Mechanisms of Uptake and Resistance to Troxacitabine, a Novel Deoxycytidine Nucleoside Analogue, in Human Leukemic and Solid Tumor Cell Lines Henriette Gourdeau, Marilyn L. Clarke, France Ouellet, et al. Cancer Res 2001;61:7217-7224.
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[CANCER RESEARCH 61, 7217–7224, October 1, 2001]
Mechanisms of Uptake and Resistance to Troxacitabine, a Novel Deoxycytidine Nucleoside Analogue, in Human Leukemic and Solid Tumor Cell Lines Henriette Gourdeau,1,2 Marilyn L. Clarke,1 France Ouellet, Delores Mowles, Milada Selner, Annie Richard, Nola Lee, John R. Mackey, James D. Young,3 Jacques Jolivet, Ronald G. Lafrenie`re, and Carol E. Cass4 Shire BioChem Inc., Laval, Que´bec, H7V 4A7 Canada [H. G., F. O., A. R., N. L., J. J., R. G. L.]; Departments of Oncology [M. L. C., J. R. M., C. E. C.] and Physiology [J. D. Y.], University of Alberta, Alberta T6G 1Z2 Canada; and Cross Cancer Institute, Edmonton, Alberta T6G 1Z2 Canada [M. L. C., D. M., M. S., J. R. M., C. E. C.]
ABSTRACT Troxacitabine (Troxatyl; BCH-4556; (-)-2ⴕ-deoxy-3ⴕ-oxacytidine), a deoxycytidine analogue with an unusual dioxolane structure and nonnatural L-configuration, has potent antitumor activity in animal models and is in clinical trials against human malignancies. The current work was undertaken to identify potential biochemical mechanisms of resistance to troxacitabine and to determine whether there are differences in resistance mechanisms between troxacitabine, gemcitabine, and cytarabine in human leukemic and solid tumor cell lines. The CCRF-CEM leukemia cell line was highly sensitive to the antiproliferative effects of troxacitabine, gemcitabine, and cytarabine with inhibition of proliferation by 50% observed at 160, 20, and 10 nM, respectively, whereas a deoxycytidine kinase (dCK)-deficient variant (CEM/dCKⴚ) was resistant to all three drugs. In contrast, a nucleoside transport-deficient variant (CEM/ARAC8C) exhibited high levels of resistance to cytarabine (1150-fold) and gemcitabine (432-fold) but only minimal resistance to troxacitabine (7-fold). Analysis of troxacitabine transportability by the five molecularly characterized human nucleoside transporters [human equilibrative nucleoside transporters 1 and 2, human concentrative nucleoside transporter (hCNT) 1, hCNT2, and hCNT3] revealed that short- and long-term uptake of 10 –30 M [3H]troxacitabine was low and unaffected by the presence of either nucleoside transport inhibitors or high concentrations of nonradioactive troxacitabine. These results, which suggested that the major route of cellular uptake of troxacitabine was passive diffusion, demonstrated that deficiencies in nucleoside transport were unlikely to impart resistance to troxacitabine. A troxacitabine-resistant prostate cancer subline (DU145R; 6300-fold) that exhibited reduced uptake of troxacitabine was crossresistant to both gemcitabine (350-fold) and cytarabine (300-fold). dCK activity toward deoxycytidine in DU145R cell lysates was
