The Approach of Triple Helix Formation in Control of Gene Expression and The Treatment of Tumors Expressing IGF-I
The triplex-based strategy as the well-known antisense strategy seems to be a pow-erful approach to control gene expression in malignant cells. Few examples of the inhibitory activity of triplex-forming oligonucleotides on target genes involved in tumori-
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THE APPROACH OF TRIPLE HELIX FORMATION IN CONTROL OF GENE EXPRESSION AND THE TREATMENT OF TUMORS EXPRESSING IGF-I Lia C. Upegui-Gonzalez1, Jean-Christophe François2, Adama Ly1, and Jerzy Trojan1 1
Laboratoire de Neurologie du Developpement INSERM-CRI 9701 48 bd Serurier 75019 Paris France 2 Laboratoire de Biophysique INSERM U201, CNRS UA481 Museum National d’Histoire Naturelle 43 rue Cuvier 75231 Paris Cedex 05 France
1. INTRODUCTION Gene therapy and gene immunotherapy provide new approaches for clinical trials (Anderson, 1992; Dodet, 1993; Guo et al., 1994; Ido et al., 1995; Miller, 1992; Sokol and Gewirtz, 1996). Among these are strategies using antisense and triple helix technologies which lead to activation of the host immune system (Shevelev et al., 1997; Trojan et al., 1992). Antisense nucleic acids are designed to bind to RNA resulting in the formation of RNA-DNA or RNA-RNA hybrids with an arrest of translation. In vitro experiments have shown the potentiality of the antisense techniques to block expression of tumorassociated genes. Antisense oligonucleotides have been tested on animal models for different cancer types as Burkitt’s lymphoma (Huang et al., 1995), Philadelphia leukemia (Okabe et al., 1993; Skorski et al., 1995) and melamona (Leonetti et al., 1996). The antisense oligonucleotides have reduced tumorigenicity of transfected cells and inhibited tumor progression. Another kind of oligonucleotides that block gene expression are the triple-helix forming oligonucleotides (TFOs). They block RNA polymerases transit by forming a triple-helical structure on DNA. These TFOs promise to be a new class of sequencespecific DNA-binding drugs which will target malignancies at the transcriptionnal level Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
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(Chan and Glazer, 1997; Hélène et al., 1998; Maher III, 1996; Vasquez and Wilson, 1998). TFOs have been used to form an intermolecular triplex structure blocking the binding of transcription factors and repressing transcription of genes such as epidermal growth factor receptor (Durland et al., 1991), oncogene myc (Kim et al., 1998; Postel et al., 1991; Thomas et al., 1995), HER2 (Ebbinghaus et al., 1993; Porumb et al., 1996), Ha-ras (Mayfield et al., 1994) or Ki-ras (Alunni-Fabbroni et al., 1996). TFOs may prove to be the basis of effective chemotherapy drugs for concerned cancers. A protein commonly associated with tumors is Insulin-like growth factor I (IGF-
I). IGF-I is expressed in many fetal tissues and is associated with cellular normal and neoplastic growth and differentiation (Baserga, 1995; Han and Hill, 1992; Kiess et al., 1989). IGF-I antisense RNA and IGF-I triple helix RNA-DNA strategies have been shown to induce the arrest and rejection of following tumors in vivo: glioma (Shevelev et al., 1997; Trojan et al., 1992; Trojan et al., 1993), teratocarcinoma (Trojan et al., 1994) and hepatoma (Lafarge-Frayssinet et al., 1997; Upegui-G
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