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Signal transduction as target of gene therapy.

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Institute of Medical Virology, University of Z├╝rich, Switzerland.


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.

[Indexed for MEDLINE]

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