Assessment of growth inhibition and morphological changes in in vitro and in vivo hepatocellular carcinoma models post treatment with dl1520 adenovirus.
OBJECTIVE
E1B-deleted virus dl1520 (ONYX-015) has been previously used in clinical trials mainly for treatment of head and neck tumors, and has been shown to have beneficial effects independent of p53 status. The main aim of this investigation was to carry out a preclinical study for assessment of the use of dl1520 in in vitro and in vivo hepatocellular carcinoma (HCC) models with various p53 status (deleted, mutant, and wild type), and study the ultrastructural changes in the carcinoma cells during and following treatment with dl1520.


METHODS
dl1520 (ONYX-015) virus was used for treatment of three HCC cell lines in culture, then for treatment of developed xenografts in SCID mice. The effects of dl1520 on HCC cell growth and accompanied morphological changes were assessed by various techniques including transmission electron microscopy. dl1520 infection was confirmed using polymerase chain reaction and immunolabeling at transmission electron microscopy level.


RESULTS
dl1520 was effective in killing cells and inhibiting HCC cell growth both in vitro and in vivo. The cell killing was at higher levels in cells possessing abnormal p53. Survival rates in SCID mice treated with dl1520 were statistically significantly higher in HCC tumors with deleted and mutant p53, than in tumors with wild-type p53.


CONCLUSIONS
The findings in this study suggest that dl1520 could be safely and effectively used for treatment of HCC dependent on the p53 status of the cells in vivo. Characteristic morphological changes that took place in the dl1520-treated HCC cells/tumors were distinct at transmission electron microscopy level and are the first of their kind to be reported.
Habib
Nagy A
NA
Department of Surgery, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. nagy.habib@ic.ac.uk
Mitry
Ragai R
RR
Sarraf
Catherine E
CE
Jiao
Long R
LR
Havlík
Roman
R
Nicholls
Joanna
J
Jensen
Steen L
SL
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002455:Cell Division; D002470:Cell Survival; D017353:Gene Deletion; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D015151:Immunoblotting; D008113:Liver Neoplasms / Q000628:therapy*; D008114:Liver Neoplasms, Experimental / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D008854:Microscopy, Electron; D009154:Mutation; D009368:Neoplasm Transplantation; D013997:Time Factors; D014407:Tumor Cells, Cultured