Carcinogenesis, Vol 18, 2457-2459, Copyright © 1997 by Oxford University Press
SC Liu, JS Murley, G Woloschak and DJ Grdina
The clinically approved cytoprotector amifostine, designated WR-2721,
[S-2-(3-aminopropylamino)ethylphosphorothioic acid], protects against both
radiation and drug-induced mutagenesis in animal systems. These effects
extend over a wide concentration range making amifostine a strong candidate
for evaluation as a possible cancer chemopreventive agent. To better
identify and develop potential intermediate biomarkers for chemoprevention
at the molecular level we applied the technique of differential display
RT-PCR to assess the effects of both the thiol (SH), i.e. WR1065 and the
disulfide (SS), i.e. WR-33278, metabolites of amifostine on gene expression
in CHO-AA8 cells. Cells were exposed to either 40 microM or 4 mM of each
agent for 30 min, and subsequent changes in gene expression were identified
and contrasted to that found in corresponding untreated control cells. One
band that showed a differential response was sequenced and was found to
have 78% homology with a segment of the human pHL-1 cDNA clone contained in
GenBank. This clone contains a COX III mitochondrial DNA insert and two
exons of human c-myc. Northern blot analyses were performed by using the
cloned human c-myc exon 1 probe to confirm whether c-myc gene expression
was affected. Repression of c-myc expression was observed under all of the
conditions evaluated. An exposure of cells to 40 microM of the disulfide
form of amifostine was the most effective in repressing c- myc, i.e. 27% of
control level. A concentration of 4 mM of the disulfide form reduced gene
expression to 45% of the control level, while the thiol form was less
effective, with 4 mM and 40 microM concentrations reducing c-myc gene
expression to 65% and 46% of control levels, respectively.
ARTICLES
Repression of c-myc gene expression by the thiol and disulfide forms of the cytoprotector amifostine
Center for Mechanistic Biology and Biotechnology, Argonne National Laboratory, IL 60439, USA.
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