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Engineering drug resistance in human cells
L J Fairbairn1, J A Rafferty, L S Lashford
1Department of Experimental Haematology, Paterson Institute for Cancer Research, Manchester, UK.
Bone Marrow Transplantation
|August 10, 2000
Summary
Gene therapy using a DNA repair protein protects bone marrow from chemotherapy side effects. This approach shows multi-lineage protection and encourages clinical trials for safer cancer treatments.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Chemotherapy lacks tumor specificity, causing collateral damage to normal tissues.
- Developing gene therapy to protect normal tissues from chemotherapy's toxic effects is crucial.
Purpose of the Study:
- To evaluate the DNA repair protein O6-alkylguanine-DNA-alkyltransferase (ATase) for conferring chemoprotection to bone marrow.
- To assess the efficacy of a mutant ATase resistant to O6-benzylguanine (O6-beG) in protecting against chemotherapy-induced toxicity.
Main Methods:
- Gene therapy approach involving the transfer and expression of a mutant ATase protein.
- In vitro studies using murine bone marrow exposed to O6-benzylguanine (O6-beG) and temozolomide.
Main Results:
- Demonstrated protection of murine bone marrow from cytotoxic and clastogenic effects.
- Protection observed across multiple lineages, including erythroid, granulocyte/macrophage progenitors, and primitive cells.
- Significant protection and faster recovery of the platelet lineage.
Conclusions:
- The O6-alkylguanine-DNA-alkyltransferase (ATase) gene therapy approach effectively protects bone marrow from chemotherapy.
- Multi-lineage protection observed supports the advancement of this strategy towards clinical trials.