Miao H Q, Elkin M, Aingorn E, Ishai-Michaeli R, Stein C A, Vlodavsky I
Department of Oncology, Hadassah University Hospital, Jerusalem, Israel.
Int J Cancer. 1999 Oct 29;83(3):424-31. doi: 10.1002/(sici)1097-0215(19991029)83:3<424::aid-ijc20>3.0.co;2-l.
Heparanase activity correlates with the metastatic potential of tumor cells. Moreover, the anti-metastatic effect of non-anti-coagulant species of heparin and certain sulfated polysaccharides was attributed to their heparanase-inhibiting activity. We investigated the effect of a chemically sulfated polysaccharide (laminarin), consisting primarily of beta-1,3 glucan (sodium laminarin), and of synthetic phosphorothioate oligodeoxynucleotides, primarily phosphorothioate homopolymer of cytidine (SdC28), on heparanase activity and tumor metastasis. Investigation of the ability of tumor cells to degrade heparan sulfate in intact extracellular matrix revealed that heparanase activity expressed by B16-BL6 mouse melanoma cells and 13762 MAT rat mammary adenocarcinoma cells was effectively inhibited by LS (50% inhibition at 0.2-1 microgram/ml), but there was no inhibition by sodium laminarin up to a concentration of 50 microgram/ml. Complete inhibition of the melanoma heparanase was obtained in the presence of 0.1 microM SdC28. A single i.p. injection of laminarin sulfate, but not of sodium laminarin, before i.v. inoculation of the melanoma or breast-carcinoma cells inhibited the extent of lung colonization by the tumor cells by 80 to 90%. Similar inhibition was exerted by 0.1 microM SdC28. At the effective concentrations, both compounds had a small effect on proliferation of the tumor cells and on growth of the primary tumors in vivo. These results further emphasize the involvement of heparanase in tumor metastasis and the potential clinical application of diverse heparanase-inhibiting molecules such as sulfated polysaccharides and synthetic polyanionic molecules.
乙酰肝素酶活性与肿瘤细胞的转移潜能相关。此外，肝素的非抗凝血类物质及某些硫酸化多糖的抗转移作用归因于它们的乙酰肝素酶抑制活性。我们研究了一种主要由β-1,3-葡聚糖组成的化学硫酸化多糖（海带多糖）及其钠盐（海带多糖钠），以及合成的硫代磷酸酯寡脱氧核苷酸（主要是胞苷硫代磷酸酯均聚物，SdC28）对乙酰肝素酶活性和肿瘤转移的影响。对肿瘤细胞在完整细胞外基质中降解硫酸乙酰肝素能力的研究表明，B16-BL6小鼠黑色素瘤细胞和13762 MAT大鼠乳腺腺癌细胞所表达的乙酰肝素酶活性可被海带多糖有效抑制（在0.2 - 1微克/毫升时抑制50%），但海带多糖钠在浓度高达50微克/毫升时无抑制作用。在存在0.1微摩尔/升SdC28的情况下，黑色素瘤乙酰肝素酶被完全抑制。在静脉接种黑色素瘤或乳腺癌细胞前，腹腔单次注射硫酸化海带多糖而非海带多糖钠，可使肿瘤细胞在肺部的定植程度降低80%至90%。0.1微摩尔/升SdC28也有类似的抑制作用。在有效浓度下，这两种化合物对肿瘤细胞增殖和体内原发性肿瘤生长的影响较小。这些结果进一步强调了乙酰肝素酶在肿瘤转移中的作用，以及多种乙酰肝素酶抑制分子如硫酸化多糖和合成聚阴离子分子的潜在临床应用价值。
