báo cáo hóa học: Identifying alemtuzumab as an anti-myeloid cell antiangiogenic therapy for the treatment of ovarian cancer

Tuyển tập các báo cáo nghiên cứu về hóa học được đăng trên tạp chí sinh học quốc tế đề tài : Identifying alemtuzumab as an anti-myeloid cell antiangiogenic therapy for the treatment of ovarian cancer
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báo cáo hóa học:" Identifying alemtuzumab as an anti-myeloid cell antiangiogenic therapy for the treatment of ovarian cancer"Journal of Translational Medicine BioMed Central Open AccessResearchIdentifying alemtuzumab as an anti-myeloid cell antiangiogenictherapy for the treatment of ovarian cancerHeather L Pulaski1, Gregory Spahlinger2, Ines A Silva2, Karen McLean1,Angela S Kueck1, R Kevin Reynolds1, George Coukos3, Jose R Conejo-Garcia4and Ronald J Buckanovich*1,2Address: 1Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, USA, 2Department of Internal Medicine, University ofMichigan, Ann Arbor, USA, 3Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, USA and 4Departments ofMicrobiology and Immunology, Dartmouth Medical School, Hanover, USAEmail: Heather L Pulaski - heascott@umich.edu; Gregory Spahlinger - Gspahlin@umich.edu; Ines A Silva - iness@umich.edu;Karen McLean - khajra@mich.edu; Angela S Kueck - akueck@umich.edu; R Kevin Reynolds - rkr@umich.edu;George Coukos - gcks@mail.med.upenn.edu; Jose R Conejo-Garcia - Jose.R.Conejo-Garcia@Dartmouth.edu;Ronald J Buckanovich* - ronaldbu@umich.edu* Corresponding authorPublished: 19 June 2009 Received: 7 January 2009 Accepted: 19 June 2009Journal of Translational Medicine 2009, 7:49 doi:10.1186/1479-5876-7-49This article is available from: http://www.translational-medicine.com/content/7/1/49© 2009 Pulaski et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Murine studies suggest that myeloid cells such as vascular leukocytes (VLC) and Tie2+ monocytes play a critical role in tumor angiogenesis and vasculogenesis. Myeloid cells are a primary cause of resistance to anti-VEGF therapy. The elimination of these cells from the tumor microenvironment significantly restricts tumor growth in both spontaneous and xenograft murine tumor models. Thus animal studies indicate that myeloid cells are potential therapeutic targets for solid tumor therapy. Abundant VLC and Tie2+ monocytes have been reported in human cancer. Unfortunately, the importance of VLC in human cancer growth remains untested as there are no confirmed therapeutics to target human VLC. Methods: We used FACS to analyze VLC in ovarian and non-ovarian tumors, and characterize the relationship of VLC and Tie2-monocytes. We performed qRT-PCR and FACS on human VLC to assess the expression of the CD52 antigen, the target of the immunotherapeutic Alemtuzumab. We assessed Alemtuzumabs ability to induce complement-mediated VLC killing in vitro and in human tumor ascites. Finally we assessed the impact of anti-CD52 immuno-toxin therapy on murine ovarian tumor growth. Results: Human VLC are present in ovarian and non-ovarian tumors. The majority of VLC appear to be Tie2+ monocytes. VLC and Tie2+ monocytes express high levels of CD52, the target of the immunotherapeutic Alemtuzumab. Alemtuzumab potently induces complement-mediated lysis of VLC in vitro and ex-vivo in ovarian tumor ascites. Anti-CD52 immunotherapy targeting VLC restricts tumor angiogenesis and growth in murine ovarian cancer. Conclusion: These studies confirm VLC/myeloid cells as therapeutic targets in ovarian cancer. Our data provide critical pre-clinical evidence supporting the use of Alemtuzumab in clinical trials to test its efficacy as an anti-myeloid cell antiangiogenic therapeutic in ovarian cancer. The identification of an FDA approved anti-VLC agent with a history of clinical use will allow immediate proof-of-principle clinical trials in patients with ovarian cancer. Page 1 of 14 (page number not for citation purposes)Journal of Translational Medicine 2009, 7:49 http://www.translational-medicine.com/content/7/1/49 ...