Ypsilantis Petros, Tentes Ioannis, Assimakopoulos Stelios F, Kortsaris Alexandros, Scopa Chrisoula D, Simopoulos Constantinos
Laboratory of Experimental Surgery, School of Medicine, Democritus University of Thrace, 68 100 Alexandroupolis, Greece.
J Surg Res. 2004 Sep;121(1):84-91. doi: 10.1016/j.jss.2004.03.003.
Cancer chemotherapy may lead to mucositis, a serious dose-limiting side effect. The alkylating agent ifosfamide is used in the treatment of various forms of cancer in combination with the uroprotective thiol mesna (2-mercaptoethane-sulfonate). The aims of this study were to assess the dose response intestinal mucosa damage of ifosfamide and to investigate the potential protective effect of mesna on rabbit intestinal epithelium.
Fifty New Zealand White rabbits were randomly assigned to 10 groups of five animals each and received intravenously every week for 10 weeks either normal saline, ifosfamide, mesna, or ifosfamide plus mesna at three escalating dose levels (ifosfamide: 30, 45, or 60 mg/kg; mesna: 12, 18, or 24 mg/kg divided into two equal doses administered 4 h apart). Intestinal mucosa damage was assessed on the basis of crypt cell apoptosis and proliferation as well as intestinal morphometry. Apoptosis was detected by agarose gel electrophoresis and quantified by the DNA fragmentation assay and a standard terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) method by which the percentage of fragmented DNA and the apoptotic index were determined, respectively. The mitotic index and the crypt-villus (c/v) unit height were also measured in histological sections.
Ifosfamide caused a dose-related increase of crypt cell apoptosis and shortening of c/v unit, while it had a steady antimitotic effect. Mesna as a sole agent had no apoptotic or trophic effect on intestinal mucosa and hence no effect on intestinal morphometry. However, mesna, when administered concurrently with ifosfamide, ameliorated apoptosis, hypoproliferation, and mucosal atrophy at a dose-related manner.
Ifosfamide causes intestinal mucosa damage, which may be ameliorated in a dose-related manner by coadministration of mesna.
癌症化疗可能导致黏膜炎，这是一种严重的剂量限制性副作用。烷化剂异环磷酰胺与尿路保护剂硫乙磺酸钠（2-巯基乙烷磺酸盐）联合用于治疗各种癌症。本研究的目的是评估异环磷酰胺对肠黏膜损伤的剂量反应，并研究硫乙磺酸钠对兔肠上皮的潜在保护作用。
50只新西兰白兔随机分为10组，每组5只，每周静脉注射10周，分别给予生理盐水、异环磷酰胺、硫乙磺酸钠或异环磷酰胺加硫乙磺酸钠，剂量分三个递增水平（异环磷酰胺：30、45或60mg/kg；硫乙磺酸钠：12、18或24mg/kg，分为两个等份剂量，间隔4小时给药）。根据隐窝细胞凋亡和增殖以及肠道形态学评估肠黏膜损伤。通过琼脂糖凝胶电泳检测凋亡，并通过DNA片段化分析和标准的末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸生物素缺口末端标记（TUNEL）方法进行定量，分别测定片段化DNA的百分比和凋亡指数。还在组织学切片中测量有丝分裂指数和隐窝-绒毛（c/v）单位高度。
异环磷酰胺导致隐窝细胞凋亡剂量相关增加和c/v单位缩短，同时具有稳定的抗有丝分裂作用。硫乙磺酸钠作为单一药物对肠黏膜没有凋亡或营养作用，因此对肠道形态学没有影响。然而，硫乙磺酸钠与异环磷酰胺同时给药时，以剂量相关方式改善了凋亡、增殖低下和黏膜萎缩。
异环磷酰胺导致肠黏膜损伤，联合使用硫乙磺酸钠可按剂量相关方式改善这种损伤。
