PMID:11731295
| Citation |
Zewail-Foote, M, Li, VS, Kohn, H, Bearss, D, Guzman, M and Hurley, LH (2001) The inefficiency of incisions of ecteinascidin 743-DNA adducts by the UvrABC nuclease and the unique structural feature of the DNA adducts can be used to explain the repair-dependent toxicities of this antitumor agent. Chem. Biol. 8:1033-49 |
|---|---|
| Abstract |
Ecteinascidin 743 (Et 743), a natural product derived from a marine tunicate, is a potent antitumor agent presently in phase II clinical trials. Et 743 binds in the minor groove of DNA and alkylates N2 of guanine via a unique mechanism involving catalytic activation. The sequence selectivity of Et 743 is governed by different patterns of hydrogen-bonding to DNA, which results in differential reversibility of the covalent adducts. As determined by nuclear magnetic resonance spectroscopy, the preferred sequences 5'-PuGC and 5'-PyGG are stabilized by a hydrogen-bonding network, while the non-preferred sequences 5'-NG(A/T) are much less stabilized due to the lack of a key hydrogen bond to the GC base pair on the 3'-side of the alkylated guanine. |
| Links | |
| Keywords |
Animals; Antineoplastic Agents, Alkylating/chemistry; Antineoplastic Agents, Alkylating/metabolism; Antineoplastic Agents, Alkylating/pharmacology; Base Sequence; Binding Sites; CHO Cells; Cell Survival/drug effects; Cricetinae; DNA/chemistry; DNA/genetics; DNA/metabolism; DNA Adducts/chemistry; DNA Adducts/metabolism; DNA Repair; Dioxoles/chemistry; Dioxoles/metabolism; Dioxoles/pharmacology; Drug Delivery Systems; Endodeoxyribonucleases/metabolism; Escherichia coli Proteins/metabolism; Gene Targeting/methods; Humans; Isoquinolines/chemistry; Isoquinolines/metabolism; Isoquinolines/pharmacology; Models, Molecular; Molecular Sequence Data; Mutagenesis, Insertional/methods; Tetrahydroisoquinolines |
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