McClarty G A, Chan A K, Wright J A
Cancer Res. 1986 Sep;46(9):4516-21.
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.
博来霉素是一种常用的化疗药物，已知会导致广泛的DNA损伤。在本文中，我们表明博来霉素可抑制小鼠L细胞中的核糖核苷酸还原酶活性。该药物的有效性源于其金属螯合特性，使其能够使该酶含有的铁M2亚基失活。使用一种对羟基脲耐药的小鼠L细胞系来表明，如果核糖核苷酸还原酶先前在体内或体外暴露于诸如羟基脲等破坏M2亚基酪氨酸自由基的试剂，博来霉素引起的抑制程度会大大增强。博来霉素有效性的提高似乎是由于暴露于羟基脲后蛋白质M2铁中心稳定性的降低。这些发现对于博来霉素作为抗癌药物的使用具有重要意义，特别是在联合化疗中，它可与作用于核糖核苷酸还原酶的其他药物一起使用。
