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.
Funamizu
Naotake
N
Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan. funamizu@jikei.ac.jp
Okamoto
Aikou
A
Kamata
Yuko
Y
Misawa
Takeyuki
T
Uwagawa
Tadashi
T
Gocho
Takeshi
T
Yanaga
Katsuhiko
K
Manome
Yoshinobu
Y
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics*; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003564:Cytidine Deaminase; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003842:Deoxycytidine Kinase / Q000037:antagonists & inhibitors / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D009700:Nucleoside Deaminases / Q000235:genetics / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D013767:Tetrahydrouridine / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation / Q000502:physiology; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D013767:Tetrahydrouridine; D003842:Deoxycytidine Kinase; D009700:Nucleoside Deaminases; D003564:Cytidine Deaminase; C011530:deoxycytidine deaminase; D000093542:Gemcitabine