Role of p53 in irinotecan-induced intestinal cell death and mucosal damage
Role of p53 in irinotecan-induced intestinal cell death and mucosal damage
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DOI：
10.1097/cad.0b013e328010ef29
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发表时间：
2007-02-01
影响因子：
2.3
通讯作者：
Keefe, Dorothy M. K.
中科院分区：
文献类型：
--
作者：
Bowen, Joanne M.;Gibson, Rachel J.;Keefe, Dorothy M. K.
伊立替康治疗结直肠癌导致大部分患者发生高度肠粘膜炎。然而，伊立替康诱导的粘膜损伤背后的机制尚未得到充分解释。本研究的目的是研究p53蛋白在两种不同情况下伊立替康治疗后肠损伤发作中的作用。IEC-6和FH 74肠细胞系用伊立替康处理，有和没有临时p53抑制剂pifithrin-alpha，并检查增殖和存活沿着p53和相关蛋白表达的变化。40只荷瘤大鼠也接受了伊立替康治疗（含和不含pifithrin-a），并评估了对肠道形态学、基因表达、细胞凋亡和其他毒性的影响。伊立替康引起细胞活力的剂量依赖性降低，这在两种细胞系中均未被匹非亭-a阻止。大鼠对伊立替康的反应包括腹泻、体重减轻、小肠和大肠的组织病理学变化、隐窝细胞凋亡增加和轻度炎症反应。匹非他林-a降低了肠细胞凋亡的严重程度和持续时间;然而，它并没有显着影响其他参数，包括p53表达。暂时抑制p53活化不能显著预防伊立替康治疗后的肠细胞死亡或粘膜炎。伊立替康可能通过上调促凋亡蛋白Bax和巴克诱导细胞死亡发挥作用。
Irinotecan treatment of colorectal cancers results in high-grade intestinal mucositis in a large proportion of patients. The mechanisms behind irinotecan-induced mucosal injury, however, have yet to be fully explained. The aim of this study was to investigate the role of the p53 protein in the onset of intestinal damage following irinotecan treatment in two different settings. IEC-6 and FHs 74 intestinal cell lines were treated with irinotecan with and without a temporary p53 inhibitor, pifithrin-alpha, and examined for changes in proliferation and survival along with expression of p53 and related proteins. Forty tumour-bearing rats also underwent irinotecan treatment with and without pifithrin-a, and the effects on intestinal morphology, gene expression, apoptosis and other toxicities were assessed. Irinotecan caused a dose-dependent reduction in cell viability that was not prevented by pifithrin-a in either cell line. Rats responded to irinotecan with diarrhoea, weight loss, histopathological changes to the small and large intestine, increased crypt apoptosis, and a mild inflammatory response. Pifithrin-a reduced severity and duration of intestinal apoptosis; however, it did not significantly affect other parameters including p53 expression. Temporary inhibition of p53 activation does not markedly prevent intestinal cell death or mucositis following irinotecan treatment. Irinotecan may act through upregulation of proapoptotic proteins Bax and Bak to induce cell death.