Reovirus as an experimental therapeutic for brain and leptomeningeal metastases from breast cancer.
Brain and leptomeningeal metastases are common in breast cancer patients and our current treatments are ineffective. Reovirus type 3 is a replication competent, naturally occurring virus that usurps the activated Ras-signaling pathway (or an element thereof) of tumor cells and lyses them but leaves normal cells relatively unaffected. In this study we evaluated reovirus as an experimental therapeutic in models of central nervous system (CNS) metastasis from breast cancer. We found all breast cancer cell lines tested were susceptible to reovirus, with > 50% of these cells lysed within 72 h of infection. In vivo neurotoxicity studies showed only mild local inflammation at the injection site and mild communicating hydrocephalus with neither diffuse encephalitis nor behavioral abnormalities at the therapeutically effective dose of reovirus (intracranial) (ie 10(7) plaque-forming units) or one dose level higher. In vivo, a single intratumoral administration of reovirus significantly reduced the size of tumors established from two human breast cancer cell lines and significantly prolonged survival. Intrathecal administration of reovirus also remarkably prolonged survival in an immunocompetent racine model of leptomeningeal metastases. These data suggest that the evaluation of reovirus as an experimental therapeutic for CNS metastases from breast cancer is warranted.
Yang
W Q
WQ
Department of Oncology, University of Calgary, Tom Baker Cancer Centre, Alberta, Canada.
Senger
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DL
Lun
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Muzik
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Shi
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Dyck
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RH
Norman
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Brasher
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Rewcastle
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George
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Stewart
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Lee
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Forsyth
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D000818:Animals; D001932:Brain Neoplasms / Q000556:secondary* / Q000628:therapy* / Q000821:virology; D001943:Breast Neoplasms / Q000628:therapy*; D016923:Cell Death; D045744:Cell Line, Tumor; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D015552:Injections, Intralesional; D007928:Lethal Dose 50; D012089:Mammalian orthoreovirus 3; D008577:Meningeal Neoplasms / Q000556:secondary / Q000628:therapy / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D023421:Models, Animal; D009374:Neoplasms, Experimental; D012088:Reoviridae Infections / Q000150:complications*; D014162:Transfection / Q000379:methods
D049452:Green Fluorescent Proteins