VP-1-16 undergoes O-demethylation to generate active intermediates that bind to proteins and DNA. The O-demetylation is P450 dependent. Peroxidases, such as horseradish or prostaglandin synthetase also activate VP- 16 and VM-26 to their O-Quinone derivatives, and catalyze binding of reactive intermedites to DNA. We have shown that both the dihydroxy and O-Quinone derivatives are cytotoxic and induce topo II-dedependent cleavage. The binding sites on tops-][[-DNA complex for these O-demothylted drugs are similar to 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.
