Hydroxyurea-induced conversion of mammalian ribonucleotide reductase to a form hypersensitive to bleomycin

Bleomycin is a commonly used chemotherapeutic agent known to cause extensive DNA damage. In this paper we show that bleomycin inhibits ribonucleotide reductase activity in mouse L-cells. The effectiveness of the drug is a result of its metal-chelating properties which enable it to inactivate the iron containing M2 subunit of the enzyme. A hydroxyurea-resistant mouse L-cell line was used to show that the degree of inhibition caused by bleomycin can be greatly enhanced if ribonucleotide reductase has been previously exposed in vivo or in vitro to agents, such as hydroxyurea, which destroy the tyrosine free radical of subunit M2. The increased effectiveness of bleomycin appears to result from a decrease in the stability of the iron center of protein M2 following exposure to hydroxyurea. These findings have important implications in terms of the use of bleomycin as an anticancer agent, especially in combination chemotherapy where it can be used with other drugs that act at ribonucleotide reductase.