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Antimetastatic Effect of an Orally Active Heparin Derivative on Experimentally Induced Metastasis

Authors' Affiliations: ¹ College of Pharmacy, Seoul National University; ² Biomedical Research Center, Korea Institute of Science and Technology; ³ Department of Otolaryngology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea; and ⁴ Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu, South Korea

Requests for reprints: Youngro Byun, College of Pharmacy, Seoul National University, San 56-1, Sillim-dong, Gwanak-gu, Seoul 151-742, South Korea. Phone: 82-2-880-7866; Fax: 82-2-872-7864; E-mail: yrbyun{at}snu.ac.kr or Sang Yoon Kim, Department of Otolaryngology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul 138-736, South Korea. Phone: 82-2-3010-3715; Fax: 82-2-489-2773; E-mail: sykim2{at}amc.seoul.kr.

Purpose: 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.

Experimental Design: 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.

Results: In mice, the plasma concentration was 7 µg/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.

Conclusions: 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.