The deoxynucleoside analogs
cytarabine (
Ara-C) and
gemcitabine (dFdC) are widely used in the treatment of
cancer. Due to their hydrophilic nature they need the equilibrative (hENT) and concentrative (hCNT)
nucleoside transporters to enter the cell. To bypass drug resistance due to decreased uptake, lipophilic 5'
elaidic acid esters were synthesized,
elacytarabine (CP-4055, from ara-C) and
CP-4126 (from
gemcitabine), which are currently in clinical development for solid and hematological
tumors. We investigated whether resistance can be induced in vitro, and treated the CEM leukemic cell line with weekly increasing
elacytarabine concentrations, up to 0.28 microM (10 times IC(50)). The IC(50) of the resistant CEM/
CP-4055 was 35 microM, about 1,000 times that of the wildtype CEM, and comparable to that of CEM/dCK- (
deoxycytidine kinase deficient) (22 microM). CEM/
CP-4055 was also cross-resistant to
Ara-C,
gemcitabine and
CP-4126 (28 and 33 microM, respectively). A low level of
mRNA dCK was observed, and similar to CEM/dCK-, CEM/
CP-4055 did not accumulate
Ara-CTP after exposure to
Ara-C or
elacytarabine, which is consistent with a deficiency in dCK. In conclusion,
elacytarabine induced resistance similar to
Ara-C. This resistance was caused by downregulation of dCK.