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

Abstract

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 f7 Ag/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.

Antiangiogenic Activity of Orally Absorbable Heparin Derivative in Different Types of Cancer Cells

“…The oral absorption of heparin derivative was attributed to the conjugated DOCA molecule constituent, which could promote intestinal absorption by enhancing the hydrophobic properties of heparin and by increasing the interaction between heparin and the intestinal membrane (26,27). Interestingly, we demonstrated that chronic administration of the orally absorbable LHD can prevent cancer progression without adverse effects of heparin, suggesting the potential therapeutic efficacy of LHD as a new oral anticancer agent (28,29).…”

“…Also, it could inhibit formation of microvessel as indicated by the results of CAM (chicken chorioallantoic membrane) and in vivo Matrigel plug assays using bFGF growth factor (28). In addition, the metastasis steps were interrupted by LHD at subsequent steps, namely the establishment and subsequent growth (i.e., colonization) of the metastasis at the lung metastasis animal model (29). The suppression of the interactions was due to the competitive inhibition by LHD of the P-or E-selectin-mediated interactions.…”

“…LHD was prepared as described previously (26)(27)(28)(29). In brief, it was synthesized by conjugating the amine group of DOCA-NH 2 with the carboxylic groups of LMWH (Fraxiparin®, average MW 4.5 kDa; GlaxoSmithKline, Brentford, Middlesex, UK).…”

“…In these tumor graft animal models, SCC7-derived tumor grafts were established in C3H/HeN mice, and B16F10-or LLC1-derived tumor grafts were established in C57BL/6J mice (28,29). Briefly, cancer cells (1×10 6 cells/100 μL) were injected subcutaneously into the flanks of mice.…”

Administration of low molecular weight heparins for prolonging the survival of patients with cancer

“…An orally active LMWH conjugate, LHTD4, exhibited anti-cancer activity, which was probably associated with the anti-angiogenic properties of LHTD4 [42], and a similar anti-metastatic activity was also revealed by some selectin-specific heparin derivatives [26,43]. Another animal experiment on orally absorbable heparin derivative demonstrated a significant attenuation of experimentally induced metastases of murine melanoma and human lung carcinoma cells [44]. In this animal model metastatic activity was primarily attributed to the interruption of the interactions between neoplastic cells and activated platelets.…”