Association of c-Raf expression with survival and its targeting with antisense oligonucleotides in ovarian cancer.
c-Raf is an essential component of the extracellular related kinase (ERK) signal transduction pathway. Immunohistochemical staining indicated that c-Raf was present in 49/53 ovarian adenocarcinomas investigated and high c-Raf expression correlated significantly with poor survival (P = 0.002). c-Raf protein was detected in 15 ovarian cancer cell lines. Antisense oligodeoxynucleotides (ODNs) (ISIS 5132 and ISIS 13650) reduced c-Raf protein levels and inhibited cell proliferation in vitro. Selectivity was demonstrated by the lack of effect of ISIS 5132 on A-Raf or ERK, while a random ODN produced only minor effects on growth and did not influence c-Raf expression. ISIS 5132 produced enhanced apoptosis and cells accumulated in S and G(2)/M phases of the cell cycle. In vivo, ISIS 5132 inhibited growth of the s.c. SKOV-3 xenograft while a mismatch ODN had no effect. These data indicate that high levels of c-Raf expression may be important in ovarian cancer and use of antisense ODNs targeted to c-Raf could provide a strategy for the treatment of this disease.
McPhillips
F
F
ICRF Medical Oncology Unit, Western General Hospital, Edinburgh, EH4 2XU, UK.
Mullen
P
P
Monia
B P
BP
Ritchie
A A
AA
Dorr
F A
FA
Smyth
J F
JF
Langdon
S P
SP
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D016373:DNA, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019908:Proto-Oncogene Proteins c-raf / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D016019:Survival Analysis; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D016373:DNA, Antisense; D019908:Proto-Oncogene Proteins c-raf