Oncolytic adenoviruses armed with thymidine kinase can be traced by PET imaging and show potent antitumoural effects by ganciclovir dosing

• Published in: PloS one 2011-10, Vol.6 (10), p.e26142
• Main Authors: Abate-Daga, Daniel, Andreu, Nuria, Camacho-Sánchez, Juan, Alemany, Ramon, Herance, Raúl, Millán, Olga, Fillat, Cristina
• Format: Article
• Language: English
• Subjects: Adenoviridae - drug effects; Adenoviridae - genetics; Adenoviridae - physiology; Adenoviruses; Animals; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacology; Binding sites; Biology; Cancer; Cancer therapies; Cell Line, Tumor; Computed tomography; Deoxyribonucleic acid; DNA; Dosage; Dose-Response Relationship, Drug; Ganciclovir; Ganciclovir - adverse effects; Ganciclovir - pharmacology; Gene expression; Gene therapy; Herpes viruses; Humans; Imaging; Immunotherapy; Kinases; Medical imaging; Medicine; Melanoma; Mice; Oncolysis; Oncolytic Viruses - drug effects; Oncolytic Viruses - genetics; Oncolytic Viruses - physiology; Pancreatic cancer; Pancreatic Neoplasms - diagnostic imaging; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - therapy; Pollution monitoring; Positron emission; Positron emission tomography; Promoter Regions, Genetic - genetics; Prostate; Proteins; Retina; Retinoblastoma; Selectivity; Suicide; Suicide genes; Thymidine; Thymidine kinase; Thymidine Kinase - genetics; TK gene; Tumors; Viral proteins; Virus Replication - drug effects; Viruses; Xenograft Model Antitumor Assays; Yeast
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0026142

Replication-competent adenoviruses armed with thymidine kinase (TK) combine the concepts of virotherapy and suicide gene therapy. Moreover TK-activity can be detected by noninvasive positron emission-computed tomography (PET) imaging, what could potentially facilitate virus monitoring in vivo. Here, we report the generation of a novel oncolytic adenovirus that incorporates the Tat8-TK gene under the control of the Major Late Promoter in a highly selective backbone thus providing selectivity by targeting the retinoblastoma pathway. The selective oncolytic TK virus, termed ICOVIR5-TK-L, showed reduced potency compared to a non-selective counterpart. However the combination of ICOVIR5-TK-L with ganciclovir (GCV) induced a potent antitumoural effect similar to that of wild type adenovirus in a preclinical model of pancreatic cancer. Although the treatment with GCV provoked a reduction in the viral yield, both in vitro and in vivo, a two-cycle treatment of virus and GCV resulted in an enhanced antitumoral response that correlated with high TK-activity, based on microPET measurements. Thus, TK-expressing oncolytic adenoviruses can be traced by PET imaging providing real time information on the activity of the virus and its antitumoral potency can be optimized by GCV dosing.