Zhang S Z, Luk G D, Hamilton S R
Department of Pathology, Johns Hopkins University School of Medicine and Hospital, Baltimore, Maryland 21205.
Cancer Res. 1988 Nov 15;48(22):6498-503.
Ornithine decarboxylase, the first regulatory enzyme in polyamine biosynthesis, is inhibited by alpha-difluoromethylornithine (DFMO), a specific enzyme-activated irreversible inhibitor. DFMO has been shown previously to inhibit experimental colonic tumorigenesis in rodents given the large bowel carcinogen azoxymethane or dimethylhydrazine. Therefore, we assessed the effects of DFMO on growth of established autochthonous experimental colonic tumors. Ten-wk-old male F344 rats were given 10 weekly s.c. injections of azoxymethane, 10 mg/kg. Starting 5 wk after the last dose, colonoscopy to the splenic flexure was performed weekly with a pediatric fiberoptic bronchoscope. When a tumor was visualized, its growth was assessed by computer image analysis of weekly colonoscopic photographs which included a scale. After two measurements for baseline tumor growth, the tumor-bearing rats were assigned in predetermined alternating sequence to the DFMO group (n = 26) or control group (n = 28). DFMO, 30 mg/ml (3%), was given in drinking water for 4 wk, resulting in mean weekly intake of 16 +/- 1 (SE) to 18 +/- 1 mg of DFMO/g of body weight. Control rats were pair-fed, resulting in reduced body weights comparable to DFMO rats. DFMO dramatically inhibited tumor growth, beginning in the first week of administration: mean tumor volume of DFMO rats reached only 7.0 +/- 2.0 mm3 compared with 17.4 +/- 3.2 mm3 in controls (P less than 0.02); and tumors in three DFMO rats disappeared. Mean change in tumor volume in DFMO rats was less than controls during all 4 wk of administration, although there was a suggestion of escape from DFMO suppression of tumor growth in the last 2 wk. At necropsy, tumor ornithine decarboxylase activity was 115 +/- 22 pmol/h/mg of protein in DFMO rats as compared with 842 +/- 576 in controls. There was a suggestion of greater tumor desmoplasia in DFMO rats, but tumor differentiation, depth of invasion, inflammation, and labeling index with tritiated thymidine showed no statistically significant differences between the DFMO and control groups. Our findings suggest that (a) ornithine decarboxylase plays a key role in growth of autochthonous experimental colonic tumors, and (b) DFMO may have potential for chemotherapy and chemoprophylaxis of colorectal neoplasms in human beings.
鸟氨酸脱羧酶是多胺生物合成中的首个调节酶，可被α-二氟甲基鸟氨酸（DFMO）抑制，DFMO是一种特异性酶激活的不可逆抑制剂。此前研究表明，DFMO可抑制给予大肠致癌物偶氮甲烷或二甲基肼的啮齿动物的实验性结肠肿瘤发生。因此，我们评估了DFMO对已形成的原位实验性结肠肿瘤生长的影响。给10周龄雄性F344大鼠每周皮下注射10次偶氮甲烷，剂量为10mg/kg。在最后一剂后5周开始，每周用小儿纤维支气管镜对脾曲进行结肠镜检查。当观察到肿瘤时，通过对包含标尺的每周结肠镜照片进行计算机图像分析来评估其生长情况。在对肿瘤生长进行两次基线测量后，将荷瘤大鼠按预定的交替顺序分为DFMO组（n = 26）或对照组（n = 28）。DFMO以30mg/ml（3%）的浓度加入饮用水中，持续4周，导致平均每周摄入量为16±1（SE）至18±1mg DFMO/克体重。对对照组大鼠进行配对喂食，使其体重减轻程度与DFMO组大鼠相当。DFMO从给药第一周开始就显著抑制肿瘤生长：DFMO组大鼠的平均肿瘤体积仅达到7.0±2.0mm³，而对照组为17.4±3.2mm³（P<0.02）；并且有3只DFMO组大鼠的肿瘤消失。在给药的所有4周内，DFMO组大鼠肿瘤体积的平均变化均小于对照组，尽管在最后2周有肿瘤生长逃脱DFMO抑制的迹象。尸检时，DFMO组大鼠肿瘤的鸟氨酸脱羧酶活性为115±22pmol/h/mg蛋白质，而对照组为842±576。DFMO组大鼠的肿瘤纤维组织增生似乎更明显，但DFMO组和对照组在肿瘤分化、浸润深度、炎症以及用氚标记胸腺嘧啶的标记指数方面均无统计学显著差异。我们的研究结果表明：（a）鸟氨酸脱羧酶在原位实验性结肠肿瘤的生长中起关键作用；（b）DFMO可能对人类结直肠肿瘤的化疗和化学预防具有潜在作用。
