Skip to main content
Top
Published in: Cancer Chemotherapy and Pharmacology 2/2012

01-02-2012 | Original Article

Nucleoside transporters are widely expressed in ovarian carcinoma effusions

Authors: Annika J. Bock, Hiep Phuc Dong, Claes G. Tropé, Anne Cathrine Staff, Björn Risberg, Ben Davidson

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2012

Login to get access

Abstract

Objective

Equilibrative and concentrative nucleoside transporters (ENTs and CNTs) mediate the cellular uptake of anticancer nucleosides and sensitivity to such compounds. We studied the expression of ENTs and CNTs in ovarian carcinoma effusions.

Methods

ENT1, ENT2, ENT4 and CNT3 expression was analyzed in 66 ovarian carcinoma effusions (61 peritoneal, 5 pleural) from 64 ovarian carcinoma patients by flow cytometry. The majority of patients received platinum-based chemotherapy. Results were analyzed for association with clinicopathologic parameters and survival.

Results

With the exception of one ENT2-negative effusion, ENT1, ENT2, ENT4 and CNT3 protein was detected on carcinoma cells in all effusions, with expression observed in 1–95% of tumor cells. Nucleoside transporter expression was comparable between peritoneal and pleural effusions and was unrelated to age, tumor grade, International Federation of Gynecology and Obstetrics (FIGO) stage, residual tumor volume after surgery, previous exposure to chemotherapy and response to chemotherapy at diagnosis (P > 0.05). No correlation was found between ENT or CNT expression and overall survival or progression-free survival, although higher ENT2 expression was associated with a trend for longer overall (45 vs. 23 months; P = 0.055) and progression-free (17 vs. 5 months; P = 0.087) survival.

Conclusion

Nucleoside transporters are frequently expressed in ovarian carcinoma effusions, but their expression generally appears to be unrelated to chemoresponse in this cancer in a cohort of patients treated by platinum-based chemotherapy. The role of ENT2 as a prognostic marker in this disease, as well as the role of these molecules in determining chemoresponse in patients treated by nucleoside analogs, merits further research.
Literature
1.
go back to reference Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249PubMedCrossRef Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249PubMedCrossRef
2.
go back to reference Davidson B (2001) Ovarian carcinoma and serous effusions. Changing views regarding tumor progression and review of current literature. Anal Cell Pathol 23:107–128PubMed Davidson B (2001) Ovarian carcinoma and serous effusions. Changing views regarding tumor progression and review of current literature. Anal Cell Pathol 23:107–128PubMed
3.
go back to reference Baldwin SA, Beal PR, Yao SYM, King AE, Cass CE, Young JD (2004) The equilibrative nucleoside transporter family, SLC29. Pflügers Arch 447:735–743PubMedCrossRef Baldwin SA, Beal PR, Yao SYM, King AE, Cass CE, Young JD (2004) The equilibrative nucleoside transporter family, SLC29. Pflügers Arch 447:735–743PubMedCrossRef
4.
go back to reference Damaraju VL, Damaraju S, Young JD, Baldwin SA, Mackey J, Sawyer MB, Cass CE (2003) Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy. Oncogene 22:7524–7536PubMedCrossRef Damaraju VL, Damaraju S, Young JD, Baldwin SA, Mackey J, Sawyer MB, Cass CE (2003) Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy. Oncogene 22:7524–7536PubMedCrossRef
5.
go back to reference Galmarini CM, Mackey JR, Dumontet C (2002) Nucleoside analogues and nucleobases in cancer treatment. Lancet Oncol 3:415–424PubMedCrossRef Galmarini CM, Mackey JR, Dumontet C (2002) Nucleoside analogues and nucleobases in cancer treatment. Lancet Oncol 3:415–424PubMedCrossRef
6.
go back to reference Farré X, Guillén-Gómez E, Sánchez L, Hardisson D, Plaza Y, Lloberas J, Casado FJ, Palacios J, Pastor-Anglada M (2004) Expression of the nucleoside-derived drug transporters hCNT1, hENT1 and hENT2 in gynecologic tumors. Int J Cancer 112:959–966PubMedCrossRef Farré X, Guillén-Gómez E, Sánchez L, Hardisson D, Plaza Y, Lloberas J, Casado FJ, Palacios J, Pastor-Anglada M (2004) Expression of the nucleoside-derived drug transporters hCNT1, hENT1 and hENT2 in gynecologic tumors. Int J Cancer 112:959–966PubMedCrossRef
7.
go back to reference Ferrandina G, Mey V, Nannizzi S, Ricciardi S, Petrillo M, Ferlini C, Danesi R, Scambia G, Del Tacca M (2010) Expression of nucleoside transporters, deoxycitidine kinase, ribonucleotide reductase regulatory subunits, and gemcitabine catabolic enzymes in primary ovarian cancer. Cancer Chemother Pharmacol 65:679–686PubMedCrossRef Ferrandina G, Mey V, Nannizzi S, Ricciardi S, Petrillo M, Ferlini C, Danesi R, Scambia G, Del Tacca M (2010) Expression of nucleoside transporters, deoxycitidine kinase, ribonucleotide reductase regulatory subunits, and gemcitabine catabolic enzymes in primary ovarian cancer. Cancer Chemother Pharmacol 65:679–686PubMedCrossRef
8.
go back to reference Dong HP, Holth A, Berner A, Davidson B, Risberg B (2007) Flow cytometric immunphenotyping of epithelial cancer cells in effusions–technical considerations and pitfalls. Cytometry B Clin Cytom 72:332–343PubMed Dong HP, Holth A, Berner A, Davidson B, Risberg B (2007) Flow cytometric immunphenotyping of epithelial cancer cells in effusions–technical considerations and pitfalls. Cytometry B Clin Cytom 72:332–343PubMed
9.
go back to reference Davidson B, Nielsen S, Christensen J, Asschenfeldt P, Berner A, Risberg B, Johansen P (2001) The role of desmin and N-cadherin in effusion cytology: a comparative study using established markers of mesothelial and epithelial cells. Am J Surg Pathol 25:1405–1412PubMedCrossRef Davidson B, Nielsen S, Christensen J, Asschenfeldt P, Berner A, Risberg B, Johansen P (2001) The role of desmin and N-cadherin in effusion cytology: a comparative study using established markers of mesothelial and epithelial cells. Am J Surg Pathol 25:1405–1412PubMedCrossRef
10.
go back to reference Dong HP, Kleinberg L, Davidson B, Risberg B (2008) Methods for simultaneous measurement of apoptosis and cell surface phenotype of epithelial cells in effusions by flow cytometry. Nat Protoc 3:955–964PubMedCrossRef Dong HP, Kleinberg L, Davidson B, Risberg B (2008) Methods for simultaneous measurement of apoptosis and cell surface phenotype of epithelial cells in effusions by flow cytometry. Nat Protoc 3:955–964PubMedCrossRef
11.
go back to reference Dong HP, Holth A, Kleinberg L, Ruud MG, Elstrand MB, Tropé CG, Davidson B, Risberg B (2009) Evaluation of cell surface expression of phosphatidylserine in ovarian carcinoma effusions using the annexin-V/7-AAD assay: clinical relevance and comparison with other apoptosis parameters. Am J Clin Pathol 132:756–762PubMedCrossRef Dong HP, Holth A, Kleinberg L, Ruud MG, Elstrand MB, Tropé CG, Davidson B, Risberg B (2009) Evaluation of cell surface expression of phosphatidylserine in ovarian carcinoma effusions using the annexin-V/7-AAD assay: clinical relevance and comparison with other apoptosis parameters. Am J Clin Pathol 132:756–762PubMedCrossRef
12.
go back to reference Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214PubMedCrossRef Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214PubMedCrossRef
14.
go back to reference Yap TA, Carden CP, Kaye SB (2009) Beyond chemotherapy: targeted therapies in ovarian cancer. Nat Rev Cancer 9:167–181PubMedCrossRef Yap TA, Carden CP, Kaye SB (2009) Beyond chemotherapy: targeted therapies in ovarian cancer. Nat Rev Cancer 9:167–181PubMedCrossRef
15.
go back to reference Lund B, Hansen OP, Theilade K, Hansen M, Neijt JP (1994) Phase II study of gemcitabine (2’, 2’-difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst 86:1530–1533PubMedCrossRef Lund B, Hansen OP, Theilade K, Hansen M, Neijt JP (1994) Phase II study of gemcitabine (2’, 2’-difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst 86:1530–1533PubMedCrossRef
16.
go back to reference Lorusso D, Di Stefano A, Fanfani F, Scambia G (2006) Role of gemcitabine in ovarian cancer treatment. Ann Oncol 17(Suppl 5):v188–v194PubMedCrossRef Lorusso D, Di Stefano A, Fanfani F, Scambia G (2006) Role of gemcitabine in ovarian cancer treatment. Ann Oncol 17(Suppl 5):v188–v194PubMedCrossRef
17.
go back to reference Pfisterer J, Plante M, Vergote I, du Bois A, Hirte H, Lacave AJ, Wagner U, Stähle A, Stuart G, Kimmig R, Olbricht S, Le T, Emerich J, Kuhn W, Bentley J, Jackisch C, Lück H, Rochon J, Zimmermann AH, Eisenhauer E (2006) Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol 24:4699–4707PubMedCrossRef Pfisterer J, Plante M, Vergote I, du Bois A, Hirte H, Lacave AJ, Wagner U, Stähle A, Stuart G, Kimmig R, Olbricht S, Le T, Emerich J, Kuhn W, Bentley J, Jackisch C, Lück H, Rochon J, Zimmermann AH, Eisenhauer E (2006) Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol 24:4699–4707PubMedCrossRef
18.
go back to reference Davidson B, Dong HP, Berner A, Christensen J, Nielsen S, Johansen P, Bryne M, Asschenfeldt P, Risberg B (2002) Detection of malignant epithelial cells in effusions using flow cytometric immunophenotyping: an analysis of 92 cases. A J Clin Pathol 118:85–92CrossRef Davidson B, Dong HP, Berner A, Christensen J, Nielsen S, Johansen P, Bryne M, Asschenfeldt P, Risberg B (2002) Detection of malignant epithelial cells in effusions using flow cytometric immunophenotyping: an analysis of 92 cases. A J Clin Pathol 118:85–92CrossRef
19.
go back to reference Pennycooke M, Chaudary N, Shuralyova I, Zhang Y, Coe IR (2001) Differential expression of human nucleoside transporters in normal and tumor tissue. Biochem Biophys Res Commun 280:951–959PubMedCrossRef Pennycooke M, Chaudary N, Shuralyova I, Zhang Y, Coe IR (2001) Differential expression of human nucleoside transporters in normal and tumor tissue. Biochem Biophys Res Commun 280:951–959PubMedCrossRef
20.
go back to reference Spratlin J, Sangha R, Glubrecht D, Dabbagh L, Young JD, Dumontet C, Cass C, Lai R, Mackey JR (2004) The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin Cancer Res 10:6956–6961PubMedCrossRef Spratlin J, Sangha R, Glubrecht D, Dabbagh L, Young JD, Dumontet C, Cass C, Lai R, Mackey JR (2004) The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin Cancer Res 10:6956–6961PubMedCrossRef
21.
go back to reference Maréchal R, Mackey JR, Lai R, Demetter P, Peeters M, Polus M, Cass CE, Young J, Salmon I, Devière J, van Laethem J (2009) Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma. Clin Cancer Res 15:2913–2919PubMedCrossRef Maréchal R, Mackey JR, Lai R, Demetter P, Peeters M, Polus M, Cass CE, Young J, Salmon I, Devière J, van Laethem J (2009) Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma. Clin Cancer Res 15:2913–2919PubMedCrossRef
Metadata
Title
Nucleoside transporters are widely expressed in ovarian carcinoma effusions
Authors
Annika J. Bock
Hiep Phuc Dong
Claes G. Tropé
Anne Cathrine Staff
Björn Risberg
Ben Davidson
Publication date
01-02-2012
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 2/2012
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-011-1716-7

Other articles of this Issue 2/2012

Cancer Chemotherapy and Pharmacology 2/2012 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine