Site Directed Delivery of Chemotherapy and Non-Anticoagulant Sulfated Heparin in Breast Cancer

• Published in: Blood 2008-11, Vol.112 (11), p.5050-5050
• Main Authors: Mousa, Shaker S, Bahrali, Dhruba, Mousa, Shaymaa S, Dier, Emmy, Yalcin, Murat, Phillips, Patricia
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V112.11.5050.5050

There is substantial literature support for the use of low molecular weight heparins (LMWH) for treating coagulation disorders in cancer patients. Recent prospective and retrospective clinical trials have also demonstrated that they provide significant advantages in terms of progression-free and overall survival in certain cancers and in certain subgroups of patients. LMWH treatments are often associated with increased bleeding, constituting a dose-limiting effect. We have developed novel non-anticoagulant heparin (NACH) compounds that have minimal effects on hemostasis (El-Naggar and Mousa, US Patents 6,908,907 B2, (2005), and 10, 667,216, (2003). We have evaluated them for efficacy vs. tumor growth and metastasis and have begun to investigate the mechanisms involved in anti-tumor activities. Modified sulfated LMWH with weak or no anticoagulant activities were still highly effective in inhibiting angiogenesis and metastasis, demonstrating that anticoagulation is not essential for attenuation of angiogenesis or metastasis. The modified heparins were characterized with respect to their ability to release endothelial tissue factor pathway inhibitor (TFPI) and inhibit selectin-mediated interactions, molecular components that have been shown to modulate tumor growth, tumor angiogenesis and metastasis. One of these modified heparin compounds that showed significant activity in a selectin-mediated tumor cell adhesion assay was also highly effective in reducing tumor burden in mice with MC-38 colon carcinoma and B16-BL6 melanoma (>70%) and in reducing the number of metastatic foci (>65%) in these animals. We also investigated the efficacy of NACH compounds on growth factor-induced angiogenesis in a mouse Matrigel model in which new vessel growth was quantified by measuring hemoglobin concentration extracted from the Matrigel plug. Values are Means ± SEM. Matrigel alone: 0.57± 0.12; bFGF + Matrigel: 7.27 ± 1.18; NAC-S-S: 0.86 ± 0.10. This sulfated compound which demonstrated no anticoagulant activity in aPTT and TEG assays, reduced capillary formation to baseline levels. These data demonstrate that non-anticoagulant heparin compounds exhibit a profile of anti-tumor activities without disrupting normal hemostasis. Site-directed therapy with non-anticoagulant heparins (NACH) and chemotherapy would allow for optimization of treatments in the tumor microenvironment. In studies that are currently underway, we are targeting the sites of tumor neovascularization using a