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 problem of collateral toxicity during anti-tumour chemotherapy we have been developing 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 O6-alkylguanine-DNA-alkyltransferase (ATase) to confer genetic chemoprotection to the bone marrow. By transfer and expression of a mutant form of this protein, which is resistant to inactivation by the tumour sensitising agent O6-benzylguanine (O6-beG), we have been able to demonstrate protection of murine bone marrow in vitro from the cytotoxic and clastogenic effects of O6-beG in combination with the anti-tumour agent temozolomide. This protection is seen in multiple lineages, including erythroid and granulocyte/macrophage progenitors, as well as more primitive cells. Importantly, significant protection of the platelet lineage is also seen, with faster recovery of platelets. The multi-lineage protection seen has encouraged us to take this approach forward to clinical trial in the near future.
Department of Experimental Haematology, Paterson Institute for Cancer Research, Manchester, UK.
L J
LJ
Fairbairn
J A
JA
Rafferty
L S
LS
Lashford
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D001853:Bone Marrow / Q000187:drug effects; D016026:Bone Marrow Transplantation; D004260:DNA Repair / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics
D000970:Antineoplastic Agents; D019853:O(6)-Methylguanine-DNA Methyltransferase