VP-16 undergoes O-demyelination 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-l6 and VM-26 to their o-Quione derivatives and catalyze the binding of reactive intermediates to DNA. We have shown that both the dihydroxy and o-Quione derivatives are cytotoxic and induce topo-II-dependent cleavage. The binding sites on the topo-II-DNA complex for these O-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. Recent studies to evaluate mechanisms of VP-16 resistance in a number of tumor cell lines suggest that overexpression and differential effects of VP-16 on c-myc and c-jun may play some roles in drug resistance. Furthermore, overexpressions of both c-myc and bcl2 in resistant cells may be important far resistance and cell survival.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01CM006523-10
Application #
3752347
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Division of Cancer Treatment
Department
Type
DUNS #
City
State
Country
United States
Zip Code