to the patient. In addition, oral dosing means patients can receive anticoagulation therapy at home. The introduction of these orally active, novel anticoagulants is likely to result in an improvement in the prevention and treatment of thromboembolic disorders, and may overcome many of the concerns associated with currently available Danusertib PHA-739358 therapies. Because of their predictable pharmacology, these newer agents are also reliable and may be safer than established antithrombotic drugs. Acknowledgments The authors would like to acknowledge Sarah Atkinson of Chameleon Communications International, who 1384 Vascular Health and Risk Management 2008:4 Lassen and Laux provided medical writing services with funding from BayerHealthcare AG. Disclosures The authors have confl icts of interest to disclose.
Abbreviations ACCP, American College of Chest Physicians, AF, atrial Tivozanib fi brillation, aPTT, activated partial thromboplastin time, ASA, acetylsalicylic acid, bid, twice daily, AT, antithrombin, DTI, direct thrombin inhibitor, DVT, deep vein thrombosis, HIT, heparin induced thrombocytopenia, INR, international normalized ratio, LMWH, low molecular weight heparin, PE, pulmonary embolism, TF, tissue factor, TKR, total knee replacement, THR, total hip replacement, od, once daily, UFH, unfractionated heparin, VKA, vitamin K antagonist, VTE, venous thromboembolism. Background Epithelial ovarian cancer is the fifth leading cause of cancer related deaths in women and is the most lethal of the gynecologic malignancies.
The standard of care for newly diagnosed EOC patients is surgical debulking and administration of a platinum and taxane based chemotherapy regimen, usually carboplatin and paclitaxel, given either as neo adjuvant or adjuvant therapy. With this regimen, 80 90% will initially respond but less than 10 15% will remain in complete remission. The percentage of non responders increases significantly to 65 75% for recurrent cancers. Additionally, some patients progress during or shortly after completion of chemotherapy. Recurrent ovarian cancer is characterized by chemoresistance to prior treatments, most commonly to Paclitaxel. Previously, we described the identification of a sub population of EOC cells that are resistant to this agent.
This sub group of cells has a functional Toll Like Receptor 4 Myeloid Differentiation Protein 88 Nuclear factor B pathway, and the ligation of TLR 4 by Paclitaxel is able to induce NF B activation and secretion of proinflammatory and pro tumor cytokines IL 6, IL 8, MCP 1, and GRO �? This response confers resistance to apoptosis, and more importantly, enhances tumor growth. In contrast, these events were not observed in the group of EOC cells that did not have a functional TLR4 MyD88 pathway and are sensitive to Paclitaxel. The treatment of Type I EOC cells with Paclitaxel is not only ineffective in killing these cells, but more importantly, can be detrimental since it may enhance tumor growth. Therefore, the identification of potential new therapies for this specific cell population would be beneficial for the treatment of ovarian cancer patients. ARRY 520 is an inhibitor of the mitotic kinesin, KSP. KSP inhibition prevents bipolar spindle formation leading to mitotic arrest and cell death. In studies comparing ARRY 520 with some of the more clinically advanced compounds and standard of care agents, ARRY 520 was shown to have superior efficacy in multiple xenograft models and is currently in a Phase I trial. More impor