Gomi K, Ohno H, Nomura K, Okabe M, Kobayashi K, Niitani H
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka-ken.
Jpn J Cancer Res. 1992 May;83(5):532-9. doi: 10.1111/j.1349-7006.1992.tb01961.x.
The combination effect of navelbine (NVB, KW-2307), a newly synthesized vinca alkaloid, and cisplatin (CDDP) was compared with that of vindesine (VDS) and CDDP using human lung adenocarcinoma PC-12 cells. The growth-inhibitory activity of NVB or VDS was time-dependent, whereas that of CDDP was AUC (area under the curve)-dependent. When NVB or VDS was used in combination with CDDP simultaneously for 24 h, antagonism was observed in terms of growth-inhibitory activity. However, additive combination effect was observed when NVB or VDS treatment was followed by CDDP treatment. On this treatment schedule, a synergistic combination effect was observed in terms of the cell-killing activity assessed by colony formation assay. The growth-inhibitory activity of NVB or VDS was detected 24 h after the treatment, whereas that of CDDP became significant 72 h after the treatment. NVB and VDS caused cell accumulation in G2M phase at 10 times their IC80 values, and cells with less than diploid DNA content were detected after 24 h at IC80. CDDP caused accumulation of cells in S phase, and the effect became detectable 16 h after the treatment. The DNA histogram of cells treated with NVB or VDS in combination with CDDP was a superposition of those of cells treated with each drug alone. Significant differences in the characteristics of anticellular activity were not detected between NVB and VDS, although NVB inhibited cell growth at a slightly lower concentration than VDS at the short exposure time of 1-8 h.
使用人肺腺癌细胞PC - 12，比较了新合成的长春花生物碱去甲长春花碱（NVB，KW - 2307）与顺铂（CDDP）的联合效应以及长春地辛（VDS）与CDDP的联合效应。NVB或VDS的生长抑制活性呈时间依赖性，而CDDP的生长抑制活性呈曲线下面积（AUC）依赖性。当NVB或VDS与CDDP同时使用24小时时，在生长抑制活性方面观察到拮抗作用。然而，当NVB或VDS治疗后再进行CDDP治疗时，观察到相加联合效应。按照这种治疗方案，通过集落形成试验评估的细胞杀伤活性方面观察到协同联合效应。NVB或VDS的生长抑制活性在治疗后24小时检测到，而CDDP的生长抑制活性在治疗后72小时变得显著。NVB和VDS在其IC80值的10倍浓度时导致细胞在G2M期积累，并且在IC80浓度下24小时后检测到DNA含量低于二倍体的细胞。CDDP导致细胞在S期积累，并且在治疗后16小时可检测到该效应。用NVB或VDS与CDDP联合处理的细胞的DNA直方图是单独用每种药物处理的细胞的DNA直方图的叠加。尽管在1 - 8小时的短暴露时间下NVB比VDS以略低的浓度抑制细胞生长，但在NVB和VDS之间未检测到抗细胞活性特征的显著差异。
