Metabolism and accumulation of the lipophilic deoxynucleoside analogs elacytarabine and CP-4126

Autor: Richard J. Honeywell, A.D. Adema, Finn Myhren, Marit Liland Sandvold, Godefridus J. Peters, Nienke Losekoot, Henk M.W. Verheul, Kees Smid
Přispěvatelé: Medical oncology, Medical oncology laboratory, CCA - Innovative therapy
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Zdroj: Investigational New Drugs
Investigational New Drugs, 30(5), 1908-1916. Kluwer Academic Publishers
Adema, A D, Smid, K, Losekoot, N, Honeywell, R J, Verheul, H M W, Myhren, F, Sandvold, M & Peters, G J 2012, ' Metabolism and accumulation of the lipophilic deoxynucleoside analogs elacytarabine and CP-4126 ', Investigational New Drugs, vol. 30, no. 5, pp. 1908-1916 . https://doi.org/10.1007/s10637-011-9756-8
ISSN: 1573-0646
0167-6997
Popis: Summary 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.
Databáze: OpenAIRE
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