MOLECULAR-BIOLOGICAL PROBLEMS OF DRUG DESIGN AND MECHANISM OF DRUG ACTION ROLE OF PRE- AND POST-REPLICATIVE MISMATCH REPAIR IN CYTOTOXICITY OF METHYLATING ANTITUMOR AGENTS (A REVIEW)

The review considers modern data on the pre- and post-replicative repair of DNA damage induced by methylating agents such as N-methyl-N-nitrosourea, temozolomide, procarbazine, dacarbazine, and aranoza. These drugs are used in the treatment of various types of tumors including Hodgkin’s disease, brain tumors, disseminated melanoma, and lymphoproliferative diseases. Resistance (both intrinsic and acquired) to methylating agents is an important problem in cancer chemotherapy. The cytotoxicity of methylating agents depends on O 6 -methylguanine-DNA-methyltransferase (MGMT) activity (prereplicative repair). Several preclinical and clinical studies have demonstrated that postreplicative mismatch repair (MMR) is responsible to a high degree for the tumor cell resistance to the methylating agents. MMR in experimental studies is determined using expression of the main proteins hMLH1, hMSH2, and hMSH6 involved in the activity of the MMR system. Resistance to methylating agents is due to hypermethylation of promoters of the corresponding genes. The deficiency of hMLH1, hMSH2, and hMSH6 in tumors and lymphocytes after pre-operative neoadjuvant chemotherapy may serve as an independent predictor of poor prognosis in the development of disease.