Cell cycle effects of fatty acid derivatives of cytarabine, CP-4055, and of gemcitabine, CP-4126, as basis for the interaction with oxaliplatin and docetaxel

Abstract

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.