DNA alkylation and interstrand cross-linking by treosulfan

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 treos...

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Bibliographic Details
Published in:British journal of cancer 1999-01, Vol.79 (2), p.264-266
Main Authors: HARTLEY, J. A, O'HARE, C. C, BAUMGART, J
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents, Alkylating - metabolism
Antineoplastic Agents, Alkylating - pharmacology
Biological and medical sciences
Busulfan - analogs & derivatives
Busulfan - metabolism
Busulfan - pharmacology
Cell Survival - drug effects
Chemotherapy
Cross-Linking Reagents - pharmacology
DNA, Neoplasm - drug effects
DNA, Neoplasm - metabolism
Humans
K562 Cells - drug effects
Medical sciences
Pharmacology. Drug treatments
Plasmids - genetics
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Summary: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.
ISSN:0007-0920
1532-1827
DOI:10.1038/sj.bjc.6690043