Celecoxib Up-Regulates the Expression of the ζ Chain of T Cell Receptor Complex in Tumor-Infiltrating Lymphocytes in Human Cervical Cancer

Ferrandina, Gabriella; Ranelletti, Franco O.; Legge, Francesco; Salutari, Vanda; Martinelli, Elisa; Fattorossi, Andrea; Lorusso, Domenica; Zannoni, Gianfranco; Vellone, Valerio Gaetano; Paglia, Amelia; Scambia, Giovanni

doi:10.1158/1078-0432.ccr-05-2530

Cited by 16 publications

(10 citation statements)

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“…However, whether lower doses of celecoxib are sufficient or not to maximally inhibit COX-2 activity is unknown: on the basis of our results, the dose of 400 mg/day can be considered clinically as adequate to the main purpose of chemosensitization. One can argue that we did not find in the sera of our patients any modulation of key angiogenesis-related factors, such as the pro-angiogenic VEGF and the anti-angiogenic endostatin, which have been previously associated with the antitumoral activity of celecoxib given at doses of 800 mg/day [16,38]. However, while higher doses are required to obtain antitumoral effects with celecoxib alone in terms of short-term modulation of molecular markers involved in tumor growth, apoptosis, immune function or angiogenesis [16], these could not be necessary for circumventing COX-2-mediated chemoresistance mechanisms in combinational study with chemotherapy.…”

Section: Discussionmentioning

confidence: 95%

“…All samples were aliquoted and stored at -80°C until assay. Serum levels of vascular endothelial growth factor (VEGF) and endostatin were measured by a solid phase chemiluminescent ELISA assay (R&D Systems, Abingdon, United Kingdom), according to the manufacturer's protocol [16]. …”

Section: Methodsmentioning

confidence: 99%

“…Indeed, selective COX-2 inhibitors have been shown in vitro and in vivo to exert a potent tumor growth inhibition not only in COX-2 positive tumors, but also indirectly in COX-2 negative tumors, through the growth inhibition of COX-2 expressing endothelial cells, and the positive modulation of immune functions [15,16]. Selective COX-2 inhibitors have been shown to be active as tumor chemopreventive agents in preclinical models as well as in humans [15,17,18], and to enhance the cytotoxicity exerted in vitro by different chemotherapeutics, including platinating agents [19,20].…”

Section: Introductionmentioning

confidence: 99%

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Phase II study of the combination carboplatin plus celecoxib in heavily pre-treated recurrent ovarian cancer patients

et al. 2011

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BackgroundCyclooxygenase-2 overexpression is associated with poor outcome and resistance to platinum-based chemotherapy in ovarian cancer. We evaluated the antitumor activity and safety of the combination carboplatin plus the COX-2 inhibitor celecoxib in recurrent heavily-treated OC patients.MethodsPatients were administered oral celecoxib (400 mg/day) in combination with intravenous carboplatin (AUC5, q28). A Simon's two-stage design was employed.Results45 patients were enrolled: 23 (51.1%) presented platinum-resistance, and 27 (60%) had received at least 3 prior regimens for recurrence. The response rate was 28.9% with 3 complete and 10 partial responses (median duration of response = 6 months). Only one (0.4%) G4 non-febrile neutropenia was observed; G3 neutropenia, anemia, or thrombocytopenia, were observed in 2.5%, 1.7%, and 1.7% of the cycles, respectively. G3-4 vomiting was reported in only 1.7%, and 0.4% of the cycles were associated with G3 dyspepsia or diarrhea or constipation. Only one patient experienced G3 hypertension associated to G2 hypersensitivity reaction. No differences in baseline versus post-treatment Quality of Life scores were observed. Median progression free survival and overall survival were 5 and 13 months, respectively.ConclusionsCelecoxib combined with carboplatin showed promising activity and it is well tolerated in heavily-treated recurrent ovarian cancer patients.Trial registration numberNCT01124435 (ClinicalTrials.gov Identifier) and 935/03 (study ID numbers).

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Section: Discussionmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phase II study of the combination carboplatin plus celecoxib in heavily pre-treated recurrent ovarian cancer patients

et al. 2011

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“…Decreased expression of CD3 zeta chain in human cancer was reviewed by Whiteside [34]. Interestingly, patients with cervical cancer after successful chemotherapy showed a restoration of zeta chain-expressing T cells [35]. Therefore, a decrease of CD3 zeta chain-expression in malignant cancer processes is reversible.…”

Section: Discussionmentioning

confidence: 99%

Dominance of CD4⁺ lymphocytic infiltrates with disturbed effector cell characteristics in the tumor microenvironment of prostate carcinoma

et al. 2007

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BACKGROUND. Prostate cancer is the most common cancer of men in the Western world. Despite the over-expression of tumor-associated antigens, like PSA or PSMA, immune activation is inefficient. The goal of this investigation was to assess in situ characteristics of prostate cancerinfiltrating lymphocytes and to determine their activation status and effector function. METHODS. We compared 17 carcinoma containing tissues, four benign prostatic hyperplasia tissues and eight healthy prostate tissues regarding lymphocyte subset composition, locoregional distribution, and functional status using immunohistological staining of cryopreserved tissues. For determination of lymphocyte subsets, serial sections were stained with CD3, CD4, and CD8 antibodies. Activation status and effector function were studied using CD69, interferon-gamma (IFNg), perforin, and CD3 zeta chain antibodies. T-cell-receptor repertoire (TCR) analysis was made to determine the complexity of infiltrating lymphocytes. RESULTS. CD3þ , CD4 þ , and CD69 þ T lymphocytes were prominent in tissues derived from patients with prostate carcinoma. CD8 þ lymphocytes were significantly less than CD4 þ lymphocytes. IFNg and perforin were downregulated on infiltrating lymphocytes compared to cells of healthy prostate tissue. Very few lymphocytes were detected within cancerous lesions whereas surrounding tissues showed extensive lymphocyte cluster formation. The TCR repertoire of infiltrating lymphocytes was broad and similar to that of healthy prostate tissue, giving no evidence for specific lymphocyte recruitment. CONCLUSIONS. In the prostate cancer microenvironment, CD4 þ T lymphocytes dominated while CD8 þ T cells were sparse. The lymphocytes exhibited signs of disturbed effector function. Consequently, the immune response against autologous tumor cells is likely to be inefficient in controlling tumor growth.

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“…Zehbe et al [16] studied cervical intraepithelial lesions CIN I (n=3), CIN III (n=7), invasive cervical carcinoma (CC) (n=13) and normal cervical tissue (n=5) and evaluated for T-cell receptor zeta chain immunohistochemistry, found that reduced T-cell receptor zeta chain expression is not necessarily linked to a chronic viral infection, or to the presence of transformed cells, but rather to the stromal invasion of the cancer lesion. Ferrandina et al [17] found celecoxib up-regulates the expression of the zeta chain of T-cell receptor complex in tumor-infiltrating lymphocytes in human cervical cancer. Using expression microarray analysis, Watson et al [18] revealed ACTG2 genes may be associated with cisplatin resistance to breast cancer cell.…”

Section: Tab 3 Identification Of Protein Spots By Mass Spectrometrymentioning

confidence: 99%

Two-dimensional electrophoresis analysis of differential protein expression in squamous carcinoma of the cervix

Zhu¹,

Wu²,

Yu³

et al. 2008

Chin. J. Cancer Res.

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Objective:To establish and optimize the two-dimensional gel electrophoresis (2-DE) maps of squamous carcinoma of the cervix and to study the protein difference between squamous carcinoma of the cervix (SCC) and normal cervical tissue. Methods: Using Two-dimensional gel electrophoresis followed by computer-assisted image analysis, the differential proteins between squamous carcinoma of the cervical tissue and normal cervical tissue were compared. Then using matrix-assisted laser desorption/ionization-time of flight mass spectrometry, the differential proteins were identified.Results: The well-resolved and reproducible two-dimensional gel electrophoresis patterns of squamous carcinoma of the cervix tissue and normal cervical tissue were obtained. After silver staining, the average matching ratio of squamous carcinoma of the cervix was 86.1%. There was a good reproducibility of spot position in 2-DE map, with average deviation in IEF direction of 0.95±0.13 mm, while in SDS-PAGE direction it was 1.20±0.18 mm. Ten protein spots were identified by mass spectrometry, some of which were involved in cell proliferation, cell apoptosis, intracellular enzymes, structural proteins, cycle regulation, and tumor occurrence. Conclusion: The differentially expressed proteins provide a fundamental basis for further study of human squamous carcinoma of the cervix and screening of its specific markers.

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Celecoxib Up-Regulates the Expression of the ζ Chain of T Cell Receptor Complex in Tumor-Infiltrating Lymphocytes in Human Cervical Cancer

Cited by 16 publications

References 30 publications

Phase II study of the combination carboplatin plus celecoxib in heavily pre-treated recurrent ovarian cancer patients

Phase II study of the combination carboplatin plus celecoxib in heavily pre-treated recurrent ovarian cancer patients

Dominance of CD4⁺ lymphocytic infiltrates with disturbed effector cell characteristics in the tumor microenvironment of prostate carcinoma

Two-dimensional electrophoresis analysis of differential protein expression in squamous carcinoma of the cervix

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Celecoxib Up-Regulates the Expression of the ζ Chain of T Cell Receptor Complex in Tumor-Infiltrating Lymphocytes in Human Cervical Cancer

Cited by 16 publications

References 30 publications

Phase II study of the combination carboplatin plus celecoxib in heavily pre-treated recurrent ovarian cancer patients

Phase II study of the combination carboplatin plus celecoxib in heavily pre-treated recurrent ovarian cancer patients

Dominance of CD4+ lymphocytic infiltrates with disturbed effector cell characteristics in the tumor microenvironment of prostate carcinoma

Two-dimensional electrophoresis analysis of differential protein expression in squamous carcinoma of the cervix

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Dominance of CD4⁺ lymphocytic infiltrates with disturbed effector cell characteristics in the tumor microenvironment of prostate carcinoma