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DNA repair in resistance to alkylating anticancer drugs
1Institute of Toxicology, Division of Applied Toxicology, University of Mainz, Mainz, Gernany. Kaina@mail.uni-mainz.de
Abstract:
The major critical target of alkylating antineoplastic drugs belonging to the group of methylating and chloroethylating agents is DNA. DNA alkylation lesions can be repaired by the action of alkyltransferase (MGMT) and base excision repair enzymes. The major cell killing and apoptotic alkylation lesions are O6-methylguanine (O6MeG) and O6-chloroethylguanine. O6MeG causes mispairing with thymine which is erroneously processed by mismatch repair (MMR), leading to secondary lesions that potently trigger the mitochondrial apoptotic pathway. Apoptosis induced by O6MeG is a late cellular response that requires cell proliferation to occur. Data are available indicating that DNA double-strand breaks are actively involved as the ultimate trigger of apoptosis. O6MeG and O6-chloroethylguanine are repaired by the specific action of MGMT thus counteracting the killing effects of the lesions. The expression of MGMT is highly variable and is often increased in tumors compared to normal tissue. Determination of MGMT activity in various tumors showed low expression in brain, pancreas and skin and high expression in testicle, breast, colorectal, lung and ovarian tumors. Distribution profiles of MGMT revealed non-random distribution indicating the existence of subpopulations exhibiting low and high activity. Since MGMT is one of the most important factors determining drug resistance to alkylation, strategies have been developed to inhibit MGMT in tumors with the aid of MGMT inhibitors and overexpression of MGMT in healthy, non-target tissue (e.g. blood stem cells) by transferring a mutated form of MGMT inaccessible to inhibition. Targeting MGMT inhibitors to tumors may further enhance the antineoplastic efficiency of alkylating agents. The role of base excision repair, Fos and p53 in drug resistance to alkylation is also discussed.
Insights
Alkylating drugs damage DNA, but the DNA repair enzyme O-6-alkylguanine-DNA alkyltransferase (MGMT) can counteract their effects. MGMT expression varies in tumors, influencing drug resistance and treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Alkylating antineoplastic drugs target DNA, forming lesions like O6-methylguanine (O6MeG) and O6-chloroethylguanine.
- DNA repair pathways, including alkyltransferase (MGMT) and base excision repair, counteract these drug-induced DNA lesions.
- O6MeG lesions trigger apoptosis through mismatch repair (MMR) and DNA double-strand breaks, but this requires cell proliferation.
Purpose of the Study:
- To investigate the role of MGMT in DNA repair and resistance to alkylating agents.
- To explore the variability of MGMT expression in different tumor types and its implications for cancer treatment.
- To discuss strategies for overcoming MGMT-mediated drug resistance.
Main Methods:
- Review of existing data on DNA alkylation, repair mechanisms, and apoptosis.
- Analysis of MGMT expression levels in various human tumors.
- Discussion of therapeutic strategies targeting MGMT.
Main Results:
- O6MeG and O6-chloroethylguanine are critical cytotoxic lesions repaired by MGMT.
- MGMT expression is highly variable across tumor types, with high expression in testicle, breast, colorectal, lung, and ovarian tumors, and low expression in brain, pancreas, and skin.
- Non-random distribution of MGMT activity suggests subpopulations with differing resistance levels.
Conclusions:
- MGMT is a key determinant of resistance to alkylating agents.
- Strategies to inhibit MGMT in tumors or enhance its expression in healthy tissues are being developed.
- Targeting MGMT may improve the efficacy of alkylating chemotherapy.