三氧化二砷联合5-氟尿嘧啶抗裸鼠人结肠癌移植瘤的作用及其机制的研究

Study on anti-tumor effect of arsenic trioxide combined with 5-fluorouracil on human colon carcinoma in nude mouse and its mechanism

目的探讨三氧化二砷(A s2O3)联合5-氟尿嘧啶(5-FU)对裸鼠人结肠癌移植瘤的抗肿瘤作用、作用机制以及药物毒性。方法建立裸鼠人结肠癌模型,随机分为生理盐水组、A s2O3组、5-FU组和A s2O3联合5-FU组,腹腔分别注射生理盐水、A s2O3、5-FU和A s2O3+5-FU,观察各组抑瘤作用和裸鼠一般状态的变化,并对体内标本行光镜、电镜、原位末端标记(TUNEL)、免疫组化和血常规检测。结果与单药作用相比,A s2O3联合5-FU可显著抑制结肠癌移植瘤的增长,CD I值<1,并显著增强诱导瘤细胞凋亡作用、调控凋亡相关基因(B cl-2、B ax、F as和F asL)表达。联合用药并未增加裸鼠肝、肾和造血系统的毒性。结论A s2O3与5-FU联合应用对结肠癌移植瘤有协同抗肿瘤作用,其机制可能与增强诱导癌细胞凋亡、细胞周期特异性药物与细胞周期调控剂联合增效以及调控凋亡相关基因表达有关;同时联合用药对于荷瘤裸鼠的肝、肾和造血系统无明显毒性。

Objective To study the effect of arsenic trioxide（AszO3） combined with fluorouracil（5-FU）on human colon carcinoma cell line implanted on nude mice in vivo,its related mechanism and toxicity. Methods The transplantable human colon carcinoma models in nude mice were established and divided into 4 groups at random. Then saline, As2O3,5-FU and As2O3＋5-FU were injected intraperitoneally into nude mice, respectively. The anti-tumor effect of each group and general condition of nude mice were studied. The specimens obtained from the mice were detected by optical microscope ,transmission electron microscope （TEM）, TdT-mediated dUTP nick end labeling （TUNEL） and immunohistochemical staining. Mouse blood routine examinations were also made. Results Compared with As2O3 or 5-FU individual drug group, As2O3 combined with 5-FU could obviously increase the inhibition and apoptosis rate of the tumor, CDI value was less than 1.0,and could regulate the related apoptosis gene （Bcl-2,Pax, Fas and FasL） expression. As2O3 combined with 5-FU did not increase the toxicity to the hepatic, renal and hematopoietic system in the nude mice. Conclusions As2O3 combined with 5-FU may obviously improve the anti-tumor effect in nude mice and maybe the mechanism is increasing apoptosis-inducing effect which is regulated by the several genes and enhancing anti-tumor effect of cell cycle specific agent combined with cell cycle regulatory agent. As2O3 combined with 5-FU has no obvious toxicity to the hepatic, renal and hematopoietic system in the nude mice.