Immune changes in patients with advanced breast cancer undergoing chemotherapy with taxanes

Abstract

Besides cytotoxicity, taxanes induce other biological effects, especially in the immune system. Taxanes have demonstrated immunostimulatory effects against neoplasms, supporting the idea that these agents suppress cancer through several mechanisms and not solely through inhibiting cell division. The purpose of the present study was to evaluate the effect of taxanes (paclitaxel and docetaxel) and investigate their ability in alterating important immunological parameters in breast cancer patients. Thirty women with advanced breast cancer undergoing chemotherapy were randomly assigned into two groups treated with either single agent Paclitaxel or Docetaxel. Sera from patients before the first and after the last treatment cycle and from normal donors were assayed by ELISA for IL-2, IL-1b, IFN-g, GM-CSF, IL-6, TNF-a, and PGE2 levels. In these same blood samples, NK and LAK cell activity was tested in the total PBMC population against NK-sensitive K562 tumour targets, respectively, and autologous mixed lymphocyte reaction was tested by 3 H-thymidine proliferation assays. All patients in both groups responded to therapy. Significant differences were observed in the following immune parameters between the control group of healthy blood donors and the pretreatment values of both taxane groups; IL-2, GM-CSF, IFN-g levels and NK and LAK cell cytotoxicity were depressed, whereas TNF-a and IL-6 levels were raised in breast cancer patients before treatment compared to controls. There were no significant differences between the two treatment groups regarding any of the parameters studied. Both drugs led to increases in MLR values, NK and LAK cell cytotoxicity, and IL-6, GM-CSF, IFN-g levels, and decreases for IL-1, TNF, and PGE2 levels. The percentage of these differences was greater for docetaxel in comparison to paclitaxel (P50.0001). More specifically, docetaxel demonstrated a more pronounced effect on enhancing MLR, NK, LAK activity and IFN-g, IL-2, IL-6, and GM-CSF levels, as well as caused more potent reduction in IL-1 and TNF-a levels when compared to paclitaxel. The present study indicates that patients responded to treatment of advanced breast cancer with single-agent paclitaxel or docetaxel leads to an increase in serum IFN-g, IL-2, IL-6, GM-CSF cytokine levels and enhancement of PBMC NK and LAK cell activity, while they both lead to a decrease of acute phase serum cytokine levels of IL-1 and TNF-a. Moreover, the effects of docetaxel are in all the above parameters more pronounced than those of paclitaxel. Over the last decade, taxanes (namely paclitaxel and docetaxel) have emerged as effective antitumour agents in a variety of malignancies. Paclitaxel is a semi-synthetic taxane, isolated from the bark of the Pacific yew tree. Doxetaxel is a semi-synthetic taxane, derived from the needles of the European yew (Taxus Baccata). These compounds bind to tubulin, leading to microtubule stabilisation, mitotic arrest and, subsequently, cell death. Plasma clearance of paclitaxel exhibits non-linear kinetics, which results in ...

Evaluation of an inflammation-based prognostic score (GPS) in patients with metastatic breast cancer

“…Patients who developed other malignancies, and patients with Creactive protein measured during a course of taxane therapy were excluded from the study since they may produce a hypersensitivity reaction and elevated concentrations of interleukin-6 (Tsavaris et al, 2002;Williams et al, 2003), which is a primary mediator of C-reactive protein (Gabay and Kushner, 1999). In total, 96 out of 295 (33%) patients with metastatic disease were eligible for the study.…”

Suppression of endotoxin-induced inflammation by taxol

“…Furthermore, taxol may still inhibit cytokine production and secretion by other pulmonary cell types, including epithelial and endothelial cells, resulting in a net decrease in pulmonary cytokine accumulation. Importantly, studies on breast cancer patients indicate that taxanes (paclictaxel and docetaxel) decrease levels of the serum cytokines IL-1 and TNF-a and increase levels of interferon-c, IL-2 and IL-6 [23].…”

Biologic and therapeutic role of HER2 in cancer

“…If, in fact, the major mechanism is ADCC, the combination of trastuzumab with immunosuppressive chemotherapeutic drugs requires optimal timing of trastuzumab delivery to enable rescue of ADCC effectors such as NK cells after chemotherapy. In that context, clinical studies have demonstrated a synergistic action between trastuzumab and the drug taxane (Slamon et al, 2001), which induces suppression of adaptive immunity, but selectively increases NK activity (Tsavaris et al, 2002). To improve therapeutic activity, stimulation of NK activity might also be considered, utilizing cytokines or 'danger signals' such as unmethylated CpG-oligodeoxynucleotides that enhance innate immunity (Sfondrini et al, 2002).…”