Metabolism and accumulation of the lipophilic deoxynucleoside analogs elacytarabine and CP-4126.
Metabolism and accumulation of the lipophilic deoxynucleoside analogs elacytarabine and CP-4126.
复制标题
DOI：
10.1007/s10637-011-9756-8
复制
发表时间：
2012-10
影响因子：
3.4
通讯作者：
Peters, Godefridus J.
中科院分区：
文献类型：
--
作者：
Adema, Auke D.;Smid, Kees;Losekoot, Nienke;Honeywell, Richard J.;Verheul, Henk M.;Myhren, Finn;Sandvold, Marit L.;Peters, Godefridus J.
关键词：
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.
登录
查看更多内容
影响因子：
3.4
作者：
Bergman, Andries M.;Adema, Auke D.;Balzarini, Jan;Bruheim, Skjalg;Fichtner, Iduna;Noordhuis, Paul;Fodstad, Oystein;Myhren, Finn;Sandvold, Marit L.;Hendriks, Hans R.;Peters, Godefridus J.
通讯作者：
Peters, Godefridus J.
影响因子：
5.8
作者：
Ramalingam, Suresh;Belani, Chandra
通讯作者：
Belani, Chandra
影响因子：
5.2
作者：
Adema, A. D.;Laan, A. C.;Peters, G. J.
通讯作者：
Peters, G. J.
影响因子：
1.3
作者：
Bergman, AM;Kuiper, CM;Peters, GJ
通讯作者：
Peters, GJ
影响因子：
2.7
作者：
Noordhuis, P;Kazemier, KM;Peters, GJ
通讯作者：
Peters, GJ