Cellular Immune Profile of Patients With Advanced Cancer Before and After Taxane Treatment

Tong, Alex W.; Seamour, B.; Lawson, Jennifer; Ordóñez, Graciela; Vukelja, Svetislava J.; Hyman, William; Richards, Donald A.; Stein, Lincoln; Maples, Phillip B.; Nemunaitis, John

doi:10.1097/00000421-200010000-00007

Cited by 50 publications

(41 citation statements)

References 19 publications

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“…The most commonly documented immune response in patients receiving paclitaxel is the development of myelosuppression in the weeks after the administration of this cytotoxic agent (21). However, an analysis of leukocyte subsets in patients receiving taxane therapy revealed no alterations in T-cell or B-cell frequency or CD4: CD8 ratio (9). Other reports purporting a stimulatory effect of paclitaxel have focused on its ability to activate immune effectors such as monocytes/macrophages that have receptors for lipopolysaccharides and other foreign compounds that can cross-react with the paclitaxel molecule (22).…”

Section: Discussionmentioning

confidence: 99%

“…Tong et al (9) studied lymphocyte subsets, levels of circulating cytokines, T-cell mitogenic function, and NK cell function in 10 patients with advanced cancer who received paclitaxel or docetaxel. They found that patients exhibiting a partial or complete response to therapy demonstrated higher than normal CD4:CD8 T-cell ratios and increased T-cell proliferation in response to phytohemagglutinin (PHA) at 4 weeks posttreatment.…”

Section: Introductionmentioning

confidence: 99%

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Cellular Immunity in Breast Cancer Patients Completing Taxane Treatment

Carson

Shapiro

Crespin

et al. 2004

Clinical Cancer Research

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Purpose: A field study of postchemotherapy immune functioning relative to the use of taxanes is reported. Immune responses in breast cancer patients were analyzed as a function of whether patients received taxane as part of their adjuvant chemotherapy.Experimental Design: Immune levels of 227 stage II/III breast cancer patients were measured immediately after surgery prior to chemotherapy and again 12 months later when all chemotherapies had been completed. T-cell blastogenesis and natural killer (NK) cell lysis levels of patients receiving taxanes (n ‫؍‬ 55) were compared with levels of patients not receiving taxanes (n ‫؍‬ 172).Results: Regression analyses were conducted. The administration of taxane as part of combination chemotherapy predicted increased T-cell blastogenesis and NK cell cytotoxicity after the conclusion of all chemotherapies. For the Taxane group, average phytohemagglutinin-induced blastogenesis was 37% higher and NK cell cytotoxicity was 39% higher than the values for the No-Taxane group.Conclusions: Data from group comparisons with appropriate controls in a sizable clinical sample contravene traditional wisdom that taxanes suppress patients' immune cell functions. Problems in generalizing direct-contact laboratory models to the field of cancer treatment are highlighted.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cellular Immunity in Breast Cancer Patients Completing Taxane Treatment

Carson

Shapiro

Crespin

et al. 2004

Clinical Cancer Research

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“…Taxanes are immunostimulatory against neoplasms, supporting the idea that these agents suppress cancer through several mechanisms and not solely through inhibiting cell division (Lee et al, 2000a;Tong et al, 2000). Immune function was affected more significantly after docetaxel treatment (Chan and Yang, 2000).…”

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confidence: 90%

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

Tsavaris¹,

Kosmas²,

Vadiaka³

et al. 2002

Br J Cancer

318

213

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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 ...

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“…However, the actions of these drugs on Bcl-2 and on the mitochondria might be expected to be non-selective and affect all cells. Indeed paclitaxel treatment is associated with serious side effects, including neuropathy (12) and low white blood cell counts (13). These side effects occur rapidly, appear to be due to drug action on terminally differentiated cells, and are slowly reversible.…”

mentioning

confidence: 99%

Paclitaxel Affects Cytosolic Calcium Signals by Opening the Mitochondrial Permeability Transition Pore

Kidd¹,

Pilkington²,

Schell³

et al. 2002

Journal of Biological Chemistry

182

130

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and the effect on Ca 2؉ spikes. We conclude that paclitaxel exerts rapid effects on the cytosolic Ca 2؉ signal via the opening of the mitochondrial permeability transition pore. This work indicates that some of the more rapidly developing side effects of chemotherapy might be due to an action of antimitotic drugs on mitochondrial function and an interference with the Ca 2؉ signal cascade.Antimitotic drugs are used extensively for the treatment of cancer. For example, paclitaxel (Taxol) is used in the treatment of breast and ovarian cancers and for AIDS 1 -related Kaposi's sarcoma, and vinblastine is used in the treatment of Hodgkin's disease (1). The mechanism of action of antimitotic drugs, that leads to cancer cell death, is not clear. It is known that paclitaxel stabilizes microtubule dynamics thereby preventing the proper formation of the mitotic spindle apparatus and arresting cancer cells at the G 2 -M phase of the cell cycle (2, 3). While it is thought that this action of paclitaxel on the cell cycle machinery precedes an apoptotic response of cells (4, 5), some recent work has suggested that paclitaxel-induced apoptosis results from more direct effects of the drug on the mitochondria. In this context paclitaxel has been shown to bind to Bcl-2 (6) and this binding may regulate Bcl-2 effects on the mitochondrial permeability transition pore (PTP) (7,8). Furthermore, deletion of the loop region of Bcl-2 (which prevents Bcl-2 phosphorylation) blocks the apoptotic action of paclitaxel on cancer cells (9). Other proteins may also be involved in the paclitaxel effects on mitochondria, such as APAF-1 (10). In isolated mitochondria paclitaxel acts to release cytochrome c (11). This effect is blocked by cyclosporin A providing further evidence that paclitaxel directly targets mitochondria, independent of actions on microtubules.The effect of antimitotic drugs on microtubule dynamics would confer drug specificity on actively dividing cancer cells. However, the actions of these drugs on Bcl-2 and on the mitochondria might be expected to be non-selective and affect all cells. Indeed paclitaxel treatment is associated with serious side effects, including neuropathy (12) and low white blood cell counts (13). These side effects occur rapidly, appear to be due to drug action on terminally differentiated cells, and are slowly reversible. Thus it is unlikely that these side effects are mediated by either mitotic block or apoptosis. Given that the clinical use of antimitotic drugs is limited by these side effects, understanding the mechanisms by which these drugs act is an important step toward optimizing the therapeutic benefits.In our studies, on terminally differentiated epithelial cells, we now show rapid actions of paclitaxel on the cytosolic Ca 2ϩ signal that can be accounted for by effects of paclitaxel on the PTP of the mitochondria. Given the universality of Ca 2ϩ signaling, it is likely that this action of paclitaxel accounts for some of the side effects of antimitotic drugs. EXPERIMENTAL PROCEDURESCell Preparatio...

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Cellular Immune Profile of Patients With Advanced Cancer Before and After Taxane Treatment

Cited by 50 publications

References 19 publications

Cellular Immunity in Breast Cancer Patients Completing Taxane Treatment

Cellular Immunity in Breast Cancer Patients Completing Taxane Treatment

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

Paclitaxel Affects Cytosolic Calcium Signals by Opening the Mitochondrial Permeability Transition Pore

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