Thrombocytopenia Induced-Tumor Vascular Leakiness Increases Drug Efficacy

Abstract 2105

Important research goals in cancer therapy include delivering high doses of drug to tumor sites for maximum treatment efficacy while minimizing side effects to healthy organs. We have recently demonstrated that platelets contribute to tumor vascular homeostasis through prevention of severe tumor hemorrhage. In order to define a new way of increasing drug delivery to the tumor site, we hypothesized that the selective induction of tumor vascular leakiness by thrombocytopenia may facilitate the delivery of chemotherapeutic agents to tumors. Using a mammary carcinoma murine model, we showed that platelet depletion induced hemorrhage specifically at the tumor site and favored the accumulation of fluorescently-labeled microspheres in the tumor. Moreover, the induction of thrombocytopenia in tumor-bearing mice before injection of the chemotherapeutic drug paclitaxel significantly reduced tumor growth compared to mice with normal platelet count that were treated with paclitaxel. Analysis of the tumors ex vivo revealed an increase in tumor apoptosis and a reduction in tumor cell proliferation in thrombocytopenic mice that received therapy. No increased toxicity was seen on other organs and blood cells. Taken together, our results indicate that low platelet count selectively induces leakiness of tumor vessels and allows better access of a chemotherapeutic agent to the tumor, enhancing its tumoricidal effect.