Induction of Resistance to the Lipophilic Cytarabine Prodrug Elacytarabine (CP-4055) in CEM Leukemic Cells

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,...

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Published in:Nucleosides, nucleotides & nucleic acids nucleotides & nucleic acids, 2010-06, Vol.29 (4-6), p.394-399
Main Authors: Adema, A. D., Losekoot, N., Smid, K., Kathmann, I., Myhren, F., Sandvold, M. L., Peters, G. J.
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Cell Line, Tumor
CP-4126
cytarabine
Cytarabine - analogs & derivatives
Cytarabine - pharmacology
Cytidine Deaminase
deoxycytidine
Deoxycytidine - analogs & derivatives
Deoxycytidine - pharmacology
Drug Resistance, Neoplasm - drug effects
elacytarabine
gemcitabine
Humans
Leukemia - enzymology
Leukemia - genetics
Nucleoside Deaminases - genetics
Nucleoside Deaminases - physiology
Polymerase Chain Reaction
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Summary: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 μM (10 times IC 50 ). The IC 50 of the resistant CEM/CP-4055 was 35 μM, about 1,000 times that of the wildtype CEM, and comparable to that of CEM/dCK- (deoxycytidine kinase deficient) (22 μM). CEM/CP-4055 was also cross-resistant to Ara-C, gemcitabine and CP-4126 (28 and 33 μM, 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.
ISSN:1525-7770
1532-2335
DOI:10.1080/15257771003741166