Improvement of chemotherapy efficacy by inactivation of a DNA-repair pathway.
AffiliationCancer Research UK Medical Oncology Unit, Churchill Hospital, Oxford, UK.
MetadataShow full item record
AbstractTumour resistance and dose-limiting toxic effects restrict treatment with most chemotherapeutic drugs. Elucidation of the mechanisms of these effects could permit the development of ways to improve the effectiveness of currently used agents until better therapeutic agents are developed. Several types of alkylating agents are used in the treatment of cancer. The DNA repair protein, O6-alkylguanine-DNA alkyltransferase (ATase) is an important cellular resistance mechanism to one class of alkylating agents. This enzyme removes potentially lethal damage from DNA and experiments in vitro and in vivo have shown that its inactivation can reverse resistance to such agents. Clinical trials of drugs that inactivate ATase are underway and early results indicate that they are active in tumour tissues. However, the ATase present in normal tissues, particularly bone marrow, is also inactivated, necessitating a reduction in the dose of alkylating agent. An important question is whether, in the absence of any tumour-specific delivery strategy, such drugs will improve therapeutic effectiveness; initial reports are not promising.
CitationImprovement of chemotherapy efficacy by inactivation of a DNA-repair pathway. 2003, 4 (1):37-44 Lancet Oncol.
JournalThe Lancet Oncology
- Increasing DNA repair capacity in bone marrow by gene transfer as a prospective tool in cancer therapy.
- Authors: Kleibl K, Margison GP
- Issue date: 1998
- The specific role of O<sup>6</sup>-methylguanine-DNA methyltransferase inhibitors in cancer chemotherapy.
- Authors: Sun G, Zhao L, Zhong R, Peng Y
- Issue date: 2018 Aug 1
- O6-alkylguanine-DNA alkyltransferase inactivation in cancer chemotherapy.
- Authors: McElhinney RS, McMurry TB, Margison GP
- Issue date: 2003 Aug
- O6-Methylguanine-DNA methyltransferase inactivation and chemotherapy.
- Authors: Verbeek B, Southgate TD, Gilham DE, Margison GP
- Issue date: 2008
- 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