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首页> 外文期刊>Biological chemistry >Trial of the cysteine cathepsin inhibitor JPM-OEt on early and advanced mammary cancer stages in the MMTV-PyMT-transgenic mouse model.
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Trial of the cysteine cathepsin inhibitor JPM-OEt on early and advanced mammary cancer stages in the MMTV-PyMT-transgenic mouse model.

机译：半胱氨酸组织蛋白酶抑制剂JPM-OEt在MMTV-PyMT-转基因小鼠模型的早期和晚期乳腺癌阶段的试验。

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Abstract Recent data suggest proteases of the papain-like cysteine cathepsin family as molecular targets for cancer therapy. Here, we report the treatment of polyoma middle T oncogene-induced breast cancers in mice with the cell-permeable broad-spectrum cysteine cathepsin inhibitor JPM-OEt. Up to 100 mg/kg inhibitor was intraperitoneally injected once per day in two trials on early and advanced cancers. In both trials, transient delays in tumour growth were observed. However, at the endpoint of both experiments no significant differences in tumour weights, histopathology and lung metastasis were found between the inhibitor and the control group. The invasive strand formation of collagen I-embedded tumour cell spheroids generated from primary tumours of inhibitor-treated mice in the early cancer trial could be inhibited in vitro by JPM-OEt; a result arguing against induction of resistance to the inhibitor. Measurement of cysteine cathepsin activities in tissue extracts after intraperitoneal injection ofJPM-OEt revealed effective inhibition of cysteine cathepsins in pancreas, kidneys and liver, while activities in mammary cancers and in lungs were not significantly affected. We conclude that the pharmacokinetic properties of JPM-OEt, which result in poor bioavailability, may prohibit its use for stand-alone treatment of solid mammary cancers and their lung metastases.
机译：摘要最近的数据表明，木瓜蛋白酶样半胱氨酸组织蛋白酶家族的蛋白酶可作为癌症治疗的分子靶标。在这里，我们报告细胞渗透性广谱半胱氨酸组织蛋白酶抑制剂JPM-OEt对小鼠多发性中T基因致癌乳腺癌的治疗。在两项针对早期和晚期癌症的试验中，每天一次腹膜内注射高达100 mg / kg的抑制剂。在两项试验中，均观察到肿瘤生长的短暂延迟。然而，在两个实验的终点，抑制剂和对照组之间在肿瘤重量，组织病理学和肺转移方面均未发现明显差异。在早期的癌症试验中，抑制剂治疗小鼠的原发性肿瘤产生的胶原蛋白包埋的肿瘤细胞球体的侵入性链形成可以在体外被JPM-OEt抑制。结果是反对诱导对抑制剂的抗性。腹膜内注射JPM​​-OEt后组织提取物中半胱氨酸组织蛋白酶活性的测量显示，其对胰腺，肾脏和肝脏中半胱氨酸组织蛋白酶的抑制作用得到了有效抑制，而在乳腺癌和肺脏中的半胱氨酸组织蛋白酶活性未受到明显影响。我们得出结论，导致不良生物利用度的JPM-OEt的药代动力学特性可能会禁止将其用于固体乳腺癌及其肺转移的单独治疗。

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