DNA Crosslinking (Cyclophosphamide)

DNA crosslinking, as induced by cyclophosphamide, refers to the formation of covalent bonds between DNA strands—either within a single strand (intrastrand) or between two complementary strands (interstrand). Cyclophosphamide is a prodrug that requires metabolic activation in the liver to form its active metabolites, primarily phosphoramide mustard and acrolein. The cytotoxic effect of cyclophosphamide is mainly due to its ability to alkylate DNA and induce interstrand crosslinks at guanine N-7 positions. Interstrand crosslinks are particularly toxic because they prevent separation of the two DNA strands during replication and transcription, leading to cell cycle arrest and apoptosis if not repaired. Cyclophosphamide-induced DNA crosslinking underpins its use as an antineoplastic agent in various cancers and as an immunosuppressant in autoimmune diseases. Its selectivity partly arises from higher aldehyde dehydrogenase activity in normal tissues compared with cancer cells; this enzyme detoxifies intermediates before they can form toxic metabolites like phosphoramide mustard.

Other names

Cyclophosphamide-induced DNA CrosslinkingPhosphoramide Mustard-induced DNA Adducts

Alkylation of DNA, formation of interstrand and intrastrand crosslinks, inhibition of DNA replication and transcription.