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 G2/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. © 2001 Cancer Research Campaign http://www.bjcancer.com
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References
Avruch J, Zhang XF and Kyriakis JM (1994) Raf meets Ras: completing the framework of a signal transduction pathway. Trends Biochem Sci 19: 279–283
Cho-Chung YS (1999) Antisense oligonucleotide inhibition of serine/threonine kinases: an innovative approach to cancer treatment. Pharmacol Ther 82: 437–449
Cowsert LM (1997) In vitro and in vivo activity of antisense inhibitors of ras: potential for clinical development. Anticancer Drug Des 12: 359–371
Daum G, Eisenmann-Tapp I, Fries H-W, Troppmair J and Rapp UR (1994) The inns and outs of raf kinases. TIBS 19: 474–480
Fan Z and Mendelsohn J (1998) Therapeutic application of anti-growth factor receptor antibodies. Curr Opin Oncol 10: 67–73
Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-IS Wada H, Fujimoto J and Kohno M (1999) Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 18: 813–822
Langdon SP, Lawrie SS, Hay FG, Hawkes MM, McDonald A, Hayward IP, Schol DJ, Hilgers J, Leonard RC and Smyth JF (1988) Characterization and properties of nine human ovarian adenocarcinoma cell lines. Cancer Res 4: 6166–6172
Lau QC, Brusselbach S and Muller R (1998) Abrogation of c-Raf expression induces apoptosis in tumour cells. Oncogene 16: 1899–1902
Levack PA, Mullen P, Anderson TJ, Miller WR and Forrest APM (1987) DNA analysis of breast tumour fine needle aspirates using flow cytometry. Br J Cancer 56: 643–646
Meden H and Kuhn W (1997) Overexpression of the oncogene c-erbB-2 (HER2/neu) in ovarian cancer: a new prognostic factor. Eur J Obstet Gynecol Reprod Biol 71: 173–179
Monia BP (1997) First- and second-generation antisense inhibitors targeted to human c-raf kinase: in vitro and in vivo studies. Anticancer Drug Des 12: 327–339
Monia BP, Johnston JF, Geiger T, Muller M and Fabbro D (1996a) Antitumor activity of a phosphorothioate antisense oligodeoxynucleotide targeted against C-raf kinase. Nature Med 2: 668–675
Monia BP, Sasmor H, Johnston JF, Freier SM, Lesnik EA, Muller M, Geiger T, Altmann KH, Moser H and Fabbro D (1996b) Sequence-specific antitumor activity of a phosphorothioate oligodeoxyribonucleotide targeted to human C-raf kinase supports an antisense mechanism of action in vivo. Proc Natl Acad Sci USA 93: 15481–15484
Nemunaitis J, Holmlund JT, Kraynak M, Richards D, Bruce J, Ognoskie N, Kwoh TJ, Geary R, Dorr A, Von Hoff D and Eckhardt SG (1999) Phase I evaluation of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C-alpha, in patients with advanced cancer. J Clin Oncol 17: 3586–3595
O’Dwyer PJ, Stevenson JP, Gallagher M, Cassella A Vasilevskaya I, Monia BP, Holmlund J, Dorr FA and Yao KS (1999) c-Raf-1 depletion and tumor responses in patients treated with the c-raf-1 antisense oligodeoxynucleotide ISIS 5132 (CGP 69846A). Clin Cancer Res 5: 3977–3982
Rapp UR, Cleveland JL, Bonner TI and Storm SM (1988a) The Raf oncogenes. In: Reddy EP, Skalka AM, Curran T (eds), pp 213–253, The Oncoge ne Handbook, Amsterdam, the Netherlands, Elsevier Science Publishers B.V. 1988
Rapp UR, Huleihel M, Pawson T, Linnoila I, Minna JD, Heidecker G, Cleveland JL, Beck T, Forchhammer J and Storm SM (1988b) Role of raf oncogenes in lung carcinogenisis. J Int Assoc Study Lung Cancer 4: 162
Rozakis-Adcock M, Fernley R, Wade J, Pawson T and Bowtell D (1993) The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1. Nature 363: 83–85
Stewart CJ, Owens OJ, Richmond JA and McNicol AM (1992) Expression of epidermal growth factor receptor in normal ovary and in ovarian tumors. Int J Gynecol Pathol 11: 266–272
Storm SM, Brennscheidt U, Sithanandam G and Rapp UR (1990) Raf oncogenes in carcinogenesis. Crit Rev Oncog 2: 1–8
Teneriello MG, Ebina M, Linnoila RI, Henry M, Nash JD, Park RC and Birrer MJ (1993) p53 and Ki-ras gene mutations in epithelial ovarian neoplasms. Cancer Res 53: 3103–3108
UKCCCR (1998) United Kingdom co-ordinating committee on cancer research (UKCCCR) Guidelines for the welfare of animals in experimental neoplasia. Br J Cancer 77: 1–10
Witters L, Kumar R, Mandal M, Bennett CF, Miraglia L and Lipton A (1999) Antisense oligonucleotides to the epidermal growth factor receptor. Breast Cancer Res Treat 53: 41–50
Yuen AR, Halsey J, Fisher GA, Holmlund JT, Geary RS, Kwoh TJ, Dorr A and Sikic BI (1999) Phase I study of an antisense oligonucleotide to protein kinase C-alpha (ISIS 3521/CGP64128A) in patients with cancer. Clin Cancer Res 5: 3357–3363
Zheng CF and Guan KL (1993) Properties of MEKs, the kinases that phosphorylate and activate the extracellular signal-regulated kinases. J Biol Chem 268: 23933–23939
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McPhillips, F., Mullen, P., Monia, B. et al. Association of c-Raf expression with survival and its targeting with antisense oligonucleotides in ovarian cancer. Br J Cancer 85, 1753–1758 (2001). https://doi.org/10.1054/bjoc.2001.2139
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DOI: https://doi.org/10.1054/bjoc.2001.2139
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