Oncolytic adenoviruses armed with thymidine kinase can be traced by PET imaging and show potent antitumoural effects by ganciclovir dosing.
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.
Institut D'Investigacions Biomèdiques August Pi i Sunyer-IDIBAPS, Barcelona, Spain.
Daniel
D
Abate-Daga
Nuria
N
Andreu
Juan
J
Camacho-Sánchez
Ramon
R
Alemany
Raúl
R
Herance
Olga
O
Millán
Cristina
C
Fillat
D000256:Adenoviridae / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015774:Ganciclovir / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D050504:Oncolytic Viruses / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000628:therapy; D049268:Positron-Emission Tomography; D011401:Promoter Regions, Genetic / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics*; D014779:Virus Replication / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D013937:Thymidine Kinase; D015774:Ganciclovir