Is the resistance of gemcitabine for pancreatic cancer settled only by overexpression of deoxycytidine kinase?

The prognosis of pancreatic cancer remains poor, and the standard first-line chemotherapy with gemcitabine (GEM) has a response rate of less than 20%. Since expression of deoxycytidine kinase (dCK) seems important for improvement of GEM sensitivity, overexpression of dCK was investigated using pancreatic cancer cell lines (Panc-1, MIAPaCa-2 and BxPC-3). dCK gene was introduced into the cell lines by retrovirus and changes in IC50 were examined. Sensitivity of two pancreatic cancer cell lines to GEM elevated dramatically in comparison with control cells, but change of sensitivity remained at 1.8 times in BxPC-3. Since addition of tetrahydro uridine (THU), an inhibitor of deoxycytidine deaminase (CDA), increased the sensitivity 54-fold, overexpression of CDA seems to be the mechanism for improvement of the sensitivity. In conclusion, dCK is a key enzyme of GEM, but resistance of GEM is not improved in all pancreatic cancer cells by overexpression of dCK. Combination treatment based on expression of GEM metabolism-related gene may become an effective therapy in the future.

[1]  Takashi Ishikawa,et al.  Human equilibrative nucleoside transporter 1 is associated with the chemosensitivity of gemcitabine in human pancreatic adenocarcinoma and biliary tract carcinoma cells. , 2007, Oncology reports.

[2]  Y. Takeda,et al.  Involvement of ribonucleotide reductase M1 subunit overexpression in gemcitabine resistance of human pancreatic cancer , 2007, International journal of cancer.

[3]  L. Karnitz,et al.  Pharmacological Abrogation of S-Phase Checkpoint Enhances the Anti-Tumor Activity of Gemcitabine In Vivo , 2007, Cell cycle.

[4]  E. Giovannetti,et al.  Synergistic Antitumor Activity of ZD6474, An Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, with Gemcitabine and Ionizing Radiation against Pancreatic Cancer , 2006, Clinical Cancer Research.

[5]  O. Wildner,et al.  Enhanced killing of pancreatic cancer cells by expression of fusogenic membrane glycoproteins in combination with chemotherapy , 2006, Molecular Cancer Therapeutics.

[6]  E. Giovannetti,et al.  In vitro synergistic cytotoxicity of gemcitabine and pemetrexed and pharmacogenetic evaluation of response to gemcitabine in bladder cancer patients , 2006, British Journal of Cancer.

[7]  G. Peters,et al.  Micro-Array Analysis of Resistance for Gemcitabine Results in Increased Expression of Ribonucleotide Reductase Subunits , 2006, Nucleosides, nucleotides & nucleic acids.

[8]  Franco Mosca,et al.  Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. , 2006, Cancer research.

[9]  C. Galmarini,et al.  Gemcitabine resistance due to deoxycytidine kinase deficiency can be reverted by fruitfly deoxynucleoside kinase, DmdNK, in human uterine sarcoma cells , 2006, Cancer Chemotherapy and Pharmacology.

[10]  U Creutzig,et al.  The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia , 2005, British Journal of Cancer.

[11]  A. Masamune,et al.  MSX2 overexpression inhibits gemcitabine-induced caspase-3 activity in pancreatic cancer cells. , 2005, World journal of gastroenterology.

[12]  Bauke Ylstra,et al.  In vivo induction of resistance to gemcitabine results in increased expression of ribonucleotide reductase subunit M1 as the major determinant. , 2005, Cancer research.

[13]  Xia Zhao,et al.  Enhanced antitumor effect of the combination of tumstatin gene therapy and gemcitabine in murine models. , 2005, Human gene therapy.

[14]  R. Danesi,et al.  Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells , 2005, British Journal of Cancer.

[15]  Elisa Giovannetti,et al.  Cellular and Pharmacogenetics Foundation of Synergistic Interaction of Pemetrexed and Gemcitabine in Human Non–Small-Cell Lung Cancer Cells , 2005, Molecular Pharmacology.

[16]  E. Giovannetti,et al.  Prolonged fixed dose rate infusion of gemcitabine with autologous haemopoietic support in advanced pancreatic adenocarcinoma , 2005, British Journal of Cancer.

[17]  John R. Mackey,et al.  The Absence of Human Equilibrative Nucleoside Transporter 1 Is Associated with Reduced Survival in Patients With Gemcitabine-Treated Pancreas Adenocarcinoma , 2004, Clinical Cancer Research.

[18]  Ryuzo Ueda,et al.  Determinants of sensitivity and resistance to gemcitabine: The roles of human equilibrative nucleoside transporter 1 and deoxycytidine kinase in non‐small cell lung cancer , 2004, Cancer science.

[19]  J. Mackey,et al.  Resistance to gemcitabine in a human follicular lymphoma cell line is due to partial deletion of the deoxycytidine kinase gene , 2004, BMC pharmacology.

[20]  S. Ashley,et al.  RNA interference targeting the M2 subunit of ribonucleotide reductase enhances pancreatic adenocarcinoma chemosensitivity to gemcitabine , 2004, Oncogene.

[21]  J. Mackey,et al.  Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy† , 2003, Oncogene.

[22]  A. Mazo,et al.  Nucleoside transporter profiles in human pancreatic cancer cells: role of hCNT1 in 2',2'-difluorodeoxycytidine- induced cytotoxicity. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[23]  L. Pradayrol,et al.  Gene therapy based on gemcitabine chemosensitization suppresses pancreatic tumor growth. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[24]  H. Kindler.  The pemetrexed/gemcitabine combination in pancreatic cancer , 2002, Cancer.

[25]  G. Peters,et al.  Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity. , 2002, Molecular cancer therapeutics.

[26]  J. Tepper,et al.  Tumor uptake and elimination of 2',2'-difluoro-2'-deoxycytidine (gemcitabine) after deoxycytidine kinase gene transfer: correlation with in vivo tumor response. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[27]  J. Lloberas,et al.  Role of the human concentrative nucleoside transporter (hCNT1) in the cytotoxic action of 5[Prime]-deoxy-5-fluorouridine, an active intermediate metabolite of capecitabine, a novel oral anticancer drug. , 2001, Molecular pharmacology.

[28]  D. Hedley,et al.  Equilibrative-sensitive nucleoside transporter and its role in gemcitabine sensitivity. , 2000, Cancer research.

[29]  C. A. Blau,et al.  Forced expression of cytidine deaminase confers resistance to cytosine arabinoside and gemcitabine. , 1996, Experimental hematology.

[30]  P. Wen,et al.  Viral vector transduction of the human deoxycytidine kinase cDNA sensitizes glioma cells to the cytotoxic effects of cytosine arabinoside in vitro and in vivo , 1996, Nature Medicine.

[31]  J. Laliberté,et al.  Kinetic studies on 2',2'-difluorodeoxycytidine (Gemcitabine) with purified human deoxycytidine kinase and cytidine deaminase. , 1993, Biochemical pharmacology.

[32]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.