Lee Dong Yun, Park Kyeongsoon, Kim Sang Kyoon, Park Rang-Woon, Kwon Ick Chan, Kim Sang Yoon, Byun Youngro
College of Pharmacy, Seoul National University, Seoul, South Korea.
Clin Cancer Res. 2008 May 1;14(9):2841-9. doi: 10.1158/1078-0432.CCR-07-0641.
Orally active anticancer drugs have great advantages for the treatment of cancer. Compelling data suggest that heparin exhibits critical antimetastatic effects via interference with P-selectin-mediated cell-cell binding. However, heparin should be given parenterally because it is not orally absorbed. Here, we evaluated the inhibitory effect of orally absorbable heparin derivative (LHD) on experimentally induced metastasis.
We developed LHD, which is a chemical conjugate of low molecular weight heparin and deoxycholic acid, and measured the plasma concentration of LHD after oral administration. To evaluate the antimetastatic effect of LHD, we carried out experimental lung metastasis assays in vivo using murine melanoma or human lung carcinoma cells and interruption assay between murine melanoma cells and activated platelets and human umbilical vascular endothelial cells in vitro.
In mice, the plasma concentration was approximately 7 microg/mL at 20 minutes after oral administration of LHD (10 mg/kg), indicating that bleeding was not induced at this dose. Interestingly, we found that LHD dramatically attenuated metastasis experimentally induced by murine melanoma or human lung carcinoma cells and that its antimetastatic activity was attributed to the interruption of the interactions between melanoma cells and activated platelets and between melanoma cells and human umbilical vascular endothelial cells by blocking selectin-mediated interactions. Furthermore, it prevented tumor growth in secondary organs.
On the basis of these findings, the present study shows the possibility of LHD as a suitable first-line anticancer drug that can be used for preventing metastasis and recurrence because it has therapeutic potential as an antimetastatic drug, has lower side effects, and can be orally absorbed.
口服活性抗癌药物在癌症治疗中具有巨大优势。有力的数据表明，肝素通过干扰P-选择素介导的细胞间结合发挥关键的抗转移作用。然而，肝素因不能口服吸收而需胃肠外给药。在此，我们评估了可口服吸收的肝素衍生物（LHD）对实验性诱导转移的抑制作用。
我们研发了LHD，它是低分子量肝素与脱氧胆酸的化学偶联物，并测定了口服给药后LHD的血浆浓度。为评估LHD的抗转移作用，我们在体内使用小鼠黑色素瘤或人肺癌细胞进行了实验性肺转移测定，并在体外进行了小鼠黑色素瘤细胞与活化血小板及人脐静脉血管内皮细胞之间的阻断测定。
在小鼠中，口服LHD（10 mg/kg）后20分钟血浆浓度约为7μg/mL，表明该剂量未引起出血。有趣的是，我们发现LHD显著减轻了由小鼠黑色素瘤或人肺癌细胞实验性诱导的转移，其抗转移活性归因于通过阻断选择素介导的相互作用中断了黑色素瘤细胞与活化血小板之间以及黑色素瘤细胞与人脐静脉血管内皮细胞之间的相互作用。此外，它还能抑制继发器官中的肿瘤生长。
基于这些发现，本研究表明LHD作为一种合适的一线抗癌药物具有可能性，可用于预防转移和复发，因为它具有作为抗转移药物的治疗潜力、副作用较小且可口服吸收。
