Increased Tumor Uptake of Chemotherapeutics and Improved Chemoresponse by Novel Non-anticoagulant Low Molecular Weight Heparin

Background: Recent prospective clinical trials of low molecular weight heparins (LMWHs) have demonstrated that these agents may provide significant advantages in terms of progression-free and overall survival in certain subgroups of cancer patients. The mechanisms of improved survival associated with LMWHs are not known, and may involve direct and/or indirect effects on tumor growth. The purpose of this study was to investigate the effects of LMWH and a sulfated non- anticoagulant LMWH (S-NACH) on tumor chemotherapeutic uptake and chemoresponse. Materials and Methods: LMWH and S-NACH were tested for their ability to reduce tumor growth and tumor-associated angiogenesis using three different in vivo models. Biodistribution studies were undertaken to determine the effect of these agents on uptake of paclitaxel (PACL) and doxorubicin (Dox) by breast cancer tumor xenografts. Results: LMWH and S-NACH (10 mg/kg s.c. daily) effectively limited tumor growth of human A549 lung adenocarcinoma xenografts in the nude mouse. In an MDA453/LCC6 breast tumor xenograft model, PACL plus S-NACH showed significant (p<0.01) tumor growth suppression and improved survival when compared to PACL alone. LMWH increased ( 124- I)-PACL uptake into MDA453/LCC6 tumors, with tumor:muscle ratios several fold greater than that of ( 124- I)-PACL alone 24 h post-injection. Similarly, LMWH and S-NACH significantly (p<0.01) increased the uptake of Dox by 1.5-2 fold in MCF7 Dox-resistant tumor xenografts. Conclusion: Protocols utilizing adjuvant or neo- adjuvant therapy with LMWH or S-NACH could lead to increased tumor chemo responsiveness, potentially overcoming tumor chemoresistance. A broad spectrum of clinically significant hemostatic abnormalities may afflict as many as 15-25% of cancer patients. Furthermore, hemostatic complications are the second most common cause of mortality in cancer patients, particularly in those with pancreatic, gastrointestinal or lung cancer, and 10% of newly diagnosed myeloma patients treated with any type of chemotherapy develop deep venous thrombosis (1-3). The impact of cancer cells and chemotherapy on the activation of the coagulation cascade is responsible for a pro-thrombotic state found in many cancer patients (4). Various mechanisms related to the activation of the coagulation or fibrinolytic systems in cancer may be involved in tumor development, progression and metastasis. Activation of coagulation can have both systemic and local consequences. The systemic consequences involve deep vein thrombosis or metastasis. Local consequences involve the deposition of fibrin and plasma proteins in the tumor interstitium, resulting at least in part, from tumor vasculature that is inherently leaky. This fibrin deposition results in imposition of the initial tumor structure, regulation of inflammatory cell infiltration, induction of angiogenesis and formation of a mature stroma (5). In addition, accumulation of fibrin and other plasma proteins in the tumor