Journal
ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY
Volume 8, Issue 4, Pages 351-357Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/187152008784220366
Keywords
DNA repair; base excision repair; drug targets; chemoresistance; O-60-methylguanine methyl transferase; N-methylpurine DNA-glycosylase; AP-endonuclease; temozolomide; methyl methane sulfonate; methoxyamine
Categories
Funding
- NCI NIH HHS [CA 92306, R01 CA113447, CA 113447, R01 CA092306] Funding Source: Medline
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In both bacteria and eukaryotes the alkylated, oxidized, and deaminated bases and depurinated lesions are primarily repaired via an endogenous preventive pathway, i.e. base excision repair ( BER). Radiation therapy and chemotherapy are two important modes of cancer treatment. Many of those therapeutic agents used in the clinic have the ability to induce the DNA damage; however, they may also be highly cytotoxic, causing peripheral toxicity and secondary cancer as adverse side effects. In addition, the damage produced by the therapeutic agents can often be repaired by the BER proteins, which in effect confers therapeutic resistance. Efficient inhibition of a particular BER protein(s) may increase the efficacy of current chemotherapeutic regimes, which minimizes resistance and ultimately decreases the possibility of the aforementioned negative side effects. Therefore, pharmacological inhibition of DNA damage repair pathways may be explored as a useful strategy to enhance chemosensitivity. Various agents have shown excellent results in preclinical studies in combination chemotherapy. Early phase clinical trials are now being carried out using DNA repair inhibitors targeting enzymes such as PARP, DNA-PK or MGMT. In the case of BER proteins, elimination of N-Methylpurine DNA glycosylase ( MPG) or inhibition of AP-endonuclease ( APE) increased sensitivity of cancer cells to alkylating chemotherapeutics. MPG(-/-) embryonic stem cells and cells having MPG knock-down by siRNA are hypersensitive to alkylating agents, whereas inhibition of APE by small molecule inhibitors sensitized cancer cells to alkylating chemotherapeutics. Thus, MPG and other BER proteins could be potential targets for chemosensitization.
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