Mechanistic approaches to new nitrosourea development.
Because of their broad range of effectiveness against experimental tumors in rodents, nitrosoureas could have a greater potential against human cancer than has so far been achieved with these agents. Greater effectiveness against human cancer might be attained from an understanding of the mechanisms by which these drugs kill cells. Some clues to possible mechanisms have been obtained and can be pursued using existing experimental techniques. The most promising leads center on the chemical effects of nitrosoureas on DNA. Several types of nitrosourea-induced DNA damage have been identified, including interstrand crosslinks, DNA-protein crosslinks and single-strand breaks. These DNA lesions can be sensitively measured in mammalian cells by the alkaline elution technique. The experimental results so far support the idea that cell killing is related to the formation and repair of DNA lesions. Antitumor activity would then depend on differences in sensitivity of neoplastic versus normal cells in regard to certain types of DNA damage and/or differences in the ability to repair this damage.
D000478:Alkylation; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D002219:Carbamates / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D046911:Macromolecular Substances; D009607:Nitrosourea Compounds / Q000378:metabolism* / Q000494:pharmacology
D000970:Antineoplastic Agents; D002219:Carbamates; D046911:Macromolecular Substances; D009607:Nitrosourea Compounds; D004247:DNA