金属铁与氟尿嘧啶配合物的体内抗肿瘤活性及其毒性

Antitumor activity and toxicity in vivo of iron-fluouracil complex

背景:前期研究表明,金属铁与氟尿嘧啶、邻菲罗啉的配合物具有良好的体外抗肿瘤活性,能抑制多株人癌细胞的增殖。目的:检测新型金属铁与氟尿嘧啶、邻菲罗啉配合物[Fe(5-Fu)_2(Phen)SO_4]的体内抗肿瘤活性及毒性。方法:将40只昆明小鼠随机分为4组,分别腹腔注射72,102.9,147,210 mg/kg的[Fe(5-Fu)_2(Phen)SO_4]配合物,检测配合物的半数致死量。建立昆明小鼠S180移植性肉瘤模型,造模后第2天随机分8组,分别腹腔注射[Fe(5-Fu)_2(Phen)SO_4]配合物15 mg/kg(低剂量组)、[Fe(5-Fu)_2(Phen)SO_4]配合物30 mg/kg(中剂量组)、[Fe(5-Fu)_2(Phen)SO_4]配合物60 mg/kg(高剂量组)、生理盐水(阴性对照组)、顺铂(阳性对照组)、5-氟尿嘧啶、铁盐与邻菲罗啉,1次/d,连续注射7 d后,检测肉瘤质量、小鼠体质量及主要脏器系数,以及主要脏器病理组织学变化。结果与结论:[Fe(5-Fu)_2(Phen)SO_4]配合物的半数致死量为103.9 mg/kg。与阴性对照组比较,高剂量组、阳性对照组、5-氟尿嘧啶组可明显抑制肿瘤的生长(P<0.05或P<0.01),且以高剂量组效果最明显(P<0.01)。60 mg/kg[Fe(5-Fu)_2(Phen)SO_4]配合物对肾脏的抑制作用较顺铂弱,但对小鼠肝脏、脾脏、胸腺的抑制作用较顺铂强,提示配合物的肾毒性较顺铂低,但有较强的免疫毒性及肝毒性。

BACKGROUND： Previous research indicated that iron-fluorouracil-phenanthroline complex has good antitumor activity in vitro, which can inhibit the proliferation of human cancer cells. OBJECTIVE： To detect the antitumor activity and toxicity of iron-fluouracil-phenanthroline complex, [Fe（5-Fu）_2（Phen）SO_4], in vivo. METHODS： A total of 40 Kunming mice were randomly divided into four groups, which were intraperitoneally injected with 72, 102.9, 147, 210 mg/kg [Fe（5-Fu）_2（Phen）SO_4] and the half lethal dose of the complex was detected. One day after the establishment of mouse S180 sarcoma models, the model mice were randomly divided into eight groups, and administered with the intraperitoneal injection of 15 mg/kg（low dose group）, 30 mg/kg（middle dose group）, 60 mg/kg（high dose group） [Fe（5-Fu）_2（Phen）SO_4], normal saline（negative control group）, cisplatin（positive control group）, 5-fluorouracil, iron-salt and phenanthroline, respectively. The injection was done once a day, lasting for 7 days. The weight of sarcomas, body weight, the main organ coefficient and histopathological changes of the main organs were detected. RESULTS AND CONCLUSION： The half lethal dose of [Fe（5-Fu）_2（Phen）SO_4] was 103.9 mg/kg. Compared with the negative control group, high dose group, positive control group and 5-fluorouracil could significantly inhibit the growth of the tumor（P〈0.05 or P〈0.01）, and the effect of high dose group was the most obvious（P〈0.01）. Compared with cisplatin, 60mg/kg [Fe（5-Fu）_2（Phen）SO_4] had a weaker inhibitory effect on the kidney, but higher inhibitory effect on the liver, spleen and thymus, indicating the complex has a lower nephrotoxicity, but stronger immunotoxicity and hepatotoxicity than cisplatin.