Binding of tritiated hycanthone and hycanthone N-methylcarbamate to macromolecules of drug-sensitive and drug-resistant schistosomes.

Adult Schistosoma mansoni of the hycanthone-sensitive and of the hycanthone-resistant strain were exposed in vitro to tritium-labeled hycanthone. The drug was taken up in similar amounts by the two strains, a result which is not compatible with hypothetical mechanisms of resistance based on reduced drug entry into the schistosomes. Labeled hycanthone was found to bind irreversibly to macromolecules of sensitive schistosomes, whereas the binding was minimal in resistant worms. In particular, the DNA of sensitive schistosomes showed high levels of tightly bound hycanthone, while the corresponding fraction of resistant schistosomes failed to do so. Female schistosomes and immature worms, which are less sensitive to hycanthone, showed a diminished drug-DNA binding with respect to adult males. Tritiated hycanthone N-methylcarbamate, which is effective against sensitive and resistant schistosomes, bound in similar amounts to the DNA of both strains. These results strongly support a previously proposed mechanism of action of hycanthone, which is based essentially on the alkylation of worm macromolecules by a drug derivative produced in sensitive schistosomes.