Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity.
Deoxycytidine kinase (dCK) is essential for the phosphorylation of gemcitabine (2',2'-difluorodeoxycytidine), a deoxycytidine analogue active against various solid tumors. Cytidine deaminase (CDA) catalyzes the degradation of gemcitabine. We determined whether dCK and/or CDA levels would predict response to gemcitabine. Activities of dCK and CDA were measured in a panel of eight gemcitabine-sensitive and -resistant tumors of a different origin (pancreas, lung, colon, ovary, and head and neck) grown as s.c. tumors in mice. Sensitivity to gemcitabine was expressed as treated versus control (tumor volume treated mice/control mice). Gemcitabine was given on days 0, 3, 6, and 9 (q3dx4) at its maximum tolerated dose. In addition, we measured the mRNA expression and protein levels of dCK in seven human tumor xenografts. dCK activity (mean +/- SE) ranged from 3.3+/-0.3 to 18.4+/-1.2 nmol/h/mg protein. Sensitivity to gemcitabine, expressed as treated versus control, ranged from 0.98 to 0.02, and the activity of CDA varied from 2+/-2 to 411+/-4 nmol/h/mg protein. In contrast to CDA, dCK activity was clearly related to gemcitabine sensitivity (p = -0.93; P < 0.001). This indicates that dCK might be an important prognostic marker for gemcitabine sensitivity. Protein levels were significantly related to both dCK activity (r = 0.96; P < 0.001) and gemcitabine sensitivity (rho = -0.96; P < 0.001). dCK expression as determined by competitive template reverse transcriptase PCR was significantly related with the dCK activity (r = 0.88; P = 0.025) and protein levels (p = 0.80; P = 0.052) but not with gemcitabine sensitivity, suggesting a post-translational regulation of dCK. In conclusion, the clear correlation between dCK levels and gemcitabine sensitivity in various murine tumors and human tumor xenografts may be a prognostic parameter when considering gemcitabine therapy.
Kroep
Judith R
JR
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Loves
Willem J P
WJ
van der Wilt
Clasina L
CL
Alvarez
Enrique
E
Talianidis
Iannis
I
Boven
Epie
E
Braakhuis
Boudewijn J M
BJ
van Groeningen
Cornelis J
CJ
Pinedo
Herbert M
HM
Peters
Godefridus J
GJ
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D015153:Blotting, Western; D003564:Cytidine Deaminase / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D003842:Deoxycytidine Kinase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D017931:DNA Primers; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D003841:Deoxycytidine; D003842:Deoxycytidine Kinase; D003564:Cytidine Deaminase; D000093542:Gemcitabine