Suppression of Pancreatic Cancer Progression by Sulfated Non-Anticoagulant Heparin.
Tipu Nazeer, Thangirala Sudha, Thiruvengadam Aurumugam, Murat Yalcin, Hassan Murtaza, Shaker A Mousa. Albany Medical College, NY; Albany College of Pharmacy, Rensselaer, NY; MD Anderson Cancer Center, Houston, TX
Background: Pancreatic cancer is the fourth most common cause of death from cancer in the United States, and its incidence is increasing. Curative treatment is still primarily surgical and is associated with significant morbidity and mortality. Recent evidences suggest that low molecular weight heparins (LMWHs) exert potent antitumor effects. The utility of heparin and LWMH as anticancer agent is limited due to effect on hemostasis. In contrast, sulfated non-anticoagulant heparins (s-NACHs) are preferable for potential clinical use because they could be administered at high dose with minimal to no effect on hemostasis. We systematically investigated the anti-tumor and anti-metastatic effect of sulfated NACH using bioluminescence imaging and histopathological studies in spontaneous metastatic mouse model of pancreatic cancer.
Design: We used luciferase-expressing MPanc96-luc to develop orthotropic pancreatic tumor mouse model. Treatment was initiated after the detection of tumor by IVIS imaging and continued for 4 weeks. s-NACH or LMWH formulation (Trinzaparin) was administered at 20 and 5 mg/kg respectively with or without Gemcitabine(GMC). Bioluminescent image guided evaluation of tumor growth and metastasis were monitored. Tumor luminescent signal intensity, tumor weight and histopahtology were assessed at the termination of the study to evaluate pancreatic cancer progression.
Results: s-NACH and LMWH efficiently inhibited tumor growth and metastasis. However, s-NACH was very effective in inducing tumor necrosis and had clear advantage over LMWH in term of bleeding side effects. GMC though reduced metastasis showed high luminescent intensity in the tumor, indicative of live tumor cells. Histological studies clearly demonstrated fewer necrotic areas in GMC treated tumors in contrast to s-NACH, which enhanced anti-tumor and anti-metastatic activities by decreasing viable cancer cells within tumor.
|Tumor wt (g)||0.71+/- 0.39||0.30+/-0.14||0.50+/-0.33||0.51+/-0.17|