Metallothionein and zinc homeostasis during tumor progression
Metallothionein and zinc homeostasis during tumor progression
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DOI：
10.1007/bf02950802
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发表时间：
1994-03
影响因子：
3.9
通讯作者：
J. Philcox;Michelle H. Tilley;P. Coyle;A. Rofe
中科院分区：
文献类型：
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作者：
J. Philcox;Michelle H. Tilley;P. Coyle;A. Rofe
研究了黑鼠乳腺腺癌（DAMA）诱导、生长和甲氨蝶呤（MTX）治疗过程中锌的稳态。血浆锌浓度（pZn）在肿瘤负荷小于1%体重（bw）时显著下降，在肿瘤增大期间持续下降，pZn在16.3%体重（bw）时下降54% （n=6/组）。低锌血症归因于肿瘤生长对锌的需求增加。16.3% bw肿瘤的锌含量与肌肉相当（通常为全身锌含量的60%）。肿瘤金属硫蛋白（Tumor metallothionein, tMT）足以结合肿瘤总锌<3%，在肿瘤生长早期肝脏金属硫蛋白（hepatic MT, hMT）浓度保持在基础水平，只有在大肿瘤出现明显坏死时才会翻倍。甲氨蝶呤（MTX, 0.5 mg/Kg im × 2 d）在肿瘤负荷分别为5%和10% bw （n=9, 10/组）时，根据肿瘤大小产生2种治疗效果：7只大鼠1.5% bw的肿瘤在实验结束前仍接近其原始大小，而pZn、hMT和tMT为5% bw未治疗肿瘤的典型。2. 在体重10%时给予MTX的5只大鼠肿瘤出现明显的包膜下坏死并缩小到与1组相似的大小；pZn恢复正常，而hMT是5% bw的6倍。宿主体重减轻明显减少，血浆葡萄糖和钙的肿瘤相关变化也明显减少。总之，tMT和hMT似乎都没有在DAMA锌封存和生长后的低锌血症中发挥作用。临界时间MTX可导致肿瘤消退和血浆锌、钙和葡萄糖恢复正常。这与hMT的增加和宿主体重减轻有关，表明锌从吸收肿瘤流向宿主，使hMT的合成和宿主结构蛋白的保留成为可能。
Zinc homeostasis was studied during the induction, growth, and methotrexate (MTX) treatment of Dark Agouti rat mammary adenocarcinomas (DAMA). A progressive fall in plasma Zn concentration (pZn), significant at a tumor burden of less than 1% body weight (bw), was sustained during tumor enlargement to give a 54% reduction in pZn at 16.3% bw (n=6/group). The hypozincemia was attributed to the increasing Zn demand for tumor growth. Zn content of the 16.3% bw tumors equaled that of muscle (normally 60% of total body Zn). Tumor metallothionein (tMT) was sufficient to bind <3% of total tumor Zn, and hepatic MT (hMT) remained at basal concentrations during early tumor growth, doubling only in the presence of significant necrosis in large tumors. Methotrexate (MTX, 0.5 mg/Kg im x 2 d) at respective tumor burdens of 5 and 10% bw (n=9, 10/group) gave 2 therapeutic effects, dependent on tumor size: 1.5% bw tumors in 7 rats remained close to their original size until experiment end when pZn, hMT, and tMT were typical of 5% bw untreated tumors. 2. Tumors in 5 rats given MTX at 10% bw had marked subcapsular necrosis and regression to a size similar to those in group 1; pZn returned toward normal, whereas hMT was 6 times its 5% bw counterpart. Host weight loss was significantly reduced, as were tumor-associated changes in plasma glucose and calcium.In summary, neither tMT nor hMT appears to play a role in the hypozincemia that follows DAMA Zn sequestration and growth. Critically timed MTX can result in tumor regression and return of plasma Zn, Ca, and glucose toward normal. This is associated with an increase in hMT and reduction in host weight loss, suggesting a flow of Zn from the resorbing tumor to the host, enabling the synthesis of hMT and retention of host structural proteins.