Parish C R, Freeman C, Brown K J, Francis D J, Cowden W B
Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra.
Cancer Res. 1999 Jul 15;59(14):3433-41.
Inhibitors of tumor angiogenesis and metastasis are rapidly emerging as important new drug candidates for cancer therapy. To facilitate the identification of such drugs, we recently developed novel and rapid in vitro assays for human angiogenesis and for the extracellular matrix-degrading enzyme heparanase, which has been implicated in tumor metastasis. In this study, sulfated oligosaccharides, which are structural mimics of heparan sulfate, were investigated as drug candidates because these compounds may interfere with heparan sulfate recognition by many angiogenic growth factors and may inhibit cleavage of heparan sulfate by heparanase. In the preliminary screening studies, it was found that inhibitory activity in both assay systems was critically dependent on chain length and degree of sulfation, highly sulfated linear oligosaccharides of five or more monosaccharides in length being the most active. However, two sulfated oligosaccharides stood out as potential antitumor drugs, phosphomannopentaose sulfate (PI-88) and maltohexaose sulfate, both of these compounds having the important property of simultaneously being potent inhibitors of in vitro angiogenesis and heparanase activity. Due to the ease of manufacture of the starting material, phosphomannopentaose, PI-88 was studied in more detail. PI-88 was shown to inhibit the primary tumor growth of the highly invasive rat mammary adenocarcinoma 13762 MAT by approximately 50%, inhibit metastasis to the draining popliteal lymph node by approximately 40%, and reduce the vascularity of tumors by approximately 30%, all of these effects being highly significant. Acute hematogenous metastasis assays also demonstrated that PI-88 was a potent (>90%) inhibitor of blood-borne metastasis. Thus, by the use of novel in vitro screening procedures, we have identified a promising antitumor agent.
肿瘤血管生成和转移抑制剂正迅速成为癌症治疗中重要的新型候选药物。为了便于此类药物的鉴定，我们最近开发了用于人类血管生成和细胞外基质降解酶乙酰肝素酶的新型快速体外检测方法，乙酰肝素酶与肿瘤转移有关。在本研究中，作为硫酸乙酰肝素结构模拟物的硫酸化寡糖被作为候选药物进行研究，因为这些化合物可能会干扰许多血管生成生长因子对硫酸乙酰肝素的识别，并可能抑制乙酰肝素酶对硫酸乙酰肝素的切割。在初步筛选研究中，发现两种检测系统中的抑制活性都严重依赖于链长和硫酸化程度，长度为五个或更多单糖的高度硫酸化线性寡糖活性最高。然而，有两种硫酸化寡糖脱颖而出成为潜在的抗肿瘤药物，硫酸磷酸甘露五糖（PI - 88）和硫酸麦芽六糖，这两种化合物都具有同时成为体外血管生成和乙酰肝素酶活性强效抑制剂的重要特性。由于起始原料磷酸甘露五糖易于制备，对PI - 88进行了更详细的研究。结果表明，PI - 88可使高侵袭性大鼠乳腺腺癌13762 MAT的原发肿瘤生长抑制约50%，使转移至引流腘窝淋巴结的情况抑制约40%，并使肿瘤血管生成减少约30%，所有这些效果都非常显著。急性血行转移检测还表明，PI - 88是血行转移的强效（>90%）抑制剂。因此，通过使用新型体外筛选程序，我们鉴定出了一种有前景的抗肿瘤药物。
