Antitumor efficacy of the heparanase inhibitor SST0001 alone and in combination with antiangiogenic agents in the treatment of human pediatric sarcoma models
Antitumor efficacy of the heparanase inhibitor SST0001 alone and in combination with antiangiogenic agents in the treatment of human pediatric sarcoma models
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DOI：
10.1016/j.bcp.2013.02.023
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发表时间：
2013-05-15
影响因子：
5.8
通讯作者：
Zunino, F.
中科院分区：
文献类型：
--
作者：
Cassinelli, G.;Lanzi, C.;Zunino, F.
肝素酶的活性负责硫酸肝素的裂解，从而导致硫酸肝素结合生长因子的释放。由于肝素酶活性在几种肿瘤类型中上调并与恶性行为有关，因此该酶被认为是抗肿瘤治疗的一个有希望的靶点。基于先前的证据表明，肝素酶抑制剂SST0001（一种非抗凝剂n-乙酰化乙二醇分裂肝素）对尤文氏肉瘤模型有效，本研究将SST0001的临床前评估扩展到一组儿童肉瘤模型，代表各种肿瘤组织类型（软组织和骨肉瘤），并进一步阐明其作用模式。SST0001治疗下调了肉瘤细胞条件培养基中的几种血管生成因子，抑制了肝素结合因子（VEGF、bFGF、HGF、PDGF）的促侵袭作用，并消除了PDGF受体酪氨酸磷酸化。皮下注射SST0001非常有效，对所有测试的肿瘤异种移植物都有显著的生长抑制作用（范围为64-95%）。SST0001与抗血管生成药物（贝伐单抗、舒尼替尼）联合使用时，完全缓解率高，疗效增强。SST0001联合抗血管生成药物的协同作用与肝素酶的作用方式一致，与肝素结合的促血管生成/生长因子在肉瘤细胞恶性行为中的相关作用一致。(c) 2013年Elsevier Inc.出版
The activity of heparanase is responsible for heparan sulfate cleavage, thus resulting in the release of heparan sulfate-bound growth factors. Since heparanase activity is upregulated in several tumor types and is implicated in the malignant behavior, the enzyme is regarded as a promising target for antitumor therapy. Based on previous evidence that the heparanase inhibitor SST0001, a non-anticoagulant N-acetylated glycol split heparin, is effective against an Ewing's sarcoma model, the present study was performed to extend the preclinical evaluation of SST0001 to a panel of pediatric sarcoma models, representative of various tumor histotypes (soft tissue and bone sarcomas) and to further elucidate its mode of action. SST0001 treatment downregulated several angiogenic factors in the conditioned media of sarcoma cells, inhibited the pro-invasive effect of heparin-binding factors (VEGF, bFGF, HGF, PDGF), and abrogated PDGF receptor tyrosine phosphorylation. Subcutaneous administration of SST0001 was very effective, resulting in a significant growth inhibition (range, 64-95%) of all tested tumor xenografts. The efficacy of SST0001 was enhanced in combination with antiangiogenic agents (bevacizumab, sunitinib) as documented by the high rate of complete response. The synergistic effect of SST0001 in combination with antiangiogenic agents is consistent with the heparanase mode of action and with the relevant role of heparin-binding proangiogenic/growth factors in the malignant behavior of sarcoma cells. (c) 2013 Published by Elsevier Inc.