Evans J W, Yudoh K, Delahoussaye Y M, Brown J M
Department of Radiation Oncology, Stanford University School of Medicine, California 94305, USA.
Cancer Res. 1998 May 15;58(10):2098-101.
Tirapazamine (TPZ), a new anticancer drug that is currently in Phase II and III clinical trials, has a unique mechanism of action. Its cytotoxicity is selective for hypoxic cells in solid tumors and results from DNA damage produced by a free radical, which is generated by enzymatic reduction of the parent molecule. However, there is no agreement as to which enzyme(s) are involved. Here, we have measured both DNA damage and TPZ metabolism in A549 human lung cancer cells and in isolated nuclei derived from the cells. We show that, although the nuclei metabolize TPZ at a rate that is only 20% of that of whole cells, they have levels of DNA damage that are similar to those of the cells. We also show that TPZ radicals that are formed outside nuclei do not contribute to intranuclear DNA damage. Thus, essentially all of the DNA damage from TPZ results from radicals generated within the nucleus, and the 80% of the drug metabolism that occurs in the cytoplasm is probably irrelevant for the activity of this drug in killing hypoxic cells.
替拉扎明（TPZ）是一种新型抗癌药物，目前正处于二期和三期临床试验阶段，其作用机制独特。它对实体瘤中的缺氧细胞具有选择性细胞毒性，是由母体分子经酶促还原产生的自由基导致DNA损伤所致。然而，对于参与其中的是哪种酶尚无定论。在此，我们测定了A549人肺癌细胞以及从这些细胞分离得到的细胞核中的DNA损伤和TPZ代谢情况。我们发现，尽管细胞核代谢TPZ的速率仅为全细胞的20%，但其DNA损伤水平与细胞相似。我们还表明，在细胞核外形成的TPZ自由基不会导致核内DNA损伤。因此，TPZ造成的DNA损伤基本上都源于细胞核内产生的自由基，而在细胞质中发生的80%的药物代谢可能与该药物杀死缺氧细胞的活性无关。
