A preclinical model of minimal residual cancer in the muscle highlights challenges associated with adenovirus-mediated p53 gene transfer.
OBJECTIVE
Clinical studies have revealed that tumors may recur at the operative site if radioresistant p53 mutation-positive residual disease remains in the body after treatment. Destruction of these remaining malignant cells, which can be present in both mucosal and deep muscle margins, may be achieved using p53-mediated gene transfer techniques. Most preclinical studies designed to assess the feasibility of harnessing this approach have used s.c. tumor models in nude mice, but it is anticipated that transduction of tumor cells in the muscle in immune-competent hosts may be more difficult.


METHODS
To address this point a new rodent model of residual cancer was established implanting PDVC57B tumor cells to create multiple tumor tracts in the muscle of syngeneic immune-competent C57Bl/6 mice. s.c. tumors and a s.c. model of residual disease were used as comparators.


RESULTS
In the s.c. model of residual disease a single administration of 5 x 10(10) viral particles of Ad5CMV-p53 suppressed the growth of encapsulated tumor at the treatment site in six of six animals, but two of these animals had viable nests of tumor outside of the encapsulated zone. However, Ad5CMV-p53 had no apparent effect on tumor cell progression in the model of residual cancer in the muscle. Creating the muscle model of residual cancer with a lower number of cells in the initial inoculum showed that immune-mediated effects, as well as those attributable to the transgene, are important in preventing tumor outgrowth. The frequency of transduction of tumor cells in the muscle, as determined after administration of Ad-beta-galactosidase, was typically <3% and markedly different from the 20% transduction observed for the s.c. tumor model.


CONCLUSIONS
These studies highlight the need to devise strategies to improve delivery of adenovirus-mediated gene transfer to nests of tumor in muscle before this modality is used to treat residual cancer at this site. These may involve approaches such as intravascular delivery, strategies to improve vector diffusion, or combination with chemotherapy or radiotherapy to enhance gene delivery at these less accessible sites of disease.
Oakley
Roth
R
Maxillofacial Surgery/Oncology, King's College Hospital, Denmark Hill, London SE5 8RX, UK.
Phillips
Elaine
E
Hooper
Richard
R
Wilson
Deborah
D
Partridge
Max
M
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D017931:DNA Primers / Q000737:chemistry; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D016158:Genes, p53 / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D019042:Muscle Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology; D009154:Mutation / Q000235:genetics; D018365:Neoplasm, Residual / Q000628:therapy*; D016133:Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D017931:DNA Primers; D016159:Tumor Suppressor Protein p53; D001616:beta-Galactosidase