Pyrrolidinedithiocarbamate increases the therapeutic index of 5-fluorouracil in a mouse model
Pyrrolidinedithiocarbamate increases the therapeutic index of 5-fluorouracil in a mouse model
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DOI：
10.1016/s0016-5085(00)70416-1
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发表时间：
2000-01-01
期刊：
影响因子：
29.4
通讯作者：
Watson, AJM
中科院分区：
文献类型：
--
作者：
Bach, SP;Chinery, R;Watson, AJM
背景与目的：含硫醇的抗氧化剂吡咯烷二硫代氨基甲酸酯（PDTC）在体内外均能增强5-氟尿嘧啶（5-FU）对人大肠癌细胞株的细胞毒作用。这一过程似乎是由p21表达的持续增加介导的，独立于p53的功能，导致生长停滞和细胞凋亡。我们确定了PDTC是否增强了5-FU在非荷瘤小鼠中的肠道毒性。方法：在给予5-FU （40 mg/kg）和PDTC (250 mg/kg) 72小时内，每隔一段时间测量小肠和大肠细胞位置上的凋亡和有丝分裂指数。测定5-FU （600 ~ 1200 mg/kg）和PDTC （500 mg/kg）处理后隐窝再生的比例。结果：5-FU治疗可诱导大量凋亡细胞死亡，同时抑制小肠和大肠上皮内有丝分裂活性。PDTC使5-FU诱导的结肠凋亡事件减少49%，主要发生在克隆源干细胞和转运细胞中，同时促进有丝分裂活性的早期恢复，因此，PDTC增加了5-FU治疗后再生结肠隐窝的比例。然而，PDTC没有显著调节5-FU在小肠中的毒性。结论：PDTC并未增加5-FU的肠道毒性，反而起到了保护结肠黏膜的作用。这些结果支持进一步研究PDTC及其相关化合物作为结直肠癌的治疗方法。
Background & Aims: The thiol-containing antioxidant pyrrolidinedithiocarbamate (PDTC) enhances the cytotoxic efficacy of 5-fluorouracil (5-FU) against human colorectal cancer cell lines in vitro and in vivo. This process appears to be mediated by a sustained increase in p21 expression, independent of p53 function, resulting in growth arrest and apoptosis, We determined whether PDTC augmented 5-FU intestinal toxicity in non-tumor-bearing mice. Methods: Apoptotic and mitotic indices were measured in the small and large intestine on a cell positional basis at intervals throughout the 72-hour period after administration of 5-FU (40 mg/kg) and PDTC (250 mg/kg). The proportion of crypts regenerating after 5-FU (600-1200 mg/kg) and PDTC (500 mg/kg) was also measured, Results: 5-FU therapy induces substantial apoptotic cell death with simultaneous inhibition of mitotic activity within the small and large intestinal epithelium. PDTC reduces 5-FU-induced apoptotic events in the colon by 49%, predominantly among clonogenic stem and transit cells while promoting the early recovery of mitotic activity, As a consequence, PDTC increased the proportion of regenerating colonic crypts after 5-FU therapy. PDTC did not, however, significantly modulate 5-FU toxicity in the small intestine. Conclusions: PDTC does not augment the intestinal toxicity of 5-FU and actually protects the colonic mucosa. These results support further investigation of PDTC and related compounds as treatments for colorectal cancer.