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.