Combination of γ-radiation antagonizes the cytotoxic effects of vincristine and vinblastine on both mitotic arrest and apoptosis
Combination of γ-radiation antagonizes the cytotoxic effects of vincristine and vinblastine on both mitotic arrest and apoptosis
复制标题
DOI：
10.1016/j.ijrobp.2004.12.028
复制
发表时间：
2005-03-15
影响因子：
7
通讯作者：
Fan, WM
中科院分区：
文献类型：
--
作者：
Sui, MH;Fan, WM
目的：不同方式的联合治疗是癌症治疗中的常见做法。长春新碱和长春碱的前景广阔的临床特征引起了人们对将这些长春花生物碱与放射治疗结合起来治疗各种实体瘤的极大兴趣。然而，治疗效果和长春花生物碱与辐射之间的相互作用尚不完全清楚。在这项研究中，我们评估了潜在的相互作用，长春新碱或长春碱与γ-辐射对人类肿瘤cells in vitro.Methods和Materials的组合：长春新碱或长春碱和γ-辐射在三个不同的序列，设计为预辐射，共辐射，和postradiated组合在人乳腺癌细胞和人表皮样癌细胞。通过细胞毒性、形态学和生化检查等一系列试验，分析了这两种方式之间的细胞毒性相互作用和相互影响。结果：我们的研究结果表明，这两种方式的结合并没有产生任何协同或相加效应。相反，克隆形成试验显示，这些组合的存活率分别是长春新碱或长春碱单独治疗的存活率的2.17倍和2.7倍（p < 0.01）。DNA片段化、T α T介导的dUTP缺口末端标记（TUNEL）测定和流式细胞术测定也表明，γ-辐射的组合显著干扰了这些长春花生物碱诱导细胞凋亡的能力。进一步的分析表明，添加γ-辐射导致细胞周期停滞在G1期，这随后阻止了长春新碱或长春碱诱导的有丝分裂停滞。结论：γ射线可使细胞周期阻滞于G（2）期，从而干扰长春新碱或长春碱的细胞毒作用，抑制I kappa B α降解和bcl-2磷酸化。因此，它最终导致这两种模式之间的对抗性相互作用。这一发现可能与长春花生物碱和放射联合治疗的临床应用有关。(c)2005年爱思唯尔公司
Purpose: Combination therapy with different modalities is a common practice in the treatment of cancer. The promising clinical profile of vincristine and vinblastine has promoted considerable interest in combining these vinca alkaloids with radiation therapy to treat a variety of solid tumors. However, the therapeutic efficacy and the interaction between the vinca alkaloids with radiation is not entirely clear. In this study, we assessed the potential interactions in the combination of vincristine or vinblastine with gamma-radiation against human tumor cells in vitro.Methods and Materials: Vincristine or vinblastine and gamma-radiation were administrated at three different sequences designed as preradiated, coradiated, and postradiated combinations in human breast cancer cells and human epidermoid carcinoma cells. The cytotoxic interactions and mutual influences between these two modalities were analyzed by a series of assays including cytotoxic, morphologic, and biochemical examinations.Results: Our results showed that the combination of these two modalities did not produce any synergistic or additive effects. Instead, the clonogenic assays showed the survival rates of these combinations were increased up to 2.17-fold and 2.7-fold, respectively, of those treated with vincristine or vinblastine alone (p < 0.01). DNA fragmentation, T alpha T-mediated dUTP nick end labeling (TUNEL) assay, and flow cytometric assays also showed that the combination of gamma-radiation significantly interfered with the ability of these vinca alkaloids to induce apoptosis. Further analyses indicated that addition of gamma-radiation resulted in cell cycle arrest at the G, phase, which subsequently prevented the mitotic arrest induced by vincristine or vinblastine. In addition, biochemical examinations revealed that y-radiation regulated p34(cdc2)/CyClin B1 and survivin, and inhibited I kappa B alpha degradation and bcl-2 phosphoryllation.Conclusions: These results suggest that y-radiation might specifically block the cell cycle at the G(2) phase, which in turn interferes with the cytotoxic effects of vincristine or vinblastine on mitotic arrest and apoptosis. Thereby, it eventually results in an antagonistic interaction between these two modalities. This finding may be implicated in the clinical application of combination therapy of vinca alkaloids and radiation. (c) 2005 Elsevier Inc.