VP-1-16 undergoes O-demethylation to generate active intermediates that bind to proteins and DNA. The O-demethylation is P450-dependent. Peroxidases, such as horseradish or prostaglandin synthetase, also activate VP-16 and VM-26 to their O-Quinone derivatives and catalyze the binding of reactive intermediates to DNA. We have shown that both the dihydroxy and O-Quinone derivatives are cytotoxic and induce topo-II-dependent cleavage. The binding sites on the topo-II-DNA complex for these 0-demethylated drugs are similar to those of the parent compound. We have also shown that the dihydroxy VP-16 binds metal ions (iron and copper). These metal ion complexes are redox-active and induce DNA strand scission in an oxygen-dependent pathway. Thus, enzymatic activation to reactive intermediates is important in the biological activities of VP-16 and VM-26.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01CM006523-08
Application #
3838073
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Division of Cancer Treatment
Department
Type
DUNS #
City
State
Country
United States
Zip Code