Fong L Y, Li J X, Farber J L, Magee P N
Department of Pharmacology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Carcinogenesis. 1996 Sep;17(9):1841-8. doi: 10.1093/carcin/17.9.1841.
Target cell proliferation was investigated throughout the development of esophageal cancer induced by N-nitroso-methylbenzylamine (NMBA) in weanling rats maintained on zinc-deficient or sufficient diets. Deficient rats were fed ad libitum, while zinc-sufficient rats were either pair-fed to the deficient animals or fed ad libitum. After 5 weeks, half of the animals in each dietary group were given six intragastric doses of NMBA (2 mg/kg; twice weekly). The remaining rats were untreated by carcinogen. At weeks 1, 2, 3, 4, 5, 7, 9 and 11 post first dose, esophageal cell proliferation was assessed in rats from each group by in vivo bromodeoxyuridine (BrDU) labeling followed by immunohistochemical detection of cells in S-phase. At 11 weeks, the tumor incidence was 100, 23 and 6%, respectively, in the zinc-deficient, zinc-sufficient, ad libitum and pair-fed groups. In vivo BrDU labeling revealed that in the NMBA-untreated groups, the labeling index (LI), the number of labeled cells, and the total number of cells per cross section of entire esophagi were significantly increased by zinc deficiency at all time points; LI was lowest in zinc-sufficient, pair-fed rats. During NMBA treatment (weeks 6, 7 and 8), increased cell proliferation occurred in both groups of zinc-sufficient esophagi but only during week 6 in the deficient ones. In the weeks following the cessation of NMBA treatment, zinc-deficient esophagi showed significantly increased LI and greater number of labeled cells than the carcinogen treated, zinc-sufficient pair-fed or ad libitum fed groups. On the other hand, NMBA-treated zinc-sufficient pair-fed rats showed lower LI and smaller number of labeled cells than their zinc-sufficient ad libitum counterparts. Most importantly, esophageal papillomas were found in two zinc-deficient animals that had received no NMBA treatment, after 10-11 weeks of experimental diet. These data support a direct relationship between cell proliferation and tumor incidence, and also provide evidence that zinc deficiency and its associated cell proliferation could be carcinogenic.
在以缺锌或充足锌饮食喂养的断奶大鼠中，研究了由N-亚硝基甲基苄胺（NMBA）诱导的食管癌整个发展过程中的靶细胞增殖情况。缺锌大鼠随意进食，而锌充足的大鼠要么与缺锌动物配对喂食，要么随意进食。5周后，每个饮食组中的一半动物接受六次胃内注射NMBA（2mg/kg；每周两次）。其余大鼠不接受致癌物处理。在首次给药后的第1、2、3、4、5、7、9和11周，通过体内溴脱氧尿苷（BrDU）标记，随后对处于S期的细胞进行免疫组织化学检测，评估每组大鼠的食管细胞增殖情况。在第11周时，缺锌、锌充足随意进食和配对喂食组的肿瘤发生率分别为100%、23%和6%。体内BrDU标记显示，在未接受NMBA处理的组中，在所有时间点，缺锌均显著增加了标记指数（LI）、标记细胞数量以及整个食管每个横截面的细胞总数；锌充足的配对喂食大鼠的LI最低。在NMBA处理期间（第6、7和8周），两组锌充足的食管中细胞增殖均增加，但缺锌组仅在第6周出现细胞增殖增加。在停止NMBA处理后的几周内，缺锌食管的LI显著增加，且标记细胞数量比接受致癌物处理的锌充足配对喂食或随意进食组更多。另一方面，接受NMBA处理的锌充足配对喂食大鼠的LI低于其锌充足随意进食的同组大鼠，且标记细胞数量更少。最重要的是，在实验饮食10 - 11周后，在两只未接受NMBA处理的缺锌动物中发现了食管乳头状瘤。这些数据支持了细胞增殖与肿瘤发生率之间的直接关系，也提供了证据表明锌缺乏及其相关的细胞增殖可能具有致癌性。
