Association of c-Raf expression with survival and its targeting with antisense oligonucleotides in ovarian cancer.

Abstract

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.

• Authors: F McPhillips, P Mullen, B P Monia, A A Ritchie, F A Dorr, J F Smyth, S P Langdon
• Journal: British journal of cancer (Br J Cancer) Vol. 85 Issue 11 Pg. 1753-8 (Nov 30 2001) ISSN: 0007-0920 [Print] England
• PMID: 11742498 (Publication Type: Journal Article)
• Copyright: (c) 2001 Cancer Research Campaign

Chemical References

• DNA, Antisense
• Proto-Oncogene Proteins c-raf

Topics

• Animals
• Cell Cycle (drug effects, physiology)
• Cell Division (drug effects)
• DNA, Antisense (pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Female
• Humans
• Immunohistochemistry
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• Proto-Oncogene Proteins c-raf (biosynthesis, drug effects, genetics)
• Survival Analysis
• Time Factors
• Xenograft Model Antitumor Assays