Kragh Michael, Binderup Lise, Vig Hjarnaa Pernille-Julia, Bramm Erik, Johansen Kristian B, Frimundt Petersen Christian
Department of Pharmacology, LEO Pharma A/S, 55 Industriparken, DK-2750, Ballerup, Denmark.
Oncol Rep. 2005 Jul;14(1):99-104.
Experimental and clinical studies indicate that low molecular weight heparins (LMWH) may inhibit cancer and/or metastasis. The purpose of this study was to investigate whether it is possible to design non-anti-coagulant, anti-metastatic compounds based on heparin. The LMWH Tinzaparin and a series of non-anti-coagulant (NAC) heparin derivatives, varying in size from 2,500 to 10,000 Da, were tested for their anti-metastatic activity in an experimental B16F10 metastasis model. The most promising NAC heparin drug candidate and Tinzaparin were further evaluated in B16F10 model with spontaneous metastasis from a primary subcutaneous tumor. In the experimental model, Tinzaparin, NAC2500, and NAC6000 were inactive whereas both NAC8000 and NAC10000 significantly inhibited the number of induced experimental metastases by 69 and 73%, respectively. NAC8000 was chosen over NAC10000 for further studies because of its lower molecular weight with an expected better bioavailability. In the spontaneous model, Tinzaparin had no inhibitory effect on metastatic activity. In contrast, NAC8000 significantly inhibited the number of metastases by 58%. Neither Tinzaparin nor NAC8000 inhibited primary subcutaneous tumor growth. Together, these results indicate that the anti-metastatic effect of heparin derivatives is not a result of anti-coagulant activity. The non-anti-coagulant NAC8000 specifically inhibits early establishment of tumor cells, but not primary tumor growth. Therefore, NAC8000 is a promising non-anti-coagulant compound for preventing tumor metastasis.
实验和临床研究表明，低分子量肝素（LMWH）可能抑制癌症和/或转移。本研究的目的是调查是否有可能基于肝素设计出非抗凝血的抗转移化合物。在实验性B16F10转移模型中，测试了低分子量肝素替扎肝素和一系列分子量在2500至10000道尔顿之间的非抗凝血（NAC）肝素衍生物的抗转移活性。在原发性皮下肿瘤自发转移的B16F10模型中，对最有前景的NAC肝素候选药物和替扎肝素进行了进一步评估。在实验模型中，替扎肝素、NAC2500和NAC6000无活性，而NAC8000和NAC10000均显著抑制诱导的实验性转移数量，分别为69%和73%。由于NAC8000分子量较低，预期生物利用度更好，因此选择NAC8000而非NAC10000进行进一步研究。在自发模型中，替扎肝素对转移活性没有抑制作用。相比之下，NAC8000显著抑制转移数量达58%。替扎肝素和NAC8000均未抑制原发性皮下肿瘤的生长。总之，这些结果表明肝素衍生物的抗转移作用不是抗凝血活性的结果。非抗凝血的NAC8000特异性抑制肿瘤细胞的早期定植，但不抑制原发性肿瘤生长。因此，NAC8000是一种有前景的预防肿瘤转移的非抗凝血化合物。
