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

被引:62
作者
McPhillips, F
Mullen, P
Monia, BP
Dorr, FA
Smyth, JF
Langdon, SP [1 ]
机构
[1] Western Gen Hosp, Imperial Canc Res Fund, Med Oncol Unit, Edinburgh EH4 2XU, Midlothian, Scotland
[2] ISIS Pharmaceut Inc, Carlsbad, CA USA
关键词
Raf; antisense; ovarian; cancer; oligodeoxynucleotide;
D O I
10.1054/bjoc.2001.2139
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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)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. (C) 2001 Cancer Research Campaign.
引用
收藏
页码:1753 / 1758
页数:6
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