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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Biotherapy 11 (1998), S. 255-258 
    ISSN: 1573-8280
    Keywords: immunotherapy ; interleukin-2 receptor ; interferon-gamma ; clinical trial ; immunomodulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Therapy for cancer patients with biologically active immune modulators is attractive but has met with limited clinical success. Interleukin-2 (IL2) stimulates T-cells and natural killer (NK) cells to kill tumor cells and levamisole (LMS) is an immunostimulant which has been shown to increase NK cells and activated T-cells in patients receiving this adjuvantly along with 5FU for Stage III colon cancer. This study was designed to evaluate whether treatment with LMS prior to IL2 would provide synergistic activity and improve response rates. Four patients with advanced malignancies were treated with LMS at 50mg po TID for 3 days followed on day 4 with 600,000 units/kg IL2 as a single iv bolus. This treatment was repeated weekly until progression. Serum soluble IL2 receptor (sIL2R) and interferon-γ levels were monitored throughout the treatment course as markers of immune activation. All patients had eventual progression of disease. Toxicity was minimal with Grade II orthostatic hypotension the major consequence of therapy. The pattern of sIL2R levels in 3/4 patients revealed a steady increase over the several weeks of therapy, indicating ongoing immunostimulation (r =0.53 , p= 0.001). Short-term treatment with LMS, however, resulted in a significant and consistent decreases in sIL2R levels (2198 U/ml vs. 1969 U/ml, p=0.001) in all patients. In conclusion, LMS/IL2 in the dose and schedule utilized here was not clinically effective. However, LMS reduced sIL2R levels immediately following a three-day course. This reduction in sIL2R by LMS may improve the possibility of response to IL2 by facilitating a decrease in inhibitory sIL2R. Combinations of these two agents should continue to be investigated as potential synergistic anti-tumor agents.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0851
    Keywords: Levamisole ; Colon cancer ; Natural killer cells ; Soluble interleukin-2 receptor ; Immune surveillance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Levamisole (LMS) and 5-fluorouracil (5FU) administered adjuvantly are effective in reducing the relapse rate following surgical resection of Duke's stage C colon carcinoma. It has been postulated that LMS acts to stimulate the immune system and that this is one mechanism through which this drug exerts its antitumor effects. In this study, peripheral blood mononuclear cells (PBMC) were analyzed in nine patients with surgically resected colon carcinoma prior to initiation of adjuvant LMS/5FU and at several subsequent times while patients were on therapy. Changes in lymphocyte phenotype and soluble interleukin-2 receptor (sIL-2R) between pre-study samples and samples obtained during adjuvant LMS/5FU were evaluated. Significant increases were seen in the proportion of PBMC expressing natural killer (NK) antigen CD56 (14.7±2.4% versus 18.1±2.6%;P〈0.05) and surface IL-2R (CD25; 0% versus 0.42±0.15%;P〈0.05), in sIL-2R (314±86 U/ml versus 736±173 U/ml;P〈0.05), and in the CD4∶CD8 ratio (2.34±0.93 versus 3.47±1.23;P〈0.01). A significant decrease in the proportion of CD8+ PBMC (24.7±3.8% versus 18.8±2.6%;P〈0.01) and total CD8+ PBMC (537±118 versus 324±37;P〈0.01) was seen. The increase in CD56+ cells correlated with sIL2R levels (r=0.46;P〈0.05). No changes were noted for CD3, CD4, CD5, CD14, CD16, CD19, CDw49a, or TCRδ. The greatest increase in CD56+ cells and the smallest reduction in CD8+ cells were seen in the subgroup of patients who remained disease-free following adjuvant chemotherapy. This study suggests that adjuvant LMS/5FU has significant stimulatory effects on the immune system, which correlate with patient outcome and may account at least in part for its clinical efficacy.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0851
    Keywords: Key words: Levamisole – Colon cancer – Natural killer cells – Soluble interleukin-2 receptor – Immune surveillance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. Levamisole (LMS) and 5-fluorouracil (5FU) administered adjuvantly are effective in reducing the relapse rate following surgical resection of Duke’s stage C colon carcinoma. It has been postulated that LMS acts to stimulate the immune system and that this is one mechanism through which this drug exerts its antitumor effects. In this study, peripheral blood mononuclear cells (PBMC) were analyzed in nine patients with surgically resected colon carcinoma prior to initiation of adjuvant LMS/5FU and at several subsequent times while patients were on therapy. Changes in lymphocyte phenotype and soluble interleukin-2 receptor (sIL-2R) between pre-study samples and samples obtained during adjuvant LMS/5FU were evaluated. Significant increases were seen in the proportion of PBMC expressing natural killer (NK) antigen CD56 (14.7±2.4% versus 18.1±2.6%; P〈0.05) and surface IL-2R (CD25; 0% versus 0.42±0.15%; P〈0.05), in sIL-2R (314±86 U/ml versus 736±173 U/ml; P〈0.05), and in the CD4:CD8 ratio (2.34±0.93 versus 3.47±1.23; P〈0.01). A significant decrease in the proportion of CD8+ PBMC (24.7±3.8% versus 18.8±2.6%; P〈0.01) and total CD8+ PBMC (537±118 versus 324±37; P〈0.01) was seen. The increase in CD56+ cells correlated with sIL2R levels (r = 0.46; P〈0.05). No changes were noted for CD3, CD4, CD5, CD14, CD16, CD19, CDw49a, or TCRδ. The greatest increase in CD56+ cells and the smallest reduction in CD8+ cells were seen in the subgroup of patients who remained disease-free following adjuvant chemotherapy. This study suggests that adjuvant LMS/5FU has significant stimulatory effects on the immune system, which correlate with patient outcome and may account at least in part for its clinical efficacy.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0851
    Keywords: Key words Levamisole ; Natural killer cells ; Lymphocyte phenotype ; Tumor immunology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Levamisole (LMS), utilized in the adjuvant treatment of patients with stage III colon cancer, is immunomodulatory. To determine whether alterations in immune parameters before, during and after 12 months of 5FU/LMS therapy correlate with disease-free survival, 38 patients enrolled on Southwest Oncology Group (SWOG) protocol 8899 received extensive lymphocyte phenotypic analysis prior to therapy and 3, 6, 12 and 15 months after treatment initiation. The median follow-up of patients is 41 months. Significant increases in the proportion and total number of CD56+ natural killer cells were seen, starting at 3 months and continuing until 15 months (P 〈 0.001). Increases in the total numbers of cells expressing CD25 (interleukin-2 receptor), VLA4 and the combinations of CD4: CD45RA and CD4:CDw29 were not evident during therapy but were seen at 15 months (P 〈 0.05: CD25, CD4:CDw29, CD4:CD45RA; P 〈 0.001: VLA4). Low levels of CD8+ cells prior to treatment initiation and after 3 months of therapy correlated with early relapse within the first year of 5FU/LMS treatment. Patients who have remained disease-free (n = 22, median follow-up 45 months) demonstrated increases in the total numbers of CD8+, CD25+, CD56+, VLA4+, CD4: CDw29 and CD4:CD45RA cells, primarily at 15 months. In contrast, patients who relapsed had decreased numbers of CD8+, CD4:CDw29, CD4: CD45RA and VLA4+ cells and minimal increases in CD56+ and CD25+ cells. Statistically significant differences between the late-relapse group and the group remaining disease-free were seen for CD25+, CD4: CD45RA and CD4:CDw29 cells at the 15-month assay time (P = 0.0276, P = 0.0349, P = 0.0178 respectively). In conclusion, multiple alterations in lymphocyte phenotype, with increases in the proportion and total number of cells involved in cell-mediated immune responses, were seen during and especially following completion of therapy with 5FU/LMS. Many of these changes are significantly associated with clinical outcome and may be useful for risk stratification of stage III colon cancer patients following completion of adjuvant therapy.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1546-1718
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] Constitutive activation of the Wnt signaling pathway is a root cause of many colon cancers. Activation of this pathway is caused by genetic mutations that stabilize the β-catenin protein, allowing it to accumulate in the nucleus and form complexes with any member of the lymphoid enhancer ...
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1573-4919
    Keywords: endosulfan ; cytotoxicity ; mitochondria ; apoptosis ; Jurkat cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Several organochlorinated pesticides including DDT, PCBs and dieldrin have been reported to cause immune suppression and increase susceptibility to infection in animals. Often this manifestation is accompanied by atrophy of major lymphoid organs. It has been suggested that increased apoptotic cell death leading to altered T-B cell ratios, and loss of regulatory cells in critical numbers leads to perturbations in immune function. The major objective of our study was to define the mechanism by which endosulfan, an organochlorinated pesticide, induces human T-cell death using Jurkat, a human T-cell leukemic cell line, as an in vitro model. We exposed Jurkat cells to varying concentrations of endosulfan for 0-48 h and analyzed biochemical and molecular features characteristic of T-cell apoptosis. Endosulfan lowered cell viability and inhibited cell growth in a dose- and time-dependent manner. DAPI staining was used to enumerate apoptotic cells and we observed that endosulfan at 10-200 μM induced a significant percentage of cells to undergo apoptotic cell death. At 48 h, more than 90% cells were apoptotic with 50 μM of endosulfan. We confirmed these observations using both DNA fragmentation and annexin-V binding assays. It is now widely being accepted that mitochondria undergo major changes early during the apoptotic process. We examined mitochondrial transmembrane potential (ΔΨm) in endosulfan treated cells to understand the role of the mitochondria in T-cell apoptosis. Within 30 min of chemical exposure, a significant percentage of cells exhibited a decreased incorporation of DiOC6(3), a cationic lipophilic dye into mitochondria indicating the disruption of ΔΨm. This drop in ΔΨm was both dose- and time-dependent and correlated well with other parameters of apoptosis. We also examined whether this occurred by the down regulation of bcl-2 protein expression that is likely to increase the susceptibility of Jurkat cells to endosulfan toxicity. Paradoxically, the intracellular expression of bcl-2 protein was elevated in a dose dependent manner suggesting endosulfan-induced apoptosis occurred by a non-bcl-2 pathway. Based on these data, as well as those reported elsewhere, we propose the following sequence of events to account for T-cell apoptosis induced by endosulfan: uncoupling of oxidative phosphorylation → excess ROS production → GSH depletion → oxidative stress → disruption of ΔΨm → release of cytochrome C and other apoptosis related proteins to cytosol → apoptosis. This study reports for the first time that endosulfan can induce apoptosis in a human T-cell leukemic cell line which may have direct relevance to loss of T cells and thymocytes in vivo. Furthermore, our data strongly support a role of mitochondrial dysfunction and oxidative stress in endosulfan toxicity.
    Type of Medium: Electronic Resource
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