TY - JOUR
T1 - A preclinical model of minimal residual cancer in the muscle highlights challenges associated with adenovirus-mediated p53 gene transfer
AU - Oakley, R
AU - Phillips, E
AU - Hooper, R
AU - Wilson, D
AU - Partridge, M
PY - 2002
Y1 - 2002
N2 - Purpose: 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. Experimental Design: 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 C57B1/6 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
AB - Purpose: 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. Experimental Design: 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 C57B1/6 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
UR - http://www.scopus.com/inward/record.url?scp=0036278655&partnerID=8YFLogxK
M3 - Article
SN - 1557-3265
VL - 8
SP - 1984
EP - 1994
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -
