Objective We aim to develop a novel strategy for combined gene/chemotherapy of cancer with nucleoside analogues (NA) that is superior to the existing HSV-I thymidine kinase (TK)/ganciclovir treatment of cancer. NA-metabolizing enzymes, including VZV TK, mitochondrial TK-2, the insect multifunctional deoxynucleoside kinase, nucleotides and thymidine phosphorylase, will be cloned and expressed to investigate the NA substrate affinities and to crystallize the enzymes with their preferred NA. Design of novel NA and mutated enzymes will be performed. Tumour cells will be transfected with the enzyme cDNA constructs to determine the increased cytostatic potential of the NA. The effect of targeted expression of the enzymes in either the cytosolic/nuclear or in the mitochondrial compartment of the tumour cells will be investigated. Also monocyte/macrophages as a model of resting tumour cells with low replicating capacity and low dNTP pools will be transiently transfected. Metabolism and mechanism of action studies will be performed on the NA. The most promising pairs of enzyme construct/NA will be evaluated in vivo SCID mice models to prove our concept. Fields of science medical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesgeneticsnucleotidesnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programme(s) FP5-LIFE QUALITY - Specific Programme for research, technological development and demonstration on "Quality of life and management of living resources", 1998-2002 Topic(s) 1.1.1.-7. - Chronic and degenerative diseases, cancer, diabetes, cardivascular diseases and rare diseases Call for proposal Data not available Funding Scheme CSC - Cost-sharing contracts Coordinator KATHOLIEKE UNIVERSITEIT LEUVEN EU contribution No data Address 10,Minderbroedersstraat 10 3000 LOUVAIN / LEUVEN Belgium See on map Total cost No data Participants (5) Sort alphabetically Sort by EU Contribution Expand all Collapse all CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS Spain EU contribution No data Address 3,Juan de la Cierva 3 28006 MADRID See on map Total cost No data INSTITUTE FOR INFECTIOUS DISEASES "LAZZARO SPALLANZANI" Italy EU contribution No data Address Via Portuense, 292 00149 ROMA See on map Total cost No data KAROLINSKA INSTITUTE Sweden EU contribution No data Address Huddinge University Hospital 141 86 STOCKHOLM See on map Total cost No data THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD United Kingdom EU contribution No data Address Roosevelt Drive Headington OX3 7BN OXFORD/HEADINGTON See on map Total cost No data UNIVERSITA DEGLI STUDI DI PADOVA Italy EU contribution No data Address VIA U.BASSI 58/B 35131 PADOVA See on map Total cost No data
