AffiliationDepartment of Experimental Haematology, Paterson Institute for Cancer Research, Manchester, UK.
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AbstractMany 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.
CitationEngineering drug resistance in human cells. 2000, 25 Suppl 2:S110-3 Bone Marrow Transplant.
JournalBone Marrow Transplantation
- Chemoprotective gene transfer II: multilineage in vivo protection of haemopoiesis against the effects of an antitumour agent by expression of a mutant human O6-alkylguanine-DNA alkyltransferase.
- Authors: Chinnasamy N, Rafferty JA, Hickson I, Lashford LS, Longhurst SJ, Thatcher N, Margison GP, Dexter TM, Fairbairn LJ
- Issue date: 1998 Jun
- Protection of mammalian cells against chloroethylating agent toxicity by an O6-benzylguanine-resistant mutant of human O6-alkylguanine-DNA alkyltransferase.
- Authors: Hickson I, Fairbairn LJ, Chinnasamy N, Dexter TM, Margison GP, Rafferty JA
- Issue date: 1996 Oct
- Chemoprotective gene transfer I: transduction of human haemopoietic progenitors with O6-benzylguanine-resistant O6-alkylguanine-DNA alkyltransferase attenuates the toxic effects of O6-alkylating agents in vitro.
- Authors: Hickson I, Fairbairn LJ, Chinnasamy N, Lashford LS, Thatcher N, Margison GP, Dexter TM, Rafferty JA
- Issue date: 1998 Jun
- Genetic chemoprotection with mutant O6-alkylguanine-DNA-alkyltransferases.
- Authors: Hobin DA, Fairbairn LJ
- Issue date: 2002 Feb
- O6-Benzylguanine potentiates BCNU but not busulfan toxicity in hematopoietic stem cells.
- Authors: Westerhof GR, Down JD, Blokland I, Wood M, Boudewijn A, Watson AJ, McGown AT, Ploemacher RE, Margison GP
- Issue date: 2001 May