Intraductal delivery of adenoviruses targets pancreatic tumors in transgenic ela-myc mice and orthotopic xenografts

// Anabel Jose 1,2 , Luciano Sobrevals 1,2 , Juan Miguel Camacho-Sanchez 3 , Meritxell Huch 2 , Nuria Andreu 2 , Eduard Ayuso 4 , Pilar Navarro 5 , Ramon Alemany 3 , Cristina Fillat 1,2 1 Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona. 2 Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Barcelona. 3 Laboratori de Recerca Traslacional IDIBELL-Institut Catala d’Oncologia, L’Hospitalet de Llobregat. 4 Centre de Biotecnologia Animal i Terapia Genica and Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas CIBERDEM, Barcelona. 5 Institut de Recerca Hospital del Mar-IMIM, Barcelona, Spain. Correspondence: 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 Abstract 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 AduPARTK T plus ganciclovir (GCV) treatment induced tumor regression in Ela-myc mice. Moreover, the intraductal injection of ICOVIR15-TK T 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