relevance to human clinical pharmacology and toxicology and their activity in animal models of autoimmune disorders.

Section snippets

Taxanes as probes of lipopolysaccharide (LPS) signal transduction

Separate from its effects on microtubules, paclitaxel can induce genes encoding tumor necrosis factor α (TNFα) [13], [14], [15], [16], [17], [18], [19], [20], [21], interleukins (IL) [14], [16], [22], [23], [24], [25], and enzymes such as nitric oxide (NO) synthase [16], [19], [20], [21] and cyclooxygenase-2 (COX-2) [27], [28], [29], [30] that generate mediators of inflammation. Paclitaxel can also induce genes encoding transcription factors [27], colony-stimulating factors [31], and

Relevance to human clinical pharmacology and toxicology

Investigators have hypothesized that the induction of cytokines and pro-inflammatory proteins may be relevant to the pharmacological and toxicological profiles of paclitaxel and docetaxel [69]. This hypothesis is based on the observation that the immunomodulatory effects [26], [39], [72], [73], [74], [75] and the adverse reactions [76], [77] of paclitaxel and docetaxel are consistent with, and might originate from, the induction of TNFα, IL-1β, IL-8, nitric oxide synthase, COX-2, and other

Acknowledgements

Supported by the Huntsman Cancer Foundation; the Dee Glenn and Ida W. Smith Endowment, and National Institute of Allergy and Infections Diseases R01 AI26730 awarded to F.A.F. The authors thank Dr. S.N. Vogel for instructive comments and for permission to use Fig. 2.

References (98)

J. Verweij et al.
Paclitaxel (Taxol) and docetaxel (Taxotere): not simply two of a kind
Ann. Oncol.
(1994)
J. Crown et al.
The taxanes: an update
Lancet
(2000)
M. Caplow et al.
How taxol modulates microtubule disassembly
J Biol Chem.
(1994)
S. Rao et al.
Characterization of the taxol binding site on the microtubule: 2-(m-azidobenzoyl) taxol photolabels a peptide (amino acids 217–231) of tubulin
J. Biol. Chem.
(1995)
T. Kirikae et al.
Structural requirements of taxoids for nitric oxide and tumor necrosis factor production by murine macrophages
Biochem. Biophys. Res. Commun.
(1996)
T. Kirikae et al.
Structural significance of the benzoyl group at the C-3′-N position of paclitaxel for nitric oxide and tumor necrosis factor production by murine macrophages
Biochem. Biophys. Res. Commun.
(1998)
T. Kirikae et al.
Structural significance of the acyl group at the C-10 position and the A ring of the taxane core of paclitaxel for inducing nitric oxide and tumor necrosis factor production by murine macrophages
FEBS Lett.
(2000)
D.W. Mullins et al.
Taxol, a microtubule-stabilizing antineoplastic agent, differentially regulates normal and tumor-bearing host macrophage nitric oxide production
Immunopharmacology
(1997)
K. Subbaramaiah et al.
Microtubule-interfering agents stimulate the transcription of cyclooxygenase: 2. Evidence for involvement of ERK1/2 and p38 mitogen-activated protein kinase pathways
J. Biol. Chem.
(2000)
M. Zaks-Zilberman et al.
Induction of proinflammatory and chemokine genes by lipopolysaccharide and paclitaxel (Taxol) in murine and human breast cancer cell lines
Cytokine
(2001)

J. da Silva Correia et al.

MD-2 and TLR4 N-linked glycosylations are important for a functional lipopolysaccharide receptor

J. Biol. Chem.

(2002)

T.S. Juan et al.

Identification of a domain in soluble CD14 essential for lipopolysaccharide (LPS) signaling but not LPS binding

J. Biol. Chem.

(1995)

K. Tominaga et al.

Lipopolysaccharide (LPS)-induced IL-6 production by embryonic fibroblasts isolated and cloned from LPS-responsive and LPS-hyporesponsive mice

Mol. Immunol.

(1997)

K. Kawasaki et al.

Mouse toll-like receptor 4. MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol

J. Biol. Chem.

(2000)

J. Lewis et al.

Disruption of hsp90 function results in degradation of the death domain kinase, receptor-interacting protein (RIP), and blockage of tumor necrosis factor-induced nuclear factor-kappaB activation

J. Biol. Chem.

(2000)

D.S. Cissel et al.

Disruption of Raf-1/heat shock protein 90 complex and Raf signaling by dexamethasone in mast cells

J. Biol. Chem.

(2000)

S. Rousseau et al.

Vascular endothelial growth factor (VEGF)-driven actin-based motility is mediated by VEGFR2 and requires concerted activation of stress-activated protein kinase 2 (SAPK2/p38) and geldanamycin-sensitive phosphorylation of focal adhesion kinase

J. Biol. Chem.

(2000)

J. Okano et al.

Paclitaxel induces prolonged activation of the Ras/MEK/ERK pathway independently of activating the programmed cell death machinery

J. Biol. Chem.

(2001)

T. Schnaider et al.

Interactions of Hsp90 with histones and related peptides

Life Sci.

(1999)

P. Csermely et al.

The 90 kDa heat shock protein (Hsp90) induces the condensation of the chromatin structure

Biochem. Biophys. Res. Commun.

(1994)

C. Garnier et al.

Heat-shock protein 90 (hsp90) binds in vitro to tubulin dimer and inhibits microtubule formation

Biochem. Biophys. Res. Commun.

(1998)

D.W. Mullins et al.

Tumor growth modulates macrophage nitric oxide production following paclitaxel administration

Int. J. Immunopharmacol.

(1998)

D.M. Essayan et al.

Successful parenteral desensitization to paclitaxel

J. Allergy Clin. Immunol.

(1996)

R.K. Ramanathan et al.

Pulmonary infiltrates following administration of paclitaxel

Chest

(1996)

A.F. Baker et al.

Drug interactions with the taxanes: clinical implications

Cancer Treat. Rev.

(2001)

Y.W. Song et al.

Paclitaxel reduces anti-dsDNA antibody titer and BUN, prolonging survival in murine lupus

Int. J. Immunopharmacol.

(1998)

L. Cao et al.

Inhibition of experimental allergic encephalomyelitis in the Lewis rat by paclitaxel

J. Neuroimmunol.

(2000)

M. Lee et al.

Paclitaxel causes mouse splenic lymphocytes to a state hyporesponsive to lipopolysaccharide stimulation

Int. J. Immunopharmacol.

(2000)

M.C. Wani et al.

Plant antitumor agents VI Isolation and structure of taxol, a novel antileukemic and antitumor agent from taxus brevifolia

J. Am. Chem. Soc.

(1971)

P.B. Schiff et al.

Promotion of microtubule assembly in vitro by taxol

Nature

(1979)

J. Parness et al.

Taxol binds to polymerized tubulin in vitro

J. Cell Biol.

(1981)

E.K. Rowinsky

The development and clinical utility of the taxane class of antimicrotubule chemotherapy agents

Annu. Rev. Med.

(1997)

E.A. Eisenhauer et al.

The taxoids. Comparative clinical pharmacology and therapeutic potential

Drugs

(1998)

M.V. Blagosklonny et al.

Molecular effects of paclitaxel: myths and reality (a critical review)

Int. J. Cancer

(1999)

J.F. Diaz et al.

Assembly of purified GDP-tubulin into microtubules induced by taxol and taxotere: reversibility, ligand stoichiometry, and competition

Biochemistry

(1993)

M.A. Jordan et al.

Mechanism of mitotic block and inhibition of cell proliferation by taxol at low concentrations

Proc. Natl. Acad. Sci. U. S. A.

(1993)

A.H. Ding et al.

Shared actions of endotoxin and taxol on TNF receptors and TNF release

Science

(1990)

C. Bogdan et al.

Taxol, a microtubule-stabilizing antineoplastic agent, induces expression of tumor necrosis factor alpha and interleukin-1 in macrophages

J. Leukoc. Biol.

(1992)

S. Hwang et al.

Activation of NF-kappa B in murine macrophages by taxol

Cancer Biochem. Biophys.

(1995)

C.L. Manthey et al.

Taxol increases steady-state levels of lipopolysaccharide-inducible genes and protein-tyrosine phosphorylation in murine macrophages

J. Immunol.

(1992)

C.L. Manthey et al.

Lipopolysaccharide antagonists block taxol-induced signaling in murine macrophages

J. Exp. Med.

(1993)

C.A. Burkhart et al.

Relationship between the structure of taxol and other taxanes on induction of tumor necrosis factor-alpha gene expression and cytotoxicity

Cancer Res.

(1994)

L.F. Lee et al.

Taxol-dependent transcriptional activation of IL-8 expression in a subset of human ovarian cancer

Cancer Res.

(1996)

T.S. Collins et al.

Paclitaxel up-regulates interleukin-8 synthesis in human lung carcinoma through an NF-kappaB- and AP-1-dependent mechanism

Cancer Immunol. Immunother.

(2000)

C.M. White et al.

Effects of paclitaxel on cytokine synthesis by unprimed human monocytes, T lymphocytes, and breast cancer cells

Cancer Immunol. Immunother.

(1998)

J.M. Watson et al.

Identification of the structural region of taxol that may be responsible for cytokine gene induction and cytotoxicity in human ovarian cancer cells

Cancer Chemother. Pharmacol.

(1998)

P.J. Moos et al.

Taxane-mediated gene induction is independent of microtubule stabilization: induction of transcription regulators and enzymes that modulate inflammation and apoptosis

Proc. Natl. Acad. Sci. U. S. A.

(1998)

P.J. Moos et al.

Effect of taxol and taxotere on gene expression in macrophages: induction of the prostaglandin H synthase-2 isoenzyme

J. Immunol.

(1999)

P. Cassidy et al.

Cyclooxygenase-2 induction by paclitaxel, docetaxel and taxane analogs in human monocytes and murine macrophages: structure–activity relationships and their implications

Clin. Cancer Res.

(2002)

Cited by (99)

Usefulness of the measurement of neurite outgrowth of primary sensory neurons to study cancer-related painful complications
2021, Biochemical Pharmacology
Abnormal outgrowth of sensory nerves is one of the important contributors to pain associated with cancer and its treatments. Primary neuronal cultures derived from dorsal root ganglia (DRG) have been widely used to study pain-associated signal transduction and electrical activity of sensory nerves. However, there are only a few studies using primary DRG neuronal culture to investigate neurite outgrowth alterations due to underlying cancer-related factors and chemotherapeutic agents. In this study, primary DRG sensory neurons derived from mouse, non-human primate, and human were established in serum and growth factor-free conditions. A bovine serum albumin gradient centrifugation method improved the separation of sensory neurons from satellite cells. The purified DRG neurons were able to maintain their heterogeneous subpopulations, and displayed an increase in neurite growth when exposed to cancer-derived conditioned medium, while they showed a reduction in neurite length when treated with a neurotoxic chemotherapeutic agent. Additionally, a semi-automated quantification method was developed to measure neurite length in an accurate and time-efficient manner. Finally, these exogenous factors altered the gene expression patterns of murine primary sensory neurons, which are related to nerve growth, and neuro-inflammatory pain and nociceptor development. Together, the primary DRG neuronal culture in combination with a semi-automated quantification method can be a useful tool for further understanding the impact of exogenous factors on the growth of sensory nerve fibers and gene expression changes in sensory neurons.
Mechanical allodynia and enhanced responses to capsaicin are mediated by PI3K in a paclitaxel model of peripheral neuropathy
2019, Neuropharmacology
Paclitaxel chemotherapy treatment often leads to neuropathic pain resistant to available analgesic treatments. Recently spinal Toll-like receptor 4 (TLR4) and the transient receptor potential cation channel subfamily V member 1 (TRPV1) were identified to be involved in the pro-nociceptive effect of paclitaxel. The aim of this study was to investigate the role of phosphatidylinositol 3-kinase (PI3K) and serine/threonine kinases in this process, with the use of their antagonists (wortmannin, LY-294002, and staurosporine). The single paclitaxel administration (8 mg/kg i.p.) in mice induced robust mechanical allodynia measured as a reduced threshold to von Frey filament stimulation and generated reduced tachyphylaxis of capsaicin-evoked responses, recorded as changes in mEPSC frequency in patch-clamp recordings of dorsal horn neurons activity in vitro, for up to eight days. Paclitaxel application also induced increased Akt kinase phosphorylation in rat DRG neurons. All these paclitaxel-induced changes were prevented by the wortmannin in vivo pretreatment. Acute co-application of wortmannin or LY-294002 with paclitaxel in spinal cord slices also attenuated the paclitaxel effect on capsaicin-evoked responses. Staurosporine was effective in the acute in vitro experiments and on the first day after the paclitaxel treatment in vivo, but in contrast to wortmannin, it did not have a significant impact later. Our data suggest that the inhibition of PI3K signaling may help alleviate pathological pain syndromes in the paclitaxel-induced neuropathy.
Hydrogen sulfide releasing enmein-type diterpenoid derivatives as apoptosis inducers through mitochondria-related pathways
2019, Bioorganic Chemistry
In this study, we combined two enemin-type diterpenoid derivatives with two well-established hydrogen sulfide moieties via ester or different anhydride linkers, to search apoptosis inducing drug candidate capable of hydrogen sulfide generating. Therefore, a series of hybrids were synthesized and superior antiproliferative efficacy accompanied with enhanced selectivity was observed under extensive pharmacological evaluations. A standard methylene blue (MB⁺) method was applied to measure the capacity for the hydrogen sulfide generation of all the target derivatives. One particular molecule A1, which contained α-thioctic acid moiety for hydrogen sulfide donating, manifested more potent antiproliferative activity. It exerted inhibitory effects against Bel-7402, SGC-7901 and A549 cell lines with IC₅₀ values of 2.16, 5.07 and 6.98 μM respectively. While it exacted relatively low effects over human normal cell lines L-02 and PBMC with IC₅₀ values of 15.81 μM for the prior and 14.15 μM for the latter, and displayed better selectivity index (SI) than parent diterpenoids. A high dosage of H₂S release was also recorded. Hence, A1 was most suitable for mechanistic exploration on account of both safety and efficacy. The ensuing biological assays revealed central role of apoptosis in A1’s mode of action for antiproliferative efficacy, which led to further confirmation of G1 phase cell cycle arrest, mitochondria membrane potential collapse and apoptotic activation in Bel-7402 cells. Further western blot assay on intrinsic mitochondria pathway unlocked intricate interplay among a series of apoptotic related proteins in which Bax, caspase-3 and cytochrome c went through up-regulation, while Bcl-2, Bcl-xL and procaspase-3 undergone down-regulation. In a nutshell, a hydrogen sulfide releasing hybrid A1 was synthesized and antiproliferative evaluation identified it to be a worthy drug candidate for future in depth study.
Emotional acceptance, inflammation, and sickness symptoms across the first two years following breast cancer diagnosis
2016, Brain, Behavior, and Immunity
Citation Excerpt :
Nevertheless, effective emotion regulation would likely influence not only functional, but also other symptoms associated with sickness behavior, and future research that takes an integrative approach to measure sickness behavior and its association with emotion regulation is needed. These findings of increased sickness symptoms in women who received chemotherapy and/or radiation treatment, as compared to those who did not, or on assessment occasions associated with chemotherapy administration, are consistent with reports of increased inflammation associated with Adriamycin and taxanes (Fitzpatrick and Wheeler, 2003). In depth assessment of inflammatory markers potential mediation of this association is beyond the scope of this investigation but marks an important question that we will examine in future analyses.
Breast cancer diagnosis and treatment are associated with increased inflammatory activity, which can induce sickness symptoms. We examined whether emotional acceptance moderates the association between proinflammatory cytokines and self-reported sickness symptoms in women recently diagnosed with breast cancer.
Women (N = 136) diagnosed with stage 0-III breast cancer within the previous 6 months provided plasma samples and completed the FACT: Physical Well-Being Scale, as well as the Acceptance of Emotion Scale every 3 months for 2 years. At each time point, we quantified interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α using a high sensitivity multiplex assay.
Higher within-subject mean TNF-α across all time-points predicted higher mean sickness symptoms. At individual time-points, higher IL-6 and IL-8 levels were associated with higher sickness symptoms. Mean emotional acceptance across all time-points moderated the relationship between mean IL-8 and sickness symptoms, with sickness symptoms remaining persistently high in women with low emotional acceptance even when IL-8 levels were low. At individual time-points, emotional acceptance positively moderated the correlations of IL-8 and TNF-α with sickness symptoms, such that the associations between higher levels of these proinflammatory cytokines and higher sickness symptoms were attenuated when emotional acceptance was high.
Emotional acceptance was shown for the first time to moderate the associations of cytokines with sickness symptoms in breast cancer patients over time following diagnosis and treatment. The association between emotional acceptance and sickness symptoms was significantly different from zero but relatively small in comparison to the range of sickness symptoms. Results suggest that targeting emotion regulation may help to break the cycle between inflammation and sickness symptoms in women with breast cancer.
Dorsal Root Ganglion Infiltration by Macrophages Contributes to Paclitaxel Chemotherapy-Induced Peripheral Neuropathy
2016, Journal of Pain
Citation Excerpt :
Cytokine production from human macrophages and other tissues by paclitaxel has been reported supporting activation of human TLR4,13,31,59,60 but others have not observed this.44,65 LPS binds the TLR4 accessory protein MD-2 that results in activation of murine macrophages,28,36 but it is claimed that paclitaxel binds human MD-2 in a fashion that precludes activation of TLR4.38,49,65 This discrepancy has obvious importance in the context of the mechanisms of CIPN as well as in the broader scope of the utility of paclitaxel as a chemotherapeutic.
Chemotherapy-induced peripheral neuropathy (CIPN) is a disruptive and persistent side effect of cancer treatment with paclitaxel. Recent reports showed that paclitaxel treatment results in the activation of Toll-like receptor 4 (TLR4) signaling and increased expression of monocyte chemoattractant protein 1 (MCP-1) in dorsal root ganglion cells. In this study, we sought to determine whether an important consequence of this signaling and also a key step in the CIPN phenotype was the recruitment and infiltration of macrophages into dorsal root ganglia (DRG). Here, we show that macrophage infiltration does occur in a time course that matches the onset of the behavioral CIPN phenotype in Sprague-Dawley rats. Moreover, depletion of macrophages by systemic administration of liposome-encapsulated clodronate (clophosome) partially reversed behavioral signs of paclitaxel-induced CIPN as well as reduced tumor necrosius factor α expression in DRG. Intrathecal injection of MCP-1 neutralizing antibodies reduced paclitaxel-induced macrophage recruitment into the DRG and also blocked the behavioral signs of CIPN. Intrathecal treatment with the TLR4 antagonist lipopolysaccharide-RS (LPS-RS) blocked mechanical hypersensitivity, reduced MCP-1 expression, and blocked the infiltration of macrophages into the DRG in paclitaxel-treated rats. The inhibition of macrophage infiltration into DRG after paclitaxel treatment with clodronate or LPS-RS prevented the loss of intraepidermal nerve fibers (IENFs) observed after paclitaxel treatment alone. These results are the first to indicate a mechanistic link such that activation of TLR4 by paclitaxel leads to increased expression of MCP-1 by DRG neurons resulting in macrophage infiltration to the DRG that express inflammatory cytokines and the combination of these events results in IENF loss and the development of behavioral signs of CIPN.
This paper shows that activation of innate immunity by paclitaxel results in a sequence of signaling events that results in the infiltration of the dorsal root ganglia by activated macrophages. Macrophages appear to drive the development of behavioral hypersensitivity and the loss of distal epidermal nerve fibers, and hence play an important role in the mechanism of paclitaxel-related neuropathy.
Nanotechnology-Empowered Combination Cancer Immunotherapies: Mechanisms, Synergies, and Perspectives
2024, Advanced NanoBiomed Research

View all citing articles on Scopus

View full text

Review articleThe immunopharmacology of paclitaxel (Taxol®), docetaxel (Taxotere®), and related agents

Abstract

Introduction

Section snippets

Taxanes as probes of lipopolysaccharide (LPS) signal transduction

Relevance to human clinical pharmacology and toxicology

Acknowledgements

Ann. Oncol.

Lancet

J Biol Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

FEBS Lett.

Immunopharmacology

J. Biol. Chem.

Cytokine

J. Biol. Chem.

J. Biol. Chem.

Mol. Immunol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Life Sci.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Int. J. Immunopharmacol.

J. Allergy Clin. Immunol.

Chest

Cancer Treat. Rev.

Int. J. Immunopharmacol.

J. Neuroimmunol.

Int. J. Immunopharmacol.

Plant antitumor agents VI Isolation and structure of taxol, a novel antileukemic and antitumor agent from taxus brevifolia

J. Am. Chem. Soc.

Promotion of microtubule assembly in vitro by taxol

Nature

Taxol binds to polymerized tubulin in vitro

J. Cell Biol.

The development and clinical utility of the taxane class of antimicrotubule chemotherapy agents

Annu. Rev. Med.

The taxoids. Comparative clinical pharmacology and therapeutic potential

Drugs

Molecular effects of paclitaxel: myths and reality (a critical review)

Int. J. Cancer

Assembly of purified GDP-tubulin into microtubules induced by taxol and taxotere: reversibility, ligand stoichiometry, and competition

Biochemistry

Mechanism of mitotic block and inhibition of cell proliferation by taxol at low concentrations

Proc. Natl. Acad. Sci. U. S. A.

Shared actions of endotoxin and taxol on TNF receptors and TNF release

Science

Taxol, a microtubule-stabilizing antineoplastic agent, induces expression of tumor necrosis factor alpha and interleukin-1 in macrophages

J. Leukoc. Biol.

Activation of NF-kappa B in murine macrophages by taxol

Cancer Biochem. Biophys.

Taxol increases steady-state levels of lipopolysaccharide-inducible genes and protein-tyrosine phosphorylation in murine macrophages

J. Immunol.

Lipopolysaccharide antagonists block taxol-induced signaling in murine macrophages

J. Exp. Med.

Relationship between the structure of taxol and other taxanes on induction of tumor necrosis factor-alpha gene expression and cytotoxicity

Cancer Res.

Taxol-dependent transcriptional activation of IL-8 expression in a subset of human ovarian cancer

Cancer Res.

Paclitaxel up-regulates interleukin-8 synthesis in human lung carcinoma through an NF-kappaB- and AP-1-dependent mechanism

Cancer Immunol. Immunother.

Effects of paclitaxel on cytokine synthesis by unprimed human monocytes, T lymphocytes, and breast cancer cells

Cancer Immunol. Immunother.

Identification of the structural region of taxol that may be responsible for cytokine gene induction and cytotoxicity in human ovarian cancer cells

Cancer Chemother. Pharmacol.

Taxane-mediated gene induction is independent of microtubule stabilization: induction of transcription regulators and enzymes that modulate inflammation and apoptosis

Proc. Natl. Acad. Sci. U. S. A.

Effect of taxol and taxotere on gene expression in macrophages: induction of the prostaglandin H synthase-2 isoenzyme

J. Immunol.

Cyclooxygenase-2 induction by paclitaxel, docetaxel and taxane analogs in human monocytes and murine macrophages: structure–activity relationships and their implications

Clin. Cancer Res.

Review article
The immunopharmacology of paclitaxel (Taxol®), docetaxel (Taxotere®), and related agents