Luned M Badder, James A Davies, Valerie S Meniel, Mahulena Marušková, Beatriz Salvador-Barbero, Rebecca J Bayliss, Toby J Phesse, Catherine Hogan, Alan L Parker
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引用次数: 0
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) represent an unmet clinical need. Approximately 90% of PDACs express high levels of αvβ6 integrin. We have previously described Ad5NULL-A20, an adenovirus vector with ablated native means of cell entry and retargeted to αvβ6 integrin by incorporation of an A20 peptide.
Methods: Here, we incorporate suicide genes FCY1 and FCU1 encoding for cytosine deaminase (CDase) or a combination of CDase and UPRTase, capable of catalysing a non-toxic prodrug, 5-FC into the chemotherapeutic 5-FU and downstream metabolites, into replication-deficient Ad5 and Ad5NULL-A20.
Results: We show that Ad5NULL-A20 enables the transfer of suicide genes to αvβ6 integrin-positive PDAC cells which, in combination with 5-FC, results in cell death in vitro which is further mediated by a bystander effect in non-transduced cells. Intratumoural delivery of Ad5NULL-A20.FCU1 in combination with intraperitoneal delivery of 5-FC further results in tumour growth inhibition in a cell line xenograft in vivo. Using clinically-relevant 3D organoid models, we show selective transduction and therapeutic efficacy of FCU1 transgenes in combination with 5-FC.
Conclusion: Taken together these data provide the preclinical rationale for combined Ad5NULL-A20.FCU1 plus 5-FC as a promising targeted therapy to mediate "in-tumour chemotherapy" and merits further investigation for the treatment of PDAC patients.
期刊介绍:
The British Journal of Cancer is one of the most-cited general cancer journals, publishing significant advances in translational and clinical cancer research.It also publishes high-quality reviews and thought-provoking comment on all aspects of cancer prevention,diagnosis and treatment.