Effects of novel heparin-derived compounds on tumor uptake of chemotherapeutics and chemoresponse

2537 Thrombotic complications are the second most common cause of mortality in cancer patients and fibrin deposition in the tumor microenvironment might play a key role in tumor progression and inference with tumor chemotherapeutic uptake. Treatments that target these processes may result in improved uptake of chemotherapeutic agents and subsequent inhibition of tumor growth and metastasis. Tissue Factor (TF) is frequently associated with aggressive behavior and poor outcome in tumors. We have previously demonstrated potent anti-tumor efficacy for various mechanisms that interfere with TF/VIIa. The purpose of this study was to investigate the effects of low molecular weight heparins (LMWH) and sulfated non-anticoagulant LMWH (S-NACH) on tumor chemotherapeutic uptake. Studies: (1) Nude mice xenograft A549 human lung carcinoma: LMWH or S-NACH at 10 mg/kg S.C. daily effectively limited tumor growth. (2) LCC6 human lung tumor xenograft model: Paclitaxel alone or in combination with Tinzaparin or S-NACH on tumor re-growth after discontinuation of treatment: Paclitaxel + S-NACH treatment showed significant (P<0.01) tumor growth suppression and improved survival when compared to Paclitaxel. (3) Biodistribution studies: animals were injected with LMWH S.C. daily for 5 days (10 mg/kg) then injected i.v. with [124-I]-Paclitaxel. LMWH increased [124-I]-Paclitaxel uptake into LCC6 tumors with tumor: muscle ratios several fold greater than that of [124-I]-Paclitaxel alone at 24 hrs post injection. This is a highly significant result in the light of the fact that the FDA criterion for a clinically meaningful effect is a 15% increase in uptake. (4) HPLC studies of tumor uptake of Doxorubicin (DOX in mice treated with 10 mg/kg of LMWH or S-NACH for 10 days followed by Doxorubicin (2.5 mg/kg). Both LMWH and S-NACH significantly (P<0.01) increased the uptake of chemotherapeutic agent DOX in MCF7 DOX resistant tumors by 1.5–2 folds but not in heart or lung tissues, confirming the findings obtained with another agent [124-I]-Paclitaxel. Conclusions: LMWH or S-NACH increased chemotherapeutics uptake and hence chemoresponse. Protocols utilizing adjuvant or neo-adjuvant therapy with LMWH or S-NACH could lead to increase tumor chemo responsiveness and overcoming tumor chemo resistance. No significant financial relationships to disclose.