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DNA alkylation and interstrand cross-linking by treosulfan
J A Hartley1, C C O'Hare, J Baumgart
1Department of Oncology, UCL Medical School, London, UK.
British Journal of Cancer
|January 15, 1999
Summary
Treosulfan, an anti-cancer drug, requires conversion to epoxides for its cytotoxic effects. This conversion is essential for DNA alkylation and cross-linking, leading to cell death.
Area of Science:
- Pharmacology
- Molecular Biology
- Cancer Research
Background:
- Treosulfan (L-threitol 1,4-bismethanesulphonate) is an anti-tumor prodrug.
- It converts to active epoxy compounds non-enzymatically under physiological conditions.
- This conversion is hypothesized to be crucial for its cytotoxic activity.
Purpose of the Study:
- To investigate the role of treosulfan's conversion to epoxides in its cytotoxicity.
- To understand the mechanism of DNA alkylation and cross-linking induced by treosulfan.
Main Methods:
- In vitro cytotoxicity assays.
- DNA alkylation and interstrand cross-linking analysis of plasmid DNA.
- Treatment of K562 cells with treosulfan and preformed epoxides.
Main Results:
- Treosulfan's cytotoxicity in vitro is dependent on its conversion to epoxy compounds.
- DNA alkylation and interstrand cross-linking are mediated by these epoxide species.
- Alkylation occurs at guanine bases with sequence selectivity similar to nitrogen mustards.
- DNA cross-linking in K562 cells peaks at 24 hours post-treosulfan treatment.
- Preformed epoxides induce faster and more efficient DNA cross-linking.
Conclusions:
- The conversion of treosulfan to L-diepoxybutane is necessary for its anti-tumor activity.
- Treosulfan acts as an alkylating agent through its epoxide metabolites.
- The epoxide metabolites are directly responsible for DNA damage, including interstrand cross-links.