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Survivin as a novel
radiation/CIS platinum/tumor specific promoter for conditional oncolytic viral
therapy
W. O. Arafat, D. Rein, D. Buchsbaum, D. Curiel, Z. Zhu
St. Jude Hospital, Memphis, TN; UAB, Birmingham, AL
Background.
Conditional oncolytic viral therapy (CRVT) is a novel
approach in treatment of cancer.
It implies using viral genetic modification to exploit the powerful oncolytic
potency of competent virus strictly in tumor.
Using recombinant adenovirus (Ad) with tissue specific promoter (TSP) as a
vector, different clinical trial has utilized CRVT concept.
Although most of these trials employed CRVT in combination with radio or
chemotherapy, none of the vector delivered was originally designed for
combination treatment.
We hypothesize that radiotherapy (RT) and/or chemotherapy may enhance the
selectivity and level of induction of TSP leading to a powerful CRVT system.
Methods.
We have constructing eligible radiation or cis platinum
inducible promoter in context of Ad including Survivin.
Glioma cell lines, cervical cancer as well as prostate cancer cell lines were
infected with different MOI of the TSP Ad or CMV Ad then cells were exposed to a
RT or to cis platinum.
FACS analysis and Luc assay was used to detect level of gene expression.
Quantitative RTPCR to the corresponding genes was done from RNA isolated from RT
or platinum treated cells.
A replicative Ad driven by survivin promoter were constructed and tested in
glioma cell lines.
Results.
Ad driven Survivin was made and shows specificity to glioma cell
lines, prostate cell lines and cervical cell lines.
RT increase the expression of gene expression by Cells treated with RT and Ad
Luc driven by Survivin promoter up to 5-fold increase in expression after 2 Gy
of RT in compare to non-irradiated cells.
RNA analysis was done and has shown increase copy 30 fold for survivin.
Cis-platinum treatment shown similar trend in primary cancer cervix cell.
Replicative Ad driven by survivin promoter showed a significant enhancing
oncolytic effect after treatment with RT in glioma cell lines.
Conclusions.
Replicative Ad vector employing survivin promoter is a
promising tool that could lead to the enhancement of selectivity and specificity
of CRVT in radiogenetic and chemotherapy context.
Copyright 2004 American Society of Clinical Oncology All rights
reserved worldwide.
Source: http://www.asco.org/ac/1,1003,_12-002636-00_18-0026-00_19-004157,00.asp
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