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Somatic suicide gene therapy for cancer

Objective



The development of new viral vectors will focus on more efficient transduction and expression and on cell-type specific expression. Recombinant vectors containing mutant forms of herpes simplex thymidine kinase that are less toxic will be constructed and tested in vitro in combination with ganciclovir and novel antiherpetic nucleoside analogues. Vectors expressing the E. coli DeoD gene will be engineered and tested in combination with 6-methyl-purine-2'-deoxynucleoside. After studying the therapeutic index and bystander effect of these novel suicide gene/prodrug combinations in vitro, application in selected animal models will take place.

Different routes of non-traumatic and more efficient viral vector delivery will be developed including systemic administration, convection enhanced intratumoral delivery and retrovirus producing cells embedded in biopolymers. These methods will be tested partly in vitro but mostly in a variety of animal models.

In vivo imaging of the efficiency of suicide gene transfer is based on selective accumulation of some nucleoside analogues (including 5-iodo-2'-fluoro-2'-deoxy-arabinofuranosyluracil [FIAU]), after phosphorylation by herpes simplex thymidine kinase. Radiolabeled (14C, 125I, 18F) nucleoside analogues (FIAU) will first be tested in vitro using autoradiography and subsequently in vivo using autoradiography and SPECT/PET imaging.

The bystander effect will be studied in vitro (above) and in vivo in brain tumour and multiple myeloma, Iymphoma and seminoma models. Modulation of the bystander effect will be attempted in vitro and in the multiple myeloma model by upregulation of connexins, molecules involved in gapjunction formation. The anti-tumor immune response elicited by suicide gene/prodrug treatment will be analyzed and modulated by cytokine (GM-CSF and IFNy) gene transfer.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Rijksuniversiteit Leiden
Address
151,Lange Kleiweg
2280 GG Leiden
Netherlands

Participants (6)

Academisch Ziekenhuis Rotterdam
Netherlands
Address
301,Groene Hilledijk
3075 EA Rotterdam
Institut National de la Santé et de la Recherche Médicale
France
Address
8,Rue Du Général Sarrail
94010 Créteil
KAROLINSKA INSTITUTE
Sweden
Address
Haelsvaegen 7
141 57 Huddinge
University of Manchester
United Kingdom
Address
Oxford Road
M13 9PT Manchester
Université Libre de Bruxelles
Belgium
Address
808,Route De Lennik
1070 Bruxelles
Université Pierre et Marie Curie - Paris VI
France
Address
83,Boulevard De L'hôpital
75651 Paris