An E2F-responsive replication-selective adenovirus targeted to the defective cell cycle in cancer cells: potent antitumoral efficacy but no toxicity to normal cell.
To improve the transduction and distribution of adenovirus in a tumor mass, we generated an adenovirus to selectively replicate in tumors. We hypothesized that after infection the replicating adenovirus would spread throughout the tumor mass and cause direct oncolysis of tumor cells. E2F transcription factors are critical regulators of cell growth and are often overexpressed in cancer cells because of the frequent aberrations in the pRb/E2F/p16(INK4a) pathway. As a result, a majority of tumor cells exist in a high proliferative state. E2F-1 is a transcription factor that activates its own transcription and that of other genes involved in the G(1) to S transition phase of the cell cycle. We constructed an adenovirus (Ad(E2F-1(RC)) so that E1A expression and viral replication were under the control of the human E2F-1 promoter element. AdE2F-1(RC) virus replicated as efficiently as the wild-type adenovirus and caused extensive cell killing in a panel of tumor cells in vitro. In contrast, nonproliferating normal epithelial, fibroblast, and endothelial cells, which express no E2F-1, were not able to support AdE2F-1(RC) replication. In animal studies, different dosing regimens of AdE2F-1(RC) administered to flank xenografts of ovarian and lung cancers led to a significant therapeutic advantage often surpassing that seen in animals treated with the wild-type adenovirus. This novel selectively replicating adenovirus offers a promising treatment platform for a variety of cancers of which the hallmark is uncontrolled cell growth.
Tsukuda
Kazunori
K
Department of Surgery, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
Wiewrodt
Rainer
R
Molnar-Kimber
Katherine
K
Jovanovic
Vuk P
VP
Amin
Kunjlata Manibhai
KM
D000230:Adenocarcinoma / Q000473:pathology / Q000628:therapy / Q000821:virology*; D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D017500:Adenovirus E1A Proteins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000502:physiology; D003588:Cytopathogenic Effect, Viral; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000821:virology; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000628:therapy / Q000821:virology*; D051379:Mice; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy / Q000821:virology*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D014779:Virus Replication / Q000235:genetics / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; D014157:Transcription Factors