c-raf-1 depletion and tumor responses in patients treated with the c-raf-1antisense oligodeoxynucleotide ISIS 5132 (CGP 69846A)

Citation
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
Citations number
45
Categorie Soggetti
Oncology
Journal title
CLINICAL CANCER RESEARCH
ISSN journal
10780432 → ACNP
Volume
5
Issue
12
Year of publication
1999
Pages
3977 - 3982
Database
ISI
SICI code
1078-0432(199912)5:12<3977:CDATRI>2.0.ZU;2-5
Abstract
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.