TY - JOUR
T1 - Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity
AU - Kroep, Judith R.
AU - Loves, Willem J P
AU - Van Der Wilt, Clasina L.
AU - Alvarez, Enrique
AU - Talianidis, Iannis
AU - Boven, Epie
AU - Braakhuis, Boudewijn J M
AU - Van Groeningen, Cornelis J.
AU - Pinedo, Herbert M.
AU - Peters, Godefridus J.
PY - 2002/4
Y1 - 2002/4
N2 - 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 (ρ = -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 (ρ = -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 (ρ = 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.
AB - 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 (ρ = -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 (ρ = -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 (ρ = 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.
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M3 - Article
C2 - 12477049
AN - SCOPUS:0002831066
SN - 1535-7163
VL - 1
SP - 371
EP - 376
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 6
ER -