Metastasis is strongly reduced by the matrix metalloproteinase inhibitor Galardin in the MMTV-PymT transgenic breast cancer model
Metastasis is strongly reduced by the matrix metalloproteinase inhibitor Galardin in the MMTV-PymT transgenic breast cancer model
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DOI：
10.1158/1535-7163.mct-08-0251
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发表时间：
2008-09-01
影响因子：
5.7
通讯作者：
Romer, John
中科院分区：
文献类型：
--
作者：
Almholt, Kasper;Juncker-Jensen, Anna;Romer, John
基质金属蛋白酶（MMP）有几个影响癌症进展和传播的作用。然而，低分子量金属蛋白酶抑制剂（MPI）尚未在转基因/自发转移模型中进行测试。我们已经在MMTV-PymT转基因乳腺癌模型中测试了Galardin/GM 6001，一种与大多数MMP反应的有效MPI。我们跟踪了一组81只接受Galardin、安慰剂或未接受治疗的MMTV-PymT转基因小鼠。在6周龄时以100 mg/kg/d开始Galardin治疗，并在13.5周龄时处死所有小鼠。Galardin治疗显著减少原发性肿瘤生长。Galardin治疗小鼠的最终肿瘤负荷为1.69 cm（3），而安慰剂治疗小鼠为3.29 cm（3）（t检验，P = 0.0014）。我们定量了同一组小鼠中的总肺转移体积。Galardin治疗组小鼠的中位转移体积为0.003 mm 3，而安慰剂治疗组小鼠为0.56 mm 3（t检验，P < 0.0001）。因此，转移负荷减少超过100倍，而原发性肿瘤大小仅减少2倍。我们还发现Galardin治疗的小鼠的原发性肿瘤表现出较低的组织病理学肿瘤分级，增加胶原沉积和增加MMP-2活性。已知MMPs具有肿瘤促进和肿瘤抑制作用，并且广谱MPI的几个临床试验未能显示有希望的作用。然而，Galardin在MMTV-PymT模型中的非常有效的抗转移作用确实表明，有可能找到广谱MPI;具有有利的抑制特征，或者可能是单特异性MPI的组合，用于未来的临床应用。
Matrix metalloproteinases (MMP) have several roles that influence cancer progression and dissemination. However, low molecular weight metalloproteinase inhibitors (MPI) have not yet been tested in transgenic/spontaneous metastasis models. We have tested Galardin/GM6001, a potent MPI that reacts with most MMPs, in the MMTV-PymT transgenic breast cancer model. We followed a cohort of 81 MMTV-PymT transgenic mice that received Galardin, placebo, or no treatment. Galardin treatment was started at age 6 weeks with 100 mg/kg/d, and all mice were killed at age 13.5 weeks. Galardin treatment significantly reduced primary tumor growth. Final tumor burden in Galardin-treated mice was 1.69 cm(3) compared with 3.29 cm(3) in placebo-treated mice (t test, P = 0.0014). We quantified the total lung metastasis volume in the same cohort of mice. The median metastasis volume was 0.003 mm(3) in Galardin-treated mice compared with 0.56 mm(3) in placebo-treated mice (t test, P < 0.0001). Thus, metastasis burden was reduced more than 100-fold, whereas primary tumor size was reduced only 2-fold. We also found that primary tumors from Galardin-treated mice exhibited a lower histopathologic tumor grade, increased collagen deposition, and increased MMP-2 activity. MMPs are known to have tumor-promoting and tumor-inhibitory effects, and several clinical trials of broad-spectrum MPIs have failed to show promising effects. The very potent antimetastatic effect of Galardin in the MMTV-PymT model does, however, show that it may be possible to find broad-spectrum MPIs; with favorable inhibition profiles, or perhaps combinations of monospecific MPIs, for future clinical application.