Pj. O'Dwyer et al., c-raf-1 depletion and tumor responses in patients treated with the c-raf-1antisense oligodeoxynucleotide ISIS 5132 (CGP 69846A), CLIN CANC R, 5(12), 1999, pp. 3977-3982
Abnormally regulated signaling through proliferative signal transduction pa
thways characterizes many of the common solid tumors. The best described of
these involves potentially oncogenic proteins of the Ras family, which act
ivate Raf proteins in the early steps of the mitogen-activated protein kina
se cascade. ISIS 5132, a phosphorothioate antisense oligodeoxynucleotide di
rected to the 3' untranslated region of the c-raf-1 mRNA, inhibits the grow
th of human tumor cell lines in vitro and in vivo in association with speci
fic down-regulation of target message expression. Using a semiquantitative
reverse transcription-PCR assay, we analyzed changes in c-raf-l mRNA expres
sion in peripheral blood mononuclear cells collected from patients with adv
anced cancers treated with ISIS 5132 as part of a clinical trial. Specimens
were collected for analysis pretreatment and on days 3, 5, 8, and 15 of th
e first cycle and on day 1 of each subsequent cycle. We observed significan
t reductions of c-raf-l expression from baseline by day 3 in 13 of 14 patie
nts (P = 0.002). The time course and depletion of c-raf-1 message in periph
eral blood mononuclear cells paralleled the clinical benefit in two patient
s. These findings demonstrate that ISIS 5132 specifically reduces target ge
ne expression in treated patients and that peripheral blood mononuclear cel
ls are suitable tissues for biomarker studies in future trials.