Differential metabolism and accumulation of the lipophilic deoxynucleoside analogs elacytarabine and CP-4126
01 / 2011 - onbekend
Cytarabine and gemcitabine 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, 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 minutes to the radiolabeled drugs; followed by a retention period. The cellular fractions were analyzed with thin-layer-chromatography and HPLC. The derivatives were converted to the parent compounds both inside and outside the cell (35-45%). The ENT-inhibitor dipyridamole did not affect uptake or retention of the derivatives. Inside the cell the derivatives were predominantly located 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, 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 n incubation with the drugs, and decreased after drug removal; dFdCTP was 35 times higher than ara-CTP and was retained better. In contrast, ara-CTP and dFdCTP levels continued to increase for 120 minutes after removal of the elacytarabine and CP-4126. 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.