Identification of local determinants of DNA interstrand crosslink formation by cyclophosphamide metabolites.
The anti-cancer drug cyclophosphamide produces cytotoxic effects by DNA interstrand crosslink formation. Current knowledge of local physicochemical factors in DNA influencing crosslink formation in DNA has been based on physical models of Watson-Crick DNA. Specific interactions between DNA and cyclophosphamide metabolites determining formation and stabilization of interstrand crosslinks have been identified by advanced molecular computational methods. These results predict that the more favorable DNA sequence for interstrand crosslinking is 5'-GC-3' rather than the previously proposed 5'-CG-3' and that thymine methyl groups adjacent to guanine will inhibit interstrand crosslinking. In addition the conformational and energetic consequences of formamido-pyrimidine adducts and local water interactions with the drug-DNA complex were identified. These simulations of interstrand crosslinking provide a fundamental basis for understanding the mechanism of action of nitrogen mustard-type alkylating agents, and a rationale for the prospective design of more effective anti-tumor agents.
Hausheer
F H
FH
Pharmacology Laboratory, Johns Hopkins Oncology Center, Baltimore, MD 21205.
Singh
U C
UC
Saxe
J D
JD
Colvin
O M
OM
D001483:Base Sequence; D003520:Cyclophosphamide / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation
D003520:Cyclophosphamide; D004247:DNA