Alkylating Agents As Environmental Carcinogen and Chemotherapy Agents

Alkylating agents are an important class of carcinogens. O6-methylguanine (O6 MG) formed in cellular DNA by alkylating agents is a mutagenic lesion. Reactive metabolites, which are capable of alkylate in the DNA base, are produced during the catabolism of precursors of alkylating agents in the diet. Active alkylating agents can also be synthesised endogenously in the body. Endogenous alkylating agents are produced via nitrosation of primary amines by nitrates and nitrous anhydride formed by nitric oxide. Exposure of alkylating agents is at a minimum level in daily life. On the other hand, alkylating agents are used in certain chemotherapy regimens. Various investigators determined that O6-MGMT is at a high level in human tumours, thus they exhibit resistance to chemotherapy, including alkylating agents. Various anaolgs of O6-MG were suggested as a potential adjuvant in combination chemotherapy with alkylating agents to treat O6-MGMT proficient tumours. The susceptibility of any tissue to mutagenic effect of alkylating agents is dependent upon the balance between the ability of the tissue to metabolise alkylating agents to carcinogenic intermediates, the extent of O6-MG formation, rate of repair by O6-MGMT, and the extent of DNA replication which occurs when O6-MG is present. This book is a reliable reference for the sources of alkylating agents and their effects in human body.