Antiangiogenic and anticancer effect of an orally active low molecular weight heparin conjugates and its application to lung cancer chemoprevention.

Angiogenesis is well recognized as a pivotal process in tumor progression from the very early premalignant stages, thus making it an important target in cancer chemoprevention as well as in cancer treatment. In the present study, we introduce a recently developed oral heparin conjugate (LHTD4) for use as an inhibitor of angiogenesis and evaluate its therapeutic and preventive effects in two different animal models of lung cancer. The antiangiogenic activities of LHTD4 were evaluated using tube formation and Matrigel plug assays. VEGF- and bFGF-induced tube formations were reduced up to 77.2 and 67.3%, respectively, by LHTD4. Hemoglobin content was also significantly decreased by LHTD4 in the Matrigel plugs that were transplanted into mice. We observed that the VEGF- and bFGF-mediated phosphorylations of the receptors, VEGFR-2 and FGFR-1, were also inhibited by LHTD4. The in vivo antiangiogenic and anticancer effects of LHTD4 that developed following oral administration were verified in a tumor xenograft model of human A549 lung cancer cells: tumor volume was found to have decreased by 60.2% and the expressions of CD34 and Ki-67 in the LHTD4-treated group were affected. Finally, in a chemically induced lung carcinogenesis model, the number and area of each nodule were significantly reduced in the LHTD4-treated groups by 49.2% and 30.1%, respectively. In addition, the degree of angiogenesis in the lung tissue itself was decreased in the drug treatment group by 52.9%. Taken together, these results suggest that LHTD4 could be a promising candidate for angiogenesis inhibitor for the treatment and prevention of cancer.