Edelstein M P, Wolfe L A, Duch D S
Division of Cell Biology, Wellcome Research Laboratories, Research Triangle Park, NC, USA.
Semin Oncol. 1996 Apr;23(2 Suppl 5):41-7.
Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Medicament, Paris, France), a semisynthetic vinca alkaloid that is a potent inhibitor of mitotic microtubule polymerization, was recently approved for the treatment of non-small cell lung cancer. Radiotherapy also has been widely used to treat this malignancy. Since other antitumor agents that act on microtubules, such as paclitaxel and estramustine, have been shown to act as radiosensitizers, we studied the ability of vinorelbine to potentiate radiation. The in vitro activity of this combination was evaluated in the human lung carcinoma cell lines NCI-H460 and A549. when NCI-H460 cells were exposed to vinorelbine for 24 hours and then irradiated (1 to 6 Gy) the drug potentiated radiation in a dose-dependent manner, with the ratio of fractional survival (radiation) to fractional survival (drug plus radiation) ranging from 1.7:1 at 1 Gy to 5.5:1 at 6 Gy. When the treatment sequence was reversed (ie, radiation was followed by drug exposure), similar survival ratios were obtained at concentrations of vinorelbine that were five to 10 times lower. In this cell line radiation produced a block in the G2/M phase of the cell cycle, with the maximum block (60% to 70%) occurring 10 hours after treatment. The greatest potentiation was seen when irradiated cells were exposed to vinorelbine after they had plateaued in the G2/M phase of the cycle. Vinorelbine given early after irradiation, when only 10% to 30% of the cells were in G2/M, produced survival ratios similar to those of controls treated with radiation alone. In A549 cells radiation induced a G1 block. In this case, vinorelbine was unable to potentiate the effects of radiation. These studies show that vinorelbine can potentiate the antitumor effects of radiation and that the potentiation is cell cycle-dependent, with the maximal effect being obtained when the cells are in the G2 phase.
长春瑞滨（诺维本；百时美施贵宝公司，北卡罗来纳州三角研究园；法国巴黎皮尔法伯制药公司）是一种半合成长春花生物碱，是有丝分裂微管聚合的有效抑制剂，最近被批准用于治疗非小细胞肺癌。放射疗法也已广泛用于治疗这种恶性肿瘤。由于其他作用于微管的抗肿瘤药物，如紫杉醇和雌莫司汀，已被证明可作为放射增敏剂，我们研究了长春瑞滨增强放疗效果的能力。在人肺癌细胞系NCI-H460和A549中评估了这种联合用药的体外活性。当NCI-H460细胞暴露于长春瑞滨24小时后再进行照射（1至6 Gy）时，该药物以剂量依赖的方式增强放疗效果，存活分数（放疗）与存活分数（药物加放疗）之比在1 Gy时为1.7:1，在6 Gy时为5.5:1。当治疗顺序颠倒时（即先放疗后药物暴露），在长春瑞滨浓度低五至十倍的情况下可获得相似的存活比率。在该细胞系中，放疗使细胞周期阻滞于G2/M期，最大阻滞（60%至70%）出现在治疗后10小时。当处于细胞周期G2/M期平台期的照射细胞暴露于长春瑞滨时，增强效果最为明显。放疗后早期给予长春瑞滨，此时只有10%至30%的细胞处于G2/M期，其产生的存活比率与单独接受放疗的对照组相似。在A549细胞中，放疗诱导G1期阻滞。在这种情况下，长春瑞滨无法增强放疗效果。这些研究表明，长春瑞滨可增强放疗的抗肿瘤效果，且这种增强作用依赖于细胞周期，当细胞处于G2期时可获得最大效果。
