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Signal transduction as target of gene therapy
K Moelling1, B Strack, G Radziwill
1Institute of Medical Virology, University of Zürich, Switzerland.
Abstract:
Cancer development involves multistep events. Therapeutic approaches can be targeted against any of these events individually or in combination. Pancreatic cancer can involve activation of Ki-Ras, overexpression of Myc or ErbB-2, and mutational inactivation of functional p53. Three approaches with nucleic acid-based therapies have been taken. A ribozyme specific for Ki-ras mRNA carrying the activating mutation in codon 12 (GGU to GUU) was designed and shown to be stimulated by interaction with an RNA-binding protein NCp7 of HIV-1. The same protein was targeted to cell-adhesion molecules, which allowed transfer of the ribozyme and an antisense oligodeoxynucleotide (ODN) into the cell. Furthermore, proliferation may be prevented by blocking signal transduction. A transdominant negative mutant of the signaling kinase c-Raf-1 efficiently blocked transmission. A retroviral vector will be used as carrier. Furthermore, the concept of using naked DNA injected intramuscularly as an immunogen against cancer is discussed.
Insights
Novel nucleic acid therapies target pancreatic cancer by inhibiting key oncogenes like Ki-ras and blocking signal transduction pathways. These approaches utilize ribozymes, antisense oligodeoxynucleotides, and dominant-negative mutants for potential therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Cancer development is a multistep process involving genetic alterations.
- Pancreatic cancer is characterized by mutations in genes such as Ki-Ras, Myc, ErbB-2, and p53.
- Targeting these specific molecular events offers therapeutic potential.
Purpose of the Study:
- To explore nucleic acid-based therapeutic strategies for pancreatic cancer.
- To investigate the efficacy of targeting oncogenic Ki-ras mRNA and signal transduction pathways.
- To evaluate novel delivery methods for nucleic acid therapies.
Main Methods:
- Design of a ribozyme specific for mutated Ki-ras mRNA.
- Utilizing HIV-1 NCp7 protein for enhanced ribozyme activity and cellular delivery.
- Development of a transdominant negative mutant of c-Raf-1 to block signal transduction.
- Exploration of retroviral vectors and naked DNA for therapeutic delivery.
Main Results:
- A specific ribozyme targeting mutated Ki-ras mRNA was designed and shown to be stimulated by HIV-1 NCp7.
- HIV-1 NCp7 facilitated the cellular delivery of the ribozyme and antisense oligodeoxynucleotides (ODNs).
- A transdominant negative mutant of c-Raf-1 effectively inhibited proliferation by blocking signal transduction.
Conclusions:
- Nucleic acid-based therapies, including ribozymes and antisense ODNs, show promise for pancreatic cancer treatment.
- Targeting specific oncogenic mutations and signal transduction pathways are viable therapeutic approaches.
- Novel delivery systems are crucial for the effective application of these gene-based therapies.