Progen Pharmaceuticals Ltd, 16 Benson Street, Toowong, Brisbane, QLD 4066, Australia.
Br J Cancer. 2011 Feb 15;104(4):635-42. doi: 10.1038/bjc.2011.11. Epub 2011 Feb 1.
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.
PG545 是一种硫酸乙酰肝素（HS）类似物，通过将血管生成生长因子隔离在细胞外基质（ECM）中抑制肿瘤血管生成，从而限制随后与受体的结合。重要的是，PG545 还抑制肝素酶，肝素酶是唯一能在 ECM 中裂解 HS 链的内切糖苷酶。本研究旨在评估 PG545 在各种实体瘤和转移模型中的作用。
使用体内血管生成、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。还在荷瘤小鼠中生成药代动力学（PK）数据，以了解最佳给药方案和方案。
PG545 被证明可抑制体内血管生成，并在乳腺癌、前列腺癌、肝癌、肺癌、结肠癌、头颈部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，也观察到增强的抗肿瘤活性。PK 数据显示 PG545 的半衰期相对较长，在肝肿瘤中观察到具有药理相关性的放射性标记 PG545 浓度。
PG545 是一种用于癌症治疗的新型抗血管生成临床候选药物。PG545 的抗转移特性可能是由于肝素酶的抑制作用，这可能是该化合物进入 I 期临床试验的关键属性。
