Jeggo P A, Caldecott K, Pidsley S, Banks G R
National Institute for Medical Research, Ridgeway, Mill Hill, London, United Kingdom.
Cancer Res. 1989 Dec 15;49(24 Pt 1):7057-63.
xrs-1 is an ionizing radiation sensitive Chinese hamster ovary (CHO) strain and has a defect in double strand break rejoining. It is also highly sensitive to topoisomerase II inhibiting anticancer drugs. Sensitivity is specific for those drugs that inhibit the breakage/reunion mechanism of topoisomerase II. xrs-1 and its parent strain CHO-K1 have equal levels of topoisomerase II activity, assayed by their ability to unknot complex knotted P4 head DNA. Drug stimulated protein-DNA complex formation was similar in xrs-1 and CHO-K1, showing that they accrued equal levels of drug induced lesions. Thus sensitivity most likely results from subsequent differences in the processing of these lesions rather than the rate of formation. Drug sensitivity is directly related to the xrs phenotype since drug and gamma-ray resistance are coordinately reactivated by azacytidine treatment. All six members of the xrs complementation group are hypersensitive to etoposide. Sensitivity is not a feature common to all X-ray sensitive mutants but is shown by another complementation group, which also has a defect in double strand break rejoining. These results thus demonstrate a correlation between an inability to rejoin double strand breaks and sensitivity to topoisomerase II targeting antitumor drugs.
xrs - 1是一种对电离辐射敏感的中国仓鼠卵巢（CHO）细胞株，在双链断裂重新连接方面存在缺陷。它对拓扑异构酶II抑制性抗癌药物也高度敏感。其敏感性针对的是那些抑制拓扑异构酶II断裂/重连机制的药物。通过解开复杂打结的P4头部DNA的能力测定，xrs - 1及其亲本细胞株CHO - K1具有同等水平的拓扑异构酶II活性。在xrs - 1和CHO - K1中，药物刺激的蛋白质 - DNA复合物形成相似，表明它们积累了同等水平的药物诱导损伤。因此，敏感性很可能是由这些损伤后续处理过程中的差异而非形成速率导致的。药物敏感性与xrs表型直接相关，因为药物和γ射线抗性可通过氮杂胞苷处理协同恢复。xrs互补组的所有六个成员对依托泊苷均高度敏感。敏感性并非所有X射线敏感突变体的共同特征，而是由另一个互补组表现出来，该互补组在双链断裂重新连接方面也存在缺陷。因此，这些结果证明了双链断裂重新连接能力的缺失与对拓扑异构酶II靶向抗肿瘤药物的敏感性之间存在关联。
