PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models.
PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models.
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DOI：
10.1038/bjc.2011.11
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发表时间：
2011-02-15
影响因子：
8.8
通讯作者：
Bytheway, I.
中科院分区：
文献类型：
--
作者：
Dredge, K.;Hammond, E.;Handley, P.;Gonda, T. J.;Smith, M. T.;Vincent, C.;Brandt, R.;Ferro, V.;Bytheway, I.
PG545是一种硫酸肝素（HS）模拟物，通过隔离细胞外基质（ECM）中的血管生成生长因子来抑制肿瘤血管生成，从而限制随后与受体的结合。重要的是，PG545还抑制肝素酶，肝素酶是唯一在ECM中切割HS链的内糖苷酶。该研究的目的是评估PG545在各种实体肿瘤和转移模型中的作用。通过体内血管生成、实体瘤和转移模型评估PG545的抗血管生成、抗肿瘤和抗转移特性。在荷瘤小鼠中也生成了药代动力学（PK）数据，以了解最佳给药方案和方案。PG545在体内被证明抑制血管生成，并在乳腺癌、前列腺癌、肝癌、肺癌、结肠癌、头颈癌和黑色素瘤的小鼠模型中诱导抗肿瘤或抗转移作用。在肝癌模型中与索拉非尼联合使用时，也注意到抗肿瘤活性增强。PK数据显示PG545的半衰期相对较长，在肝脏肿瘤中观察到放射性标记PG545的药理学相关浓度。PG545是一种新的抗血管生成肿瘤临床候选药物。PG545的抗转移特性可能是由于抑制肝素酶，随着该化合物进入I期临床试验，可能被证明是一个关键属性。
PG545 is a heparan sulfate (HS) mimetic that inhibits tumour angiogenesis by sequestering angiogenic growth factors in the extracellular matrix (ECM), thus limiting subsequent binding to receptors. Importantly, PG545 also inhibits heparanase, the only endoglycosidase which cleaves HS chains in the ECM. The aim of the study was to assess PG545 in various solid tumour and metastasis models. The anti-angiogenic, anti-tumour and anti-metastatic properties of PG545 were assessed using in vivo angiogenesis, solid tumour and metastasis models. Pharmacokinetic (PK) data were also generated in tumour-bearing mice to gain an understanding of optimal dosing schedules and regimens. PG545 was shown to inhibit angiogenesis in vivo and induce anti-tumour or anti-metastatic effects in murine models of breast, prostate, liver, lung, colon, head and neck cancers and melanoma. Enhanced anti-tumour activity was also noted when used in combination with sorafenib in a liver cancer model. PK data revealed that the half-life of PG545 was relatively long, with pharmacologically relevant concentrations of radiolabeled PG545 observed in liver tumours. PG545 is a new anti-angiogenic clinical candidate for cancer therapy. The anti-metastatic property of PG545, likely due to the inhibition of heparanase, may prove to be a critical attribute as the compound enters phase I clinical trials.
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