BIOACTIVATION OF THE ANTI-TUMOR DRUGS 9-HYDROXYELLIPTICINE AND DERIVATIVES BY A PEROXIDASE HYDROGEN-PEROXIDE SYSTEM

Hydroxylation in position 9 of various antitumor drugs derived from ellipticine results in the possible further oxidation of the hydroxylated drugs into free radicals and quinone products in the presence of a peroxidase.sbd.H2O2 system. Except for the N6-methyl derivative, free radicals of hydroxyellipticines do not react with neighboring molecules. Quinone products were found to be strong electrophilic molecules. They can oxidize NADH into NAD+ through a nonenzymatic process, and, moreover, quinone from N2-methyl-9-hydroxyellipticine may undergo a nucleophilic attack resulting in an irreversible binding of the drug to bovine serum albumin. Among the drugs tested, those which can be oxidized by peroxidase-H2O2 exhibit the most cytotoxic effect on L1210 [mouse leukemia] cells in vitro.