Effects of iron, copper, cobalt, and their chelators on the cytotoxicity of bleomycin.

Bleomycin is widely used for treating several types of human tumors as well as a variety of experimental tumors. The ability of this antibiotic to bind and to damage DNA has been proposed to be responsible for its antitumor effect. Bleomycin is also a good chelator for several metals, e.g., iron, copper, and others. Bleomycin:metal complexes have been investigated in detail particularly for their action on isolated DNA. The conclusions from these studies indicate that metal-chelated bleomycin either is ineffective or more effective in damaging DNA. In this paper, we tested the effect of iron, copper, cobalt, and their chelators on bleomycin cytotoxicity. Our results suggest that chelating bleomycin with copper or adding an iron chelator (deferoxamine), diethylenetriamine pentaacetic acid, and a copper chelator (penicillamine) shows no effect on bleomycin cytotoxicity. On the other hand, iron dextran and a metal chelator, diethyldithiocarbamate (DDC), with bleomycin show enhanced cytotoxicity. Cobalt-chelated bleomycin is not cytotoxic but is cytotoxic when combined with DDC. We suggest that different mechanisms are contributing to the enhanced toxicity of bleomycin with iron dextran and DDC. Bleomycin acts as a ferrous oxidase which promotes the iron toxicity. In the case of DDC, it can act as a reducing agent or it can help to maintain the bleomycin:metal complex in the reduced form which can generate radicals.