Engineering drug resistance in human cells

Many of the problems with current anti-tumour therapies stem from a lack of specificity for tumour as opposed to normal tissues. To address the proble m of collateral toxicity during anti-tumour chemotherapy we have been devel oping a gene therapy approach to protect normal tissues from the toxic and potentially mutagenic effects of chemotherapeutic agents. As a paradigm for this we have been examining the potential of the DNA repair protein O-6-al kylguanine-DNA-alkyltransferase (ATase) to confer genetic chemoprotection t o the bone marrow. By transfer and expression of a mutant form of this prot ein, which is resistant to inactivation by the tumour sensitising agent O-6 -benzylguanine (O-6-beG), we have been able to demonstrate protection of mu rine bone marrow in vitro from the cytotoxic and clastogenic effects of O-6 -beG in combination with the anti-tumour agent temozolomide. This protectio n is seen in multiple lineages, including erythroid and granulocyte/macroph age progenitors, as well as more primitive cells. Importantly, significant protection of the platelet lineage is also seen, with faster recovery of pl atelets. The multi-lineage protection seen has encouraged us to take this a pproach forward to clinical trial in the near future.