title: DNA alkylation and interstrand cross-linking by treosulfan.
abstract: The anti-tumour drug treosulfan (L-threitol 1,4-bismethanesulphonate, Ovastat) is a prodrug for epoxy compounds by converting non-enzymatically to L-diepoxybutane via the corresponding monoepoxide under physiological conditions. The present study supports the hypothesis that this conversion of treosulfan is required for cytotoxicity in vitro. DNA alkylation and interstrand cross-linking of plasmid DNA is observed after treosulfan treatment, but this is again produced via the epoxide species. Alkylation occurs at guanine bases with a sequence selectivity similar to other alkylating agents such as the nitrogen mustards. In treosulfan-treated K562 cells, cross-links form slowly, reaching a peak at approximately 24 h. Incubation of K562 cells with preformed epoxides shows faster and more efficient DNA cross-linking.
authors.affiliation: Department of Oncology, UCL Medical School, London, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Hartley
authors.forename: C C
authors.initials: CC
authors.lastname: O'Hare
authors.forename: J
authors.initials: J
authors.lastname: Baumgart
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000494:pharmacology*; D002066:Busulfan / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020014:K562 Cells / Q000187:drug effects; D010957:Plasmids / Q000235:genetics
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; C018404:treosulfan; D002066:Busulfan