Therapeutic impact of methoxyamine: blocking repair of abasic sites in the base excision repair pathway.
A major obstacle to effective treatment with alkylating agents in cancer is the presence of elaborate mechanisms of DNA repair. For instance, the methylating therapeutic agent, temozolomide forms O6-methylguanine (O6mG), 7-methylguanine (N7mG) and 3-methyladenine (N3mA) DNA adducts that are repaired by at least two mechanisms. The O6mG DNA adduct, a cytotoxic and genotoxic lesion, is repaired by O6-methylguanine DNA-methyltransferase (MGMT). Thus, MGMT is a major mechanism of resistance to methylating agents. Meanwhile, cell death caused by O6mG adducts is promoted by mismatch repair (MMR) system, such that deficiency in MMR is associated with pronounced resistance to methylating agents. N7mG, the dominant lesions formed by methylating therapeutic agents, and N3mA DNA adducts are removed by the base excision repair (BER) pathway. Efficient BER repair minimizes the impact of these lesions in normal and tumor cells. Thus, only when BER is disrupted, do these abundant N-methylated DNA adducts become highly cytotoxic. Most importantly, BER disruption is able to bypass other resistance factors such as MMR defects and high MGMT activity. BER, in fact, is an important drug-resistant factor because of its variety of substrates and the ability to rapidly and efficiently repair these DNA lesions. However, the impact of both active BER and inactive BER on anticancer therapy has yet to be fully studied. This review will establish the premise that targeting abasic sites formed during BER will disrupt this pathway and enhance the therapeutic efficacy of alkylating agents.
Liu
Lili
L
Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. lxl32@po.cwru.edu
Gerson
Stanton L
SL
D000818:Animals; D004260:DNA Repair / Q000187:drug effects* / Q000502:physiology; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors* / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D015507:Drugs, Investigational / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006898:Hydroxylamines / Q000494:pharmacology* / Q000627:therapeutic use*
D015507:Drugs, Investigational; D006898:Hydroxylamines; C005214:methoxyamine; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase