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.

Fields of science

• medical and health sciences › medical biotechnology › genetic engineering › gene therapy
• medical and health sciences › clinical medicine › radiology › nuclear medicine
• medical and health sciences › clinical medicine › oncology
• medical and health sciences › basic medicine › immunology › immunotherapy

Programme(s)

• FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998

Topic(s)

• 5.4 - Somatic gene therapy

Call for proposal

Data not available

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