Cornarotti M, Capranico G, Bohm S, Oriana S, Spatti G B, Mariani L, Ballabio G, Zunino F
Division of Experimental Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Int J Cancer. 1996 Aug 7;67(4):479-84. doi: 10.1002/(SICI)1097-0215(19960807)67:4<479::AID-IJC3>3.0.CO;2-P.
DNA topoisomerases, nuclear enzymes that regulate DNA topology, are recognized as the primary targets of effective anti-tumor drugs. These enzymes may also have a role in the repair of DNA damage induced by alkylating agents and platinum compounds; therefore, their expression may be a determinant of tumor response to chemotherapy. Our study was undertaken in an attempt to establish a correlation between the enzyme expression and response of ovarian cancer to cisplatin-based chemotherapy. The expression of topoisomerase I, II alpha and II beta genes was assessed by RNase protection assay in tumor specimens obtained from 37 untreated patients with advanced epithelial ovarian cancer at initial surgery and from 13 pre-treated patients at subsequent laparotomy. The expression levels were compared with those found in 5 specimens from benign ovarian tissue and 5 specimens from normal ovarian tissue. The expression levels in untreated patients were used to establish a correlation with response to high-dose cisplatin therapy. A significant intertumor variability of mRNA expression was noted for all the genes examined. However, a comparison of median values indicated a remarkable increase of expression in malignant tumors over benign or normal tissues only for topoisomerase II alpha. This change is not related to alterations or amplification of topoisomerase II alpha gene. Interestingly, a correlation was found between tumor response to chemotherapy and the expression level of the isoform alpha (but not of topoisomerase II beta and topoisomerase I). The observed correlation suggests a contribution of the enzyme in determining tumor sensitivity. Alternatively, increased expression levels of the alpha isoenzyme gene in responsive tumors might reflect higher fractions of proliferating tumor cells that may be more drug-sensitive than resting cells.
DNA拓扑异构酶是调节DNA拓扑结构的核酶，被认为是有效抗肿瘤药物的主要靶点。这些酶在由烷化剂和铂化合物诱导的DNA损伤修复中也可能发挥作用；因此，它们的表达可能是肿瘤对化疗反应的一个决定因素。我们开展这项研究旨在建立酶表达与卵巢癌对顺铂化疗反应之间的相关性。通过核糖核酸酶保护试验评估了37例初次手术时未经治疗的晚期上皮性卵巢癌患者肿瘤标本以及13例后续剖腹手术时经治疗患者肿瘤标本中拓扑异构酶I、IIα和IIβ基因的表达。将表达水平与取自5份良性卵巢组织标本和5份正常卵巢组织标本中的表达水平进行比较。利用未经治疗患者的表达水平来建立与高剂量顺铂治疗反应的相关性。在所检测的所有基因中均观察到肿瘤间mRNA表达存在显著差异。然而，中位数比较表明，仅拓扑异构酶IIα在恶性肿瘤中的表达相较于良性或正常组织有显著增加。这种变化与拓扑异构酶IIα基因的改变或扩增无关。有趣的是，发现肿瘤对化疗的反应与α同工型（而非拓扑异构酶IIβ和拓扑异构酶I）的表达水平之间存在相关性。观察到的这种相关性表明该酶在决定肿瘤敏感性方面发挥了作用。或者，反应性肿瘤中α同工酶基因表达水平的增加可能反映了增殖性肿瘤细胞比例较高，这些细胞可能比静止细胞对药物更敏感。
