title: Anti-metastasis efficacy and safety of non-anticoagulant heparin derivative versus low molecular weight heparin in surgical pancreatic cancer models.
abstract: Heparin and its derivatives are known to attenuate cancer metastasis in preclinical models, but have not been used clinically due to adverse bleeding effects. This study compared the efficacy of S-NACH (a sulfated non-anticoagulant heparin) versus tinzaparin (a low molecular weight heparin) in inhibiting metastasis of a growing primary tumor and following surgical excision of primary tumor in a pancreatic cancer mouse model. The efficacy of S-NACH versus tinzaparin on metastasis of the primary tumor was evaluated in each experiment using IVIS imaging. Athymic female mice were treated with S-NACH or tinzaparin, and 30 min later luciferase-transfected pancreatic cancer cells (Mpanc96) were implanted into the spleen; treatment was continued daily until termination. Next we studied the effect of S-NACH versus tinzaparin on metastasis after surgical excision of the primary tumor after 3 weeks of daily treatment with S-NACH or tinzaparin. S-NACH reduced surgically induced metastasis (p<0.01) and tumor recurrence (p<0.05) relative to control. Histopathological studies demonstrated significant increase in tumor necrosis mediated by S-NACH and to lesser extent by tinzaparin as compared to control group. Furthermore, either S-NACH or tinzaparin upregulated the expression of the junctional adhesion molecule E-cadherin in pancreatic cancer cells where its low expression enhances cancer cell migration and invasion. In terms of bleeding time (BT), S-NACH did not affect BT as compared to tinzaparin, which doubled BT. These data suggest that S-NACH is an effective and safe anti-metastatic agent and warrants further clinical evaluation.
authors.affiliation: The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA.
authors.forename: Reem
authors.initials: R
authors.lastname: Alyahya
authors.affiliation: The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA.
authors.forename: Thangirala
authors.initials: T
authors.lastname: Sudha
authors.affiliation: Department of Basic and Social Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Racz
authors.affiliation: Department of Surgery, Albany Medical College, Albany, NY, USA.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Stain
authors.affiliation: The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA.
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D006493:Heparin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006495:Heparin, Low-Molecular-Weight / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000601:surgery*; D000078222:Tinzaparin; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D000078222:Tinzaparin; D006493:Heparin