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Specific, reversible G1 arrest by UCN-01 in vivo provides cytostatic protection of normal cells against cytotoxic chemotherapy in breast cancer.
British Journal of Cancer ( IF 6.4 ) Pub Date : 2020-01-16 , DOI: 10.1038/s41416-019-0707-z
Benjamin B Mull 1 , J Andrew Livingston 2 , Nalini Patel 1 , Tuyen Bui 1 , Kelly K Hunt 3 , Khandan Keyomarsi 1
Affiliation  

BACKGROUND Low-dose UCN-01 mediates G1 arrest in normal proliferating cell lines with an intact G1 to S transition but not tumour cells with a deregulated G1 to S checkpoint. Here we hypothesised that UCN-01 is effective in mediating a selective, reversible G1 arrest of normal proliferating cells, resulting in decreased chemotoxicity, improved tolerance and enhanced chemotherapeutic efficacy in vivo in both non-tumour-bearing mice and in breast cancer cell line xenograft models. METHODS Murine small bowel epithelium was used to examine the kinetics and mechanism of low-dose UCN-01-mediated arrest of normal proliferating cells and if it can protect tumour-bearing mice (MDA-MB-468 xenografts) against the toxic effects of chemotherapy (5-fluorouricil (5-FU)) allowing for its full therapeutic activity. RESULTS UCN-01 causes significant, reversible arrest of normal gut epithelial cells at 24 h; this arrest persists for up to 7 days. Normal cellular proliferation returns by 2 weeks. Pre-treatment of both non-tumour-bearing and MDA-MB-468 tumour-bearing mice with UCN-01 prior to bolus 5-FU (450 mg/kg) yielded enhanced therapeutic efficacy with significantly decreased tumour volumes and increased survival. CONCLUSIONS UCN-01 mediates a specific, reversible G1 arrest of normal cells in vivo and provides a cytoprotective strategy that decreases toxicity of cytotoxic chemotherapy without compromising efficacy.

中文翻译:


UCN-01 在体内特异性、可逆的 G1 期阻滞为正常细胞提供了细胞抑制保护,使其免受乳腺癌细胞毒性化疗的影响。



背景低剂量 UCN-01 介导具有完整 G1 至 S 转变的正常增殖细胞系的 G1 期阻滞,但不介导 G1 至 S 检查点失调的肿瘤细胞。在此,我们假设 UCN-01 可有效介导正常增殖细胞的选择性、可逆性 G1 期停滞,从而在非荷瘤小鼠和乳腺癌细胞系异种移植物中降低化疗毒性、改善耐受性并增强体内化疗效果模型。方法使用小鼠小肠上皮来检查低剂量 UCN-01 介导的正常增殖细胞停滞的动力学和机制,以及它是否可以保护荷瘤小鼠(MDA-MB-468 异种移植物)免受化疗的毒性作用(5-氟尿嘧啶(5-FU))使其具有完整的治疗活性。结果 UCN-01 在 24 小时时引起正常肠道上皮细胞显着的、可逆的停滞;这次逮捕持续长达 7 天。两周后细胞增殖恢复正常。在推注 5-FU (450 mg/kg) 之前用 UCN-01 对非荷瘤小鼠和 MDA-MB-468 荷瘤小鼠进行预处理,可增强治疗效果,显着减小肿瘤体积并提高存活率。结论 UCN-01 介导体内正常细胞的特异性、可逆性 G1 期阻滞,并提供了一种细胞保护策略,可降低细胞毒性化疗的毒性而不影响疗效。
更新日期:2020-01-16
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