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.
Funding SchemeCSC - Cost-sharing contracts
141 86 Stockholm
OX3 7BN Oxford/headington