The research objectives are to isolate, characterise and exploit, cDNAs encoding novel proteins that are involved in the resistance of mammalian cells to the toxic effects of one class of chemotherapeutic agents which is in common use in the treatment of various types of cancer. I will use well characterised cell lines that have been generated in the host institution by serial selection with increasing doses of such an agent. DNA microarray or subtractive hybridisation strategies described below will be used to isolate cDNAs encoding novel resistance factors. cDNA transfer and expression in bacteria and human cells will allow characterisation of the protein and the effects of its expression in vitro and in cell culture. The demonstration that the factor/s can indeed confer human cell resistance to the killing effects of these agents will be the major objective of the work. I will also examine if the cells have altered responses to other classes of agents (cross-resistance) and if expression affects other biological responses such as DNA repair, mutation and clastogenic effects. Exploitation of these findings will include the generation of antibodies for assessing protein expression in tumour and normal tissues sections in relation to response to these agents and the development of antisense strategies for reducing the levels of the protein in tumour cells to increase sensitivity to these agents. These studies will complement, and benefit from, the very extensive work by the host institution on other drug resistance pathways and the manipulation of these, both to increase the sensitivity of tumour cells and to increase the resistance of normal cells to the killing effects of these agents.