Tumor-targeting adenovirus OBP-401 inhibits primary and metastatic tumor growth of triple-negative breast cancer in orthotopic nude-mouse models
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Shuya Yano1,2,3, Kiyoto Takehara1,2,3, Hiroyuki Kishimoto3, Hiroshi Tazawa4, Yasuo Urata5, Shunsuke Kagawa3, Michael Bouvet2, Toshiyoshi Fujiwara3, Robert M. Hoffman1,2
1AntiCancer, Inc., San Diego, CA, USA
2Department of Surgery, University of California San Diego, CA, USA
3Department of Gastroenterological Surgery, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
4Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan
5Oncolys BioPharm Inc., Tokyo, Japan
Robert M. Hoffman, email: [email protected]
Toshiyoshi Fujiwara, email: [email protected]
Keywords: triple-negative breast cancer, TNBC, high-metastatic, variants, nude mouse, adenovirus, OBP-401
Abbreviations: GFP, green fluorescent protein; RFP, red fluorescent protein.
Received: September 27, 2016 Accepted: October 24, 2016 Published: November 11, 2016
Our laboratory previously developed a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of the human MDA-MB-231 cell line in nude mice. The isolated variant was highly-invasive in the mammary gland and lymphatic channels and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. In the present study, the tumor-selective telomerase dependent OBP-401 adenovirus was injected intratumorally (i.t.) (1 × 108 PFU) when the high-metastatic MDA-MB-231 primary tumor expressing red fluorescent protein (MDA-MB-231-RFP) reached approximately 500 mm3 (diameter; 10 mm). The mock-infected orthotopic primary tumor grew rapidly. After i.t. OBP-401 injection, the growth of the orthotopic tumors was arrested. Six weeks after implantation, the fluorescent area and fluorescence intensity showed no increase from the beginning of treatment. OBP-401 was then injected into high-metastatic MDA-MB-231-RFP primary orthotopic tumor growing in mice which already had developed metastasis within lymphatic ducts. All 7 of 7 control mice subsequently developed lymph node metastasis. In contrast, none of 7 mice which received OBP-401 had lymph node metastasis. Seven of 7 control mice also had gross lung metastasis. In contrast, none of the 7 mice which received OBP-401 had gross lung metastasis. Confocal laser microscopy imaging demonstrated that all control mice had diffuse lung metastases. In contrast, all 7 mice which received OBP-401 only had a few metastatic cells in the lung. OBP-401 treatment significantly extended survival of the treated mice.
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