Role of Heparin Derivatives and Platelet-Cancer Cell Adhesion in Tumor Metastasis.

摘要

Heparin and its derivatives are known to attenuate cancer metastasis, but have not been used clinically due to adverse bleeding effects. This study examined the ability of a low molecular weight heparin (LMWH), a sulfated non-anticoagulant heparin (S-NACH), and P-selectin inhibitor (PSI) to inhibit metastasis of a growing primary mass and metastasis following surgical excision of primary tumor in a pancreatic mouse model.;Two animal experiments were conducted using athymic female mice. The aim of the first experiment was to examine the efficacy and safety of the test compounds on experimental metastasis. Different groups of mice received either saline, LMWH, S-NACH, or PSI, and 30 minutes later, luciferase transfected pancreatic cancer cells were implanted into the mouse spleen and the treatment continued daily for two weeks. IVIS imaging was done once a week to measure the metastatic load to various organs. The tumor burden measurements were based on the bioluminescence signal intensity of the pancreatic cancer cells. The second experiment was intended to study the effect of the compounds (LMWH and S-NACH) on metastasis after tumor excision surgery, Mpanc96 cells were injected into the tail of the pancreas and one week later animals were divided into 3 groups; one group received saline as a control, another group received LMWH, and a third group received S-NACH 30 minutes before resection of the pancreatic tumor, followed by daily treatment (saline, LMWH or S-NACH) for 3 weeks. Tumor metastasis was evaluated by IVIS imagining. A bleeding time experiment was done to evaluate the relative effect of the test compounds on the bleeding time.;S-NACH and PSI significantly decreased the level of metastasis (P < 0.05) versus control and LMWH. S-NACH was also able to reduce surgically induced metastasis (P = 0.017). S-NACH and PSI did not significantly affect bleeding time as compared to control or LMWH, while LMWH significantly (P < 0.0001) prolonged bleeding. These data suggest that S-NACH and PSI are effective and safe anti-metastatic agents and warrant further clinical evaluation.