SiDNA
Signal interfering DNA (siDNA) is a class of short modified double stranded DNA molecules, 8-64 base pairs in length.[1] siDNA molecules are capable of inhibiting DNA repair activities by interfering with multiple repair pathways. In general, these molecules act by mimicking DNA breaks and interfering with recognition and repair of DNA damage induced on chromosomes by irradiation or genotoxic products.
Mechanism of action
The siDNA family, led by Dbait consists of 32 base pairs deoxyribonucleotide forming an intramolecular double helix, which mimicks DNA double-strand break lesions. Dbait binds to and hyperactivate DNA-PK, an enzyme involved in DNA breaks signaling and repair. DNA-PK hyperactivation induces pan-nuclear phosphorylation of histone H2AX among all the chromatine. H2AX phosphorylation is the signal, which allows double-strand break repair proteins (from NHEJ and Homologous recombination pathways) to form DNA repair complexes selectively on DNA double-strand breaks.[2] Dbait-dependent unspecific phosphorylation of H2AX results in inefficient double strand break recognition and repair.[3][4]
Possible Therapeutic application
Most of the anticancer therapies act by induction of DNA damage (chemotherapy and radiation therapy). DNA breaks are the most lethal damage for cells, as one single double-strand break if unrepaired is sufficient to lead to cell death. Dbait enhances the efficacy of the DNA damaging agents as demonstrated with radiation therapy and/or chemotherapy in multiple in vivo experimental models such as melanoma,[5] glioblastoma[6] and colorectal cancer.[7] Preclinical proof of concept of the synergic effect of the clinical candidate, DT01, with radiation therapy lead to a first-in-human Phase I, which is currently underway to evaluate the tolerance and efficacy of local DT01 administration in association with RT in patients suffering from in-transit metastases of melanoma.
References
- ↑ Quanz, M; Chassoux D; Berthault N; Agrario C; Sun JS; Dutreix M. (2009). "Hyperactivation of DNA-PK by double-strand break mimicking molecules disorganizes DNA damage response.". PLOS ONE. 4 (7): e6298. doi:10.1371/journal.pone.0006298. PMC 2709433
. PMID 19621083. - ↑ Huang, X; Halicka HD; Darzynkiewicz Z. (2004). "Detection of histone H2AX phosphorylation on Ser-139 is an indicator of DNA damage (DNA double-strand breaks).". Curr Protoc Cytom. Chapter 7: Unit 7.27. doi:10.1002/0471142956.cy0727s30. PMID 18770804.
- ↑ Quanz, M; Chassoux D; Berthault N; Agrario C; Sun JS; Dutreix M. (2009). "Hyperactivation of DNA-PK by double-strand break mimicking molecules disorganizes DNA damage response.". PLOS ONE. 4 (7): e6298. doi:10.1371/journal.pone.0006298. PMC 2709433. PMID 19621083.
- ↑ Quanz M, Berthault N, Roulin C, Roy M, Herbette A, Agrario C, Alberti C, Josserand V, Coll JL, Sastre-Garau X, Cosset JM, Larue L, Sun JS, Dutreix M (2009). "Small-molecule drugs mimicking DNA damage: a new strategy for sensitizing tumors to radiotherapy.". Clin Cancer Res. 15 (4): 1308–16. doi:10.1158/1078-0432.CCR-08-2108. PMID 19190126.
- ↑ Berthault, N; Maury B; Agrario C; Herbette A; Sun JS; Peyrieras N; Dutreix M. (2011). "Comparison of distribution and activity of nanoparticles with short interfering DNA (Dbait) in various living systems.". Cancer Gene Ther. 18 (10): 695–706. doi:10.1038/cgt.2011.39. PMID 21799529.
- ↑ Coquery N, Pannetier N, Farion R, Herbette A, Azurmendi L, Clarencon D, Bauge S, Josserand V, Rome C, Coll JL, Sun JS, Barbier EL, Dutreix M, Remy CC (2012). "Distribution and radiosensitizing effect of cholesterol-coupled Dbait molecule in rat model of glioblastoma.". PLOS ONE. 7 (7): e40567. doi:10.1371/journal.pone.0040567. PMC 3398898. PMID 22815765.
- ↑ Devun, F; Bousquet G; Biau J; Herbette A; Roulin C; Berger F; Sun JS; Robine S; Dutreix M. (2012). "Preclinical study of the DNA repair inhibitor Dbait in combination with chemotherapy in colorectal cancer.". J Gastroenterol. 47 (3): 266–75. doi:10.1007/s00535-011-0483-x. PMID 22068457.