CONICET | Buscador de Institutos y Recursos Humanos

TIPHANIE DURFORT, ALESYA FOKINA, MARIYA MESCHANINOVA, MERCEDES TKACH, MARTÍN A. RIVAS, PATRICIA V. ELIZALDE, ALYA VENYAMINOVA, ROXANA SCHILLACI, JEAN-CHRISTOPHE FRANÇOIS

Lugar:

Fukuoka, Japan

Reunión:

Simposio; Joint Symposium of 5th OTS-19th Antisense Symposium; 2009

Institución organizadora:

OTS

Resumen:

Type I insulin-like growth factor (IGF-I) and its receptor (IGF-IR) have been implicated in progression of a large number of cancers and represent important targets for anti-cancer strategies. Numerous nucleic acid-based strategies have been developed to block IGF-I and IGF-IR expression, such as antisense, ribozymes, siRNA and triplex-forming oligonucleotides. We will present our recent data obtained with modified DNAzyme targeted to IGF-I coding sequences and modified siRNAs targeted to IGF-IR and its ligand. A series of 10−23 DNAzymes targeted to different IGF-I mRNA sites were designed to catalyze in vitro site-speciﬁc RNA cleavage at these sites. To increase their properties, these DNAzyme were modiﬁed in their substrate binding- and catalytic domains. Using plasmid constructs with reporter gene fused to IGF-I coding sequences, we have shown the specificity and efficiency of our designed DNAzymes to cleave their target sites in rat hepatoma cells. After selecting the most efficient sequence, we were able to determine the effect of several siRNAs designed to inhibit either IGF-I or IGF-IR directly on endogenous transcript in murine breast carcinoma and hepatoma cell lines. Preliminary in vivo studies have shown that treatment with either anti-IGF-IR or IGF-I siRNAs of murine breast cancer cells induced a profound decrease of tumor growth when treated cells were injected subcutaneously in syngenic mice. Moreover, while one of the most exciting aspects regarding the potential therapeutic use of nucleic-acid based approaches targeting IGF-IR is the evidence indicating that a host immune response may be involved in the antitumoral effect, we start to explore whether the serial injection of IGF-IR siRNA-treated breast cancer cells could provide protection against wild-type tumor challenge in vivo. At the end, our designed molecules will certainly be useful to understand the role of IGF-I molecules in triggering antitumoral immune response.