PDF(Pubmed)
Abstract：
Heparanase (Hpa1) is expressed by tumor cells and cells of the tumor microenvironment and functions to remodel the extracellular matrix (ECM) and regulate the bioavailability of ECM-bound factors that support tumor growth. Heparanase expression is upregulated in human carcinomas, sarcomas, and hematological malignancies, correlating with increased tumor metastasis, vascular density, and shorter postoperative survival of cancer patients, and encouraging the development of heparanase inhibitors as anti-cancer drugs. Among these are heparin/HS mimetics, the only heparanase-inhibiting compounds that are being evaluated in clinical trials. We have synthesized dicarboxylated oxy-heparins (DCoxHs) containing three carboxylate groups per split residue (DC-Hep). The resulting lead compound (termed XII) was upscaled, characterized, and examined for its effectiveness in tumor models. Potent anti-tumorigenic effects were obtained in models of pancreatic carcinoma, breast cancer, mesothelioma, and myeloma, yielding tumor growth inhibition (TGI) values ranging from 21 to 70% and extending the survival time of the mice. Of particular significance was the inhibition of spontaneous metastasis in an orthotopic model of breast carcinoma following resection of the primary tumor. It appears that apart from inhibition of heparanase enzymatic activity, compound XII reduces the levels of heparanase protein and inhibits its cellular uptake and activation. Heparanase-dependent and -independent effects of XII are being investigated. Collectively, our pre-clinical studies with compound XII strongly justify its examination in cancer patients.
摘要：
乙酰肝素酶（Hpa1）由肿瘤细胞和肿瘤微环境的细胞表达，并具有重塑细胞外基质（ECM）和调节支持肿瘤生长的ECM结合因子的生物利用度的功能。乙酰肝素酶表达在人类癌症中上调，肉瘤,和血液恶性肿瘤，与肿瘤转移增加相关，血管密度,癌症患者的术后生存期较短，并鼓励开发乙酰肝素酶抑制剂作为抗癌药物。其中有肝素/HS模拟物，在临床试验中正在评估的唯一的乙酰肝素酶抑制化合物。我们已经合成了每个分裂残基（DC-Hep）含有三个羧酸酯基团的二羧酸化氧基肝素（DCoxHs）。将所得的铅化合物（称为XII）扩大规模，characterized,并检查了其在肿瘤模型中的有效性。在胰腺癌模型中获得了有效的抗肿瘤作用，乳腺癌,间皮瘤,和骨髓瘤，产生21％至70％的肿瘤生长抑制（TGI）值，并延长小鼠的存活时间。特别重要的是在原发肿瘤切除后乳腺癌原位模型中自发转移的抑制。似乎除了抑制乙酰肝素酶活性外，化合物XII降低乙酰肝素酶蛋白的水平并抑制其细胞摄取和活化。正在研究XII的肝素酶依赖性和非依赖性作用。总的来说，我们对化合物XII的临床前研究有力地证明了其在癌症患者中的检查.
