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Telomerase activity is not a key determinant of sensitivity to standard cytotoxic drugs in human esophageal carcinoma cell lines
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2006 (English)In: Anti-Cancer Drugs, ISSN 0959-4973, E-ISSN 1473-5741, Vol. 17, no 5, 503-509 p.Article in journal (Refereed) Published
Abstract [en]

The aim of the present study was to investigate if basal telomerase activity levels may predict sensitivity to cytotoxic drugs in a panel of human esophageal carcinoma cell lines. The TRAPeze telomerase detection assay was used to investigate telomerase activity in the cell lines. Cytotoxic drug sensitivity for 20 standard cytotoxic agents was assessed using the fluorometric microculture cytotoxicity assay (FMCA). Telomerase activity was detected in all cell lines with a broad range of activity levels. Drug sensitivity also varied considerably between the cell lines. Except for a P value towards a correlation between mitoxantrone and telomerase activity (P=0.054), no statistically significant correlation was found between telomerase activity levels and sensitivity to investigated drugs, including key drugs such as cisplatin (P=0.9), 5-fluorouracil (P=0.8) and doxorubicin (P=0.54). We therefore conclude that basal telomerase activity level is not a key determinant of sensitivity to standard cytotoxic drugs in esophageal carcinoma cell lines.

Place, publisher, year, edition, pages
2006. Vol. 17, no 5, 503-509 p.
Keyword [en]
Antineoplastic Agents/*pharmacology, Cell Line; Tumor, Cytotoxins/*pharmacology, Drug Screening Assays; Antitumor, Enzyme Activation/drug effects, Esophageal Neoplasms/drug therapy/enzymology, Humans, Predictive Value of Tests, Telomerase/*analysis, Tumor Markers; Biological
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94108ISI: 000244316500003OAI: oai:DiVA.org:uu-94108DiVA: diva2:167851
Available from: 2006-03-17 Created: 2006-03-17 Last updated: 2011-02-15Bibliographically approved
In thesis
1. Activity and Regulation of Telomerase in Malignant Cells
Open this publication in new window or tab >>Activity and Regulation of Telomerase in Malignant Cells
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

An important step in tumorgenesis is the acquisition of cellular immortality. Tumor cells accomplish this by activating the enzyme telomerase, and thereby avoiding replicative senescence. The aim of this thesis was to study the activity and regulation of telomerase in a panel of malignant cell types.

We found that TGF-β1 (transforming growth factor-β1) mediated differential effects on telomerase activity in five ATC (anaplastic thyroid carcinoma) cell lines. Cells that harbored a p53 mutation responded by up-regulation of telomerase activity after TGF-β1 treatment, whereas cell lines displaying wt p53 responded by down-regulation of telomerase activity. Thus, these results indicate a possible connection between p53 genotype and telomerase response to TGF-β1 treatment. Furthermore, the decreased telomerase activity appeared to be due to transcriptional repression of the hTERT promoter and the increased activity possibly involved hTERT activation via phosphorylation.

We have previously shown that IFNs (interferons) sensitize MM (multiple myeloma) cells to Fas-mediated apoptosis. In the present investigation both IFN-α and IFN-γ down regulated telomerase activity in the MM cell line U-266-1970. The mechanism underlying the reduction of telomerase activity by IFN was shown to be transcriptional repression of the hTERT gene. We suggest that one potential mechanism whereby IFN sensitize MM cells to Fas-mediated apoptosis is by repressing hTERT activity at the transcriptional level.

In the next study we demonstrated that basal telomerase activity is not a key determinant of sensitivity to cytotoxic drugs in ESCC (esophageal squamous cell carcinoma) cell lines. Furthermore, we observed no correlation between c-Myc amplification, p53 mutations and high telomerase activity levels in these cell lines.

Finally, neuroblastoma cell lines were shown to up-regulate telomerase activity in response to hypoxic exposure and the main regulatory mechanism was not mediated by increased hTERT mRNA expression. This finding might constitute an adaptive stress response of tumor cells exposed to hypoxia.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 119
Keyword
Medicine, apoptosis, ATC, c-Myc, drug sensitivity, ESCC, hTERT, hypoxia, IFN, MM, neuroblastoma, p53, telomerase, TGF-β, Medicin
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:uu:diva-6623 (URN)91-554-6486-6 (ISBN)
Public defence
2006-04-07, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 13:15
Opponent
Supervisors
Available from: 2006-03-17 Created: 2006-03-17Bibliographically approved
2. Predictive Factors in Esophageal Carcinoma
Open this publication in new window or tab >>Predictive Factors in Esophageal Carcinoma
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Esophageal carcinoma is a malignancy with a poor prognosis and is the sixth cause of cancer related death worldwide. In Sweden approximately 400 new cases are diagnosed every year. The aim of this present thesis was to investigate predictive factors for esophageal carcinoma patients.126 esophageal carcinoma patients admitted to the department of Oncology at the University Hospital in Uppsala between 1990-2000 were investigated with focus on known and potential prognostic factors. Performance status and stage of the disease were the only independent prognostic factors (p-values <0.001).

Angiogenic factors VEGF and bFGF were correlated to platelet and leukocyte counts and VEGF was correlated to tumor volume (p=0.04) whereas bFGF was not (p=0.08) in pre-treatment serum samples from 42 esophageal carcinoma patients. The use of the angiogenic factors as prognostic factors, prior to therapy in patients with esophageal carcinoma, according to the results from the present study, seems limited.

HER-2 overexpression was seen in 17% of 97 investigated esophageal tumor samples. In squamous cell carcinoma patients, HER-2 overexpression correlated with poorer survival (p=0.035), whereas in adenocarcinoma patients, HER-2 status did not. HER-2 overexpression seems to be associated with poorer survival in esophageal carcinomas, especially in patients with squamous cell esophageal carcinoma.

Telomerase activity was detected in all esophageal cell lines, with a broad range of activity levels. No correlation was found between telomerase activity levels and sensitivity to investigated cytotoxic drugs. We therefore conclude that basal telomerase activity level is not a key determinant of sensitivity to standard cytotoxic drugs in esophageal carcinoma cell lines.

The virus HPV-16 was detected in 16 % of the patients; no other type HPV was detected. HPV-16 infection had no significant effect on survival (p=0.72). Our results did not show that HPV-16 increases survival or improve therapy response in patients with esophageal carcinoma.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 85 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 147
Keyword
Oncology, Esophageal carcinoma, Survival, Prognosis, Angiogenesis, HER-2, Telomerase, FMCA, HPV, Onkologi
Identifiers
urn:nbn:se:uu:diva-6831 (URN)91-554-6550-1 (ISBN)
Public defence
2006-05-20, Skoogsalen, Akademiska sjukhuset, Ingång 78, Uppsala, 09:15
Opponent
Supervisors
Available from: 2006-04-28 Created: 2006-04-28 Last updated: 2011-02-15Bibliographically approved

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