Intraductal Delivery of Adenoviruses Targets Pancreatic Tumors in Transgenic Ela-myc Mice and Orthotopic Xenografts
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Anabel José1,2, Luciano Sobrevals1,2, Juan Miguel Camacho-Sánchez3, Meritxell Huch2, Núria Andreu2, Eduard Ayuso4, Pilar Navarro5, Ramon Alemany3, Cristina Fillat1,2
1 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona.
2 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona.
3 Laboratori de Recerca Traslacional IDIBELL-Institut Català d’Oncologia, L’Hospitalet de Llobregat.
4 Centre de Biotecnologia Animal i Teràpia Gènica and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM, Barcelona.
5 Institut de Recerca Hospital del Mar-IMIM, Barcelona, Spain.
Cristina Fillat, email:
Keywords: Pancreatic cancer, adenovirus, orthotopic xenografts, transgenic mice, thymidine kinase.
Received: December 21, 2012, Accepted: January 10, 2013, Published: January 12, 2013
Gene-based anticancer therapies delivered by adenoviruses are limited by the poor viral distribution into the tumor. In the current work we have explored the feasibility of targeting pancreatic tumors through a loco-regional route.
We have taken advantage of the ductal network in the pancreas to retrogradelly inject adenoviruses through the common bile duct in two different mouse models of pancreatic carcinogenesis: The transgenic Ela-myc mice that develop mixed neoplasms displaying both acinar-like and duct-like neoplastic cells affecting the whole pancreas; and mice bearing PANC-1 and BxPC-3 orthotopic xenografts that constitute a model of localized human neoplastic tumors. We studied tumor targeting and the anticancer effects of newly thymidine kinase-engineered adenoviruses both in vitro and in vivo, and conducted comparative studies between intraductal or intravenous administration. Our data indicate that the intraductal delivery of adenovirus efficiently targets pancreatic tumors in the two mouse models. The in vivo application of AduPARTKT plus ganciclovir (GCV) treatment induced tumor regression in Ela-myc mice. Moreover, the intraductal injection of ICOVIR15-TKT oncolytic adenoviruses significantly improved mean survival of mice bearing PANC-1 and BxPC-3 pancreatic xenografts from 30 to 52 days and from 20 to 68 days respectively (p<0.0001) when combined with GCV. Of notice, both AduPARTKT and ICOVIR15-TKT antitumoral responses were stronger by ductal viral application than intravenously, in line with the 38-fold increase in pancreas transduction observed upon ductal administration.
In summary our data show that cytotoxic adenoviruses retrogradelly injected to the pancreas can be a feasible approach to treat localized pancreatic tumors.
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