Department of Medical Oncology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands.
Int J Oncol. 2010 Jan;36(1):285-94.
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.
为了克服因进入细胞受限而产生的耐药性，人们开发了在核苷 5'位连接脂肪酸链的阿糖胞苷（CP-4055，依拉他滨）和吉西他滨（CP-4126）的衍生物。CP-4055 显示出活性代谢物三磷酸酯的保留增加。这种特性可能有利于与微管蛋白拮抗剂多西他赛、铂类奥沙利铂和抗叶酸培美曲塞等药物联合应用。确定了 CP-4055 和 CP-4126 的细胞周期作用对与多西他赛或培美曲塞联合应用的疗效的影响。还在小鼠异种移植模型中评估了 CP-4055 与奥沙利铂和多西他赛的联合应用。CP-4055 诱导 G2/M 和 S 期积累，CP-4126 诱导 S 期积累。这两种类似物均诱导剂量依赖性细胞杀伤（凋亡和坏死）。多西他赛的联合应用没有诱导出协同作用。CP-4055 或 CP-4126 与多西他赛联合应用诱导 A549（肺癌）细胞系的 G2/M 积累，但诱导 WiDR（结肠癌）细胞系的 G0/G1 积累。预先用多西他赛孵育可在两种细胞系中增加细胞杀伤。与奥沙利铂的联合应用在两种细胞系中均显示出协同作用。与培美曲塞的联合应用在两种细胞系中均表现为拮抗作用。在 A549 细胞系中，CP-4055 与培美曲塞联合应用导致 G0/G1 期和 S 期增加。在 WiDR 中，CP-4055 与培美曲塞的联合应用增加了 G0/G1 期并增加了细胞杀伤。CP-4126 与培美曲塞联合应用可增加 A549 细胞系中的 G0/G1 期和 S 期。在异种移植研究中，在结肠癌和肺转移模型中，CP-4055 与多西他赛的联合应用显示出最佳效果。CP-4055 治疗后 4 小时再用多西他赛治疗可减少肺转移模型中的转移，并观察到有利的毒性谱。总之，联合奥沙利铂在联合研究中显示出协同作用。尽管 CP-4055 与多西他赛的联合应用在体外研究中没有显示出增强的效果，但这种联合应用在异种移植模型中显示出增强的效果。
