EGF-related antisense oligonucleotides inhibit the proliferation of human ovarian carcinoma cells.
BACKGROUND
The epidermal growth factor (EGF)-like peptides CRIPTO (CR), amphiregulin (AR) and transforming growth factor alpha (TGFalpha) are expressed in human ovarian carcinomas.


METHODS
The expression of AR, CR and TGFalpha in ovarian carcinoma cell lines was assessed by immunocytochemistry and reverse transcriptase polymerase chain reaction (RT-PCR). The antiproliferative effects of antisense phosphorothioate oligodeoxynucleotides (AS S-Oligos) directed against either AR, CR or TGFalpha was evaluated by using a clonogenic assay.


RESULTS
A majority of the ovarian carcinoma cell lines was found to express TGFalpha, AR and CR mRNAs and proteins. AS S-Oligos directed against either AR, CR or TGFalpha were able to inhibit the anchorage-independent growth of NIH:OVCAR3 and NIH:OVCAR8 cells in a dose dependent manner. A 30%-50% growth inhibition was observed at a 2 microM concentration of the AS S-Oligos. Treatment of these cells with combinations of EGF-related AS S-Oligos resulted in a more significant growth inhibition when compared to treatment with a single AS S-oligo. A 60%-75% growth inhibition was observed using combinations of AR, CR and TGFalpha AS S-oligos at a total concentration of 2 microM. An additive growth-inhibitory effect occurred when ovarian carcinoma cells were exposed to the AS S-Oligos after treatment with either paclitaxel or cis-platinum.


CONCLUSIONS
These data suggest that EGF-related peptides function as autocrine growth factors in ovarian carcinoma cells, and that they might represent targets for experimental therapy of ovarian carcinoma.
Casamassimi
A
A
Novel Therapeutic Approaches Section-Oncologia Sperimentale D, ITN-Fondazione Pascale, Napoli, Italy.
De Luca
A
A
Agrawal
S
S
Stromberg
K
K
Salomon
D S
DS
Normanno
N
N
D066258:Amphiregulin; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013873:Thionucleotides; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
C587848:AREG protein, human; D066258:Amphiregulin; D066255:EGF Family of Proteins; D006023:Glycoproteins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D013873:Thionucleotides; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor