Galli A, Schiestl R H
Department of Molecular and Cellular Toxicology, Harvard School of Public Health, Boston, MA 02115, USA.
Mutat Res. 1996 Jul 5;354(1):69-75. doi: 10.1016/0027-5107(96)00037-1.
Hydroxyurea, a chemotherapeutic and radiosensitizing agent, inhibits ribonucleotide reductase, arrests cells in the S-phase and is mutagenic and recombinagenic. In this paper we investigated whether the recombinagenic activity of hydroxyurea is due to the same activity that leads to arrest in the S-phase or to a more direct action on DNA. The effect of hydroxyurea on intrachromosomal and interchromosomal recombination was investigated in dividing and in G1 or G2 cell cycle-arrested cells of the yeast Saccharomyces cerevisiae. Treatment of dividing cells with hydroxyurea resulted in a large increase in recombination frequencies, even at low non-toxic doses. In contrast, in cells arrested in the G1 or G2 phase, hydroxyurea failed to induce recombination, even at 60-fold higher toxic doses. The presence of metabolic activation (S9 mix) did not change the effects of hydroxyurea on recombination. The data suggest that the recombinagenic activity of hydroxyurea may not be due to any direct effect of hydroxyurea on DNA, but may be linked to the inhibition of ribonucleotide reductase causing inhibition of DNA synthesis leading to S-phase arrest and possibly causing recombinagenic lesions.
羟基脲是一种化疗和放射增敏剂，它能抑制核糖核苷酸还原酶，使细胞停滞于S期，具有致突变和重组活性。在本文中，我们研究了羟基脲的重组活性是由于导致细胞停滞于S期的相同活性，还是对DNA有更直接的作用。我们在酿酒酵母的分裂细胞以及处于G1期或G2期细胞周期停滞的细胞中，研究了羟基脲对染色体内和染色体间重组的影响。用羟基脲处理分裂细胞会导致重组频率大幅增加，即使在低无毒剂量下也是如此。相比之下，在停滞于G1期或G2期的细胞中，即使在高60倍的有毒剂量下，羟基脲也无法诱导重组。代谢激活剂（S9混合物）的存在并没有改变羟基脲对重组的影响。数据表明，羟基脲的重组活性可能不是由于其对DNA的任何直接作用，而是可能与抑制核糖核苷酸还原酶有关，从而抑制DNA合成，导致细胞停滞于S期，并可能导致重组性损伤。
