Antimetastatic effect of an orally active heparin derivative on experimentally induced metastasis.
OBJECTIVE
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.


METHODS
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 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.


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.
Lee
Dong Yun
DY
College of Pharmacy, Seoul National University, Seoul, South Korea.
Park
Kyeongsoon
K
Kim
Sang Kyoon
SK
Park
Rang-Woon
RW
Kwon
Ick Chan
IC
Kim
Sang Yoon
SY
Byun
Youngro
Y
D000284:Administration, Oral; D000818:Animals; D045744:Cell Line, Tumor; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D004195:Disease Models, Animal; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000517:prevention & control*; D019007:P-Selectin / Q000378:metabolism*
D006495:Heparin, Low-Molecular-Weight; C521279:LMWH-DOCA conjugate; D019007:P-Selectin; D003840:Deoxycholic Acid