Ferrandina G, Scambia G, Damia G, Tagliabue G, Fagotti A, Benedetti Panici P, Mangioni C, Mancuso S, D'Incalci M
Department of Gynecology and Obstetrics, Catholic University, Rome, Italy.
Ann Oncol. 1997 Apr;8(4):343-50. doi: 10.1023/a:1008247428385.
Conflicting data have been reported about the association between glutathione S-transferase (GST), a family of proteins implicated in detoxification of cytotoxic drugs in human ovarian in vitro models, and response to chemotherapy and prognosis in ovarian cancer patients. The aim of this study was to analyze the possible clinical role of GST activity in a large series of primary ovarian cancer patients.
The study included a large series of primary untreated ovarian cancer patients who underwent cytoreductive surgery and chemotherapy and who were followed up in a single institution. GST activity levels were assessed in tumor extracts by using a biochemical assay. A cut-off of 250 units of enzymatic activity was chosen according to the receiver operating characteristics (ROC) curve.
GST activity levels were distributed in an asymmetrical manner (median: 266 units; range: 4-918 units) and did not seem to be associated with stage, histopathological grading, ascites, or residual tumor after surgery. Higher GST activity levels were found in patients who responded to chemotherapy (median: 298 units, range: 50-691) than in those who responded only partially (median: 227 units, range: 19-747) or not at all to chemotherapy (median: 246 units, range: 4-811) (H = 7.02, P = 0.029). Moreover, the percentage of cases with > 250 units was significantly higher among complete responders (66%) than partial responders (37%) or non-responders (48%) (chi 2 = 7.32; P = 0.025). When multivariate analysis, including clinico-pathological parameters and GST activity status as predictors of response to chemotherapy, was carried out, residual tumor, stage and GST status retained independent predictive value. Patients with high GST activity had more favourable prognosis than those with low GST activity. The median PFS was 42 months for patients with high GST activity compared to 17 months for those with low GST activity (P = 0.037). The median overall survival was 72 months for high-GST-activity and 42 months for low-GST-activity patients (P = 0.043). Substantially similar results were obtained in the subgroup of stage II-III-IV ovarian cancer patients. Multivariate analysis including the clinico-pathological parameters and GST activity status was performed in stage III-IV ovarian cancer patients: Stage IV disease, residual tumor > 2 cm, the presence of ascites and low GST activity status retained independent negative prognostic roles.
A direct association between high GST activity and a better clinical outcome in terms of response to chemotherapy and survival has been observed in a large series of primary untreated ovarian cancer patients. These results, which are contrary to the expectations raised by in vitro studies, emphasize the need for caution when translating in vitro-generated hypotheses to the clinical setting.
关于谷胱甘肽S-转移酶（GST）（一类参与人类卵巢体外模型中细胞毒性药物解毒的蛋白质家族）与卵巢癌患者化疗反应及预后之间的关联，已有相互矛盾的数据报道。本研究的目的是分析GST活性在大量原发性卵巢癌患者中的可能临床作用。
本研究纳入了大量未经治疗的原发性卵巢癌患者，这些患者接受了肿瘤细胞减灭术和化疗，并在单一机构进行随访。通过生化检测评估肿瘤提取物中的GST活性水平。根据受试者工作特征（ROC）曲线选择酶活性250单位作为临界值。
GST活性水平呈不对称分布（中位数：266单位；范围：4 - 918单位），似乎与分期、组织病理学分级、腹水或术后残留肿瘤无关。化疗有反应的患者GST活性水平较高（中位数：298单位，范围：50 - 691），而部分有反应（中位数：227单位，范围：19 - 747）或对化疗无反应（中位数：246单位，范围：4 - 811）的患者GST活性水平较低（H = 7.02，P = 0.029）。此外，完全缓解者中酶活性>250单位的病例百分比（66%）显著高于部分缓解者（37%）或无反应者（48%）（χ² = 7.32；P = 0.025）。当进行多因素分析，将临床病理参数和GST活性状态作为化疗反应的预测指标时，残留肿瘤、分期和GST状态保留独立的预测价值。GST活性高的患者预后比活性低的患者更有利。GST活性高的患者中位无进展生存期为42个月，而活性低的患者为17个月（P = 0.037）。GST活性高的患者中位总生存期为72个月，活性低的患者为42个月（P = 0.043）。在II - III - IV期卵巢癌患者亚组中获得了基本相似的结果。对III - IV期卵巢癌患者进行了包括临床病理参数和GST活性状态的多因素分析：IV期疾病、残留肿瘤>2 cm、腹水的存在以及低GST活性状态保留独立的负面预后作用。
在大量未经治疗的原发性卵巢癌患者中，观察到高GST活性与化疗反应及生存方面更好的临床结果之间存在直接关联。这些结果与体外研究提出的预期相反，强调了将体外产生的假设转化到临床环境时需谨慎。
