cp-4126 and 5--oleoyl-cytarabine

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.

Topics: Antineoplastic Agents; Cell Line; Cytarabine; Deoxycytidine; Deoxycytidine Kinase; Dipyridamole; Drug Resistance, Neoplasm; Gemcitabine; Humans; Leukemia; Nucleoside Transport Proteins; Nucleotidases

The clinical activity of pyrimidine analogues (araC and gemcitabine) is impaired by different mechanisms of resistance and several efforts to overcome this problem have been undertaken. Elacytarabine (CP-4055, araC-5'elaidic acid ester) and CP-4126 (gemcitabine-5'elaidic acid ester) are lipophilic fatty acid derivatives of the nucleoside analogues araC and gemcitabine, respectively, that are currently investigated in clinical trials in solid tumors and hematological malignancies. Here, we present results on the activity of elacytarabine and CP-4126 in a panel of tumor cell lines that are resistant to araC and gemcitabine and we discuss the potential use of these agents in the treatment of patients with drug resistance phenotypes. We conclude that elacytarabine and CP-4126 are active in cells with deficient nucleoside membrane transport and altered mismatch repair. These results should be taking into consideration for future clinical development of elacyatrabine and CP-4126.

Topics: Antineoplastic Agents; Caco-2 Cells; Cell Line, Tumor; Cytarabine; Deoxycytidine; Drug Resistance, Neoplasm; HT29 Cells; Humans; Pyrimidines

To bypass resistance due to limited entry into the cell derivatives of cytarabine (CP-4055, elacytarabine) and gemcitabine (CP-4126) containing a fatty acid chain at the 5' position of the nucleoside were developed. CP-4055 showed an increased retention of the active metabolite, the triphosphate. This characteristic was supposed to favor combinations, such as with the tubulin antagonist docetaxel, the platinum oxaliplatin and the antifolate pemetrexed. The role of the cell cycle effects of CP-4055 and CP-4126 on the efficacy of the combination with docetaxel or pemetrexed was determined. The combination of CP-4055 with oxaliplatin and docetaxel was also evaluated in a mouse xenograft model. CP-4055 induced a G2/M and S phase accumulation and CP-4126 an S phase accumulation. Both analogs induced a dose-dependent cell kill (apoptosis and necrosis). None of the docetaxel combinations induced a synergistic effect. The combination of docetaxel with CP-4055 or CP-4126 induced a G2/M accumulation in the A549 (lung cancer) cell line, but a G0/G1 accumulation in the WiDR (colon cancer) cell line. Preincubation with docetaxel induced an increased cell kill in both cell lines. The combination with oxaliplatin showed a synergistic effect in both cell lines. Combinations with pemetrexed were antagonistic in both cell lines. In the A549 cell line pemetrexed with CP-4055 led to an increase of the G0/G1 phase and the S phase. In WiDR the combination of pemetrexed with CP-4055 increased the G0/G1 phase and increased the cell kill. Pemetrexed with CP-4126 induced an increase in the G0/G1 phase and the S phase in the A549 cell line. In the xenograft study, on a colon cancer and a lung metastasis model, the combination of CP-4055 with docetaxel showed the best results. Treatment with CP-4055 followed by docetaxel after 4 h resulted in a reduction in metastasis in a lung metastasis model, and a favorable toxicity profile was observed. In conclusion, the combinations with oxaliplatin showed a synergistic effect in the combination studies. Although the combinations with docetaxel did not show an enhanced effect in the in vitro studies, this combination revealed an increased effect in the xenograft model.

Topics: Animals; Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Chemistry, Pharmaceutical; Cytarabine; Deoxycytidine; Docetaxel; Drug Design; Drug Screening Assays, Antitumor; Fatty Acids; Humans; Inhibitory Concentration 50; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Organoplatinum Compounds; Oxaliplatin; Taxoids

Topics: Cell Line, Tumor; Cell Membrane; Cytarabine; Deoxycytidine; Drug Resistance, Neoplasm; Gemcitabine; Humans; Lymphoma