Lönn U, Lönn S
Cancer Res. 1986 Aug;46(8):3866-70.
We have examined the induction of alkali-labile regions in DNA of human neoplastic cells treated with 5-fluorouracil and 5-fluorodeoxyuridine. 5-Fluorouracil induces DNA lesions by two mechanisms: incorporation of drug into DNA and a second mechanism not involving the incorporation. The second mechanism is seen in cells treated with aphidicolin, a specific inhibitor of DNA polymerase alpha, to stop the movement of the DNA replication forks. 5-Fluorodeoxyuridine is not incorporated into DNA of these cells; only the second mechanism of induction of alkali-labile DNA is detected. The second mechanism is in all probability due to inefficient DNA repair of normally occurring defects in purine and pyrimidine residues. Furthermore there is a correlation between increasing levels of alkali-labile regions in the DNA and cytotoxicity of the drugs. This may be one explanation for the cytocidal effects of 5-fluoropyrimidines.
我们研究了用5-氟尿嘧啶和5-氟脱氧尿苷处理的人类肿瘤细胞DNA中碱不稳定区域的诱导情况。5-氟尿嘧啶通过两种机制诱导DNA损伤：药物掺入DNA以及另一种不涉及掺入的机制。在用阿非迪霉素（一种DNA聚合酶α的特异性抑制剂）处理的细胞中可观察到第二种机制，以阻止DNA复制叉的移动。5-氟脱氧尿苷不会掺入这些细胞的DNA中；仅检测到诱导碱不稳定DNA的第二种机制。第二种机制很可能是由于嘌呤和嘧啶残基中正常出现的缺陷的DNA修复效率低下。此外，DNA中碱不稳定区域水平的增加与药物的细胞毒性之间存在相关性。这可能是5-氟嘧啶细胞杀伤作用的一种解释。
