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Departments of Medical Oncology [J. R. K., W. J. P. L., C. L. v. d. W., E. B., C. J. v. G., H. M. P., G. J. P.], and Head and Neck Surgery [B. J. M. B.], VU University Medical Center, Amsterdam, 1007 MB The Netherlands; Eli Lilly Research Laboratories, Indianapolis, Indiana 46285 [E. A.]; and Institute for Molecular Biology, 71110 Heraklion, Crete, Greece [I. T.]

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 ( = -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 ( = -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 ( = 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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