Oligonucleotide therapies

Macaulay, Val

doi:10.1007/978-1-4899-3111-5_26

Cited by 1 publication

(1 citation statement)

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“…However, unlike antisense, which can be targeted to any sequence, the triplex approach is limited to purine-rich target sequences. Furthermore the interaction is weak at physiological pH and temperature, although it can be stabilised by incorporation of reactive groups [88,89].…”

Section: Rna Interferencementioning

confidence: 99%

Development of Molecular Agents for IGF Receptor Targeting

Salisbury

Macaulay²

2003

Horm Metab Res

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The type 1 insulin-like growth factor receptor (IGF1R) is a promising anticancer treatment target, being frequently overexpressed by tumours, and mediating proliferation, motility and apoptosis protection. Design of specific kinase inhibitors is problematic because of homology between the IGF1R and insulin receptor. This obstacle can be circumvented using sequence-specific molecular agents including antisense, triplex and ribozymes. Recent studies indicate that profound sequence-specific IGF1R gene silencing can be induced by small interfering RNAs that mediate RNA interference in mammalian cells. IGF1R downregulation blocks tumour growth and metastasis, and enhances sensitivity to cytotoxic drugs and irradiation. In murine melanoma cells, radiosensitisation is associated with impaired activation of Atm, which is required for initiation of cell cycle checkpoints and DNA repair pathways after double-strand DNA breaks. Furthermore, tumour cells killed in vivo following IGF1R downregulation can provoke an immune response, protecting against tumour rechallenge. After years of studying the role of the IGF system in tumour biology, novel agents for IGF1R targeting will soon be available for clinical testing. This review summarises the development of molecular agents, and considers factors that will influence clinical activity, including the requirement of established tumours for IGF signalling, and the efficacy and toxicity of IGF1R inhibitors.

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Section: Rna Interferencementioning

confidence: 99%