title: Metabolism and accumulation of the lipophilic deoxynucleoside analogs elacytarabine and CP-4126.
abstract: Cytarabine (ara-C) and gemcitabine (dFdC) are commonly used anticancer drugs, which depend on the equilibrative (ENT) and concentrative-nucleoside-transporters to enter the cell. To bypass transport-related drug resistance, lipophilic derivatives elacytarabine (CP-4055), ara-C-5'elaidic-acid-ester, and CP-4126, (CO 1.01) gemcitabine-5'elaidic-acid-ester, were investigated for the entry into the cell, distribution, metabolism and retention. The leukemic CEM-cell-line and its deoxycytidine-kinase deficient variant (CEM/dCK-) were exposed for 30 and 60 min to the radiolabeled drugs; followed by culture in drug-free medium in order to determine drug retention in the cell. The cellular fractions were analyzed with thin-layer-chromatography and HPLC. Elacytarabine and CP-4126 were converted to the parent compounds both inside and outside the cell (35-45%). The ENT-inhibitor dipyridamole did not affect their uptake or retention. Inside the cell Elacytarabine and CP-4126 predominantly localized in the membrane and cytosolic fraction, leading to a long retention after removal of the medium. In contrast, in cells exposed to the parent drugs ara-C and dFdC, intracellular drug concentration increased during exposure but decreased to undetectable levels after drug removal. In the dCK- cell line, no metabolism was observed. The concentrations of ara-CTP and dFdCTP reached a peak at the end of the incubation with the drugs, and decreased after drug removal; peak levels of dFdCTP were 35 times higher than ara-CTP and was retained better. In contrast, after exposure to elacytarabine or CP-4126, ara-CTP and dFdCTP levels continued to increase not only during exposure but also during 120 min after removal of the elacytarabine and CP-4126. Levels of ara-CTP and dFdCTP were higher than after exposure to the parent drugs. In conclusion, the lipophilic derivatives elacytarabine and CP-4126 showed a nucleoside-transporter independent uptake, with long retention of the active nucleotides. These lipophilic nucleoside analogues are new chemical entities suitable for novel clinical applications.
authors: Department of Medical Oncology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, the Netherlands.
authors: Auke D
authors: AD
authors: Adema
authors: Kees
authors: K
authors: Smid
authors: Nienke
authors: N
authors: Losekoot
authors: Richard J
authors: RJ
authors: Honeywell
authors: Henk M
authors: HM
authors: Verheul
authors: Finn
authors: F
authors: Myhren
authors: Marit L
authors: ML
authors: Sandvold
authors: Godefridus J
authors: GJ
authors: Peters
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D002460:Cell Line; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D003842:Deoxycytidine Kinase / Q000378:metabolism; D004176:Dipyridamole / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007938:Leukemia / Q000378:metabolism; D033703:Nucleoside Transport Proteins / Q000378:metabolism; D009708:Nucleotidases / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; C538828:CP 4126; D033703:Nucleoside Transport Proteins; D003561:Cytarabine; D003841:Deoxycytidine; C047645:5'-oleoyl cytarabine; D004176:Dipyridamole; D003842:Deoxycytidine Kinase; D009708:Nucleotidases; C028331:deoxynucleotidase; D000093542:Gemcitabine