Hanigan M H, Frierson H F, Taylor P T
Department of Cell Biology, University of Virginia, Charlottesville 22908, USA.
Am J Obstet Gynecol. 1998 Aug;179(2):363-7. doi: 10.1016/s0002-9378(98)70365-5.
Gamma-glutamyl transpeptidase activity has been shown to be essential for the nephrotoxicity of cisplatin. The purpose of this study was to determine whether expression of gamma-glutamyl transpeptidase in ovarian carcinomas is necessary for the antitumor effect of cisplatin.
Tumor tissue from 18 patients with stage III or IV ovarian serous papillary carcinoma or poorly differentiated adenocarcinoma was analyzed for expression of gamma-glutamyl transpeptidase by histochemical or immunohistochemical staining. Response to cisplatin-based combination chemotherapy was evaluated on the basis of clinical response, progression-free interval, and survival.
Gamma-glutamyl transpeptidase expression in the tumors ranged from 0% to 100% of the tumor cells gamma-glutamyl transpeptidase positive. Patient survival ranged from 15 months to 9 years. Twelve of the 18 patients had a complete response to the initial course of cisplatin-based combination chemotherapy. There was no statistically significant correlation between either response or time to relapse and gamma-glutamyl transpeptidase expression. However, there was a correlation between high levels of gamma-glutamyl transpeptidase in the tumor and acute ototoxicity in patients treated with cisplatin. Expression of high levels of gamma-glutamyl transpeptidase in the tumor was also found to be associated with shorter patient survival, suggesting that gamma-glutamyl transpeptidase might have a role in resistance to drugs used in second- and third-line therapy.
Expression of gamma-glutamyl transpeptidase in ovarian serous papillary or poorly differentiated adenocarcinomas is not necessary for the antitumor activity of cisplatin. A correlation was found between high levels of gamma-glutamyl transpeptidase in the tumor and both increased ototoxicity from cisplatin and decreased patient survival. These data suggest that administering an inhibitor of gamma-glutamyl transpeptidase activity to block the nephrotoxicity of cisplatin would not interfere with its therapeutic effect.
γ-谷氨酰转肽酶活性已被证明对顺铂的肾毒性至关重要。本研究的目的是确定γ-谷氨酰转肽酶在卵巢癌中的表达对于顺铂的抗肿瘤作用是否必要。
通过组织化学或免疫组织化学染色分析18例III期或IV期卵巢浆液性乳头状癌或低分化腺癌患者的肿瘤组织中γ-谷氨酰转肽酶的表达。根据临床反应、无进展生存期和生存率评估对基于顺铂的联合化疗的反应。
肿瘤中γ-谷氨酰转肽酶的表达范围为肿瘤细胞γ-谷氨酰转肽酶阳性的0%至100%。患者生存期为15个月至9年。18例患者中有12例对初始疗程的基于顺铂的联合化疗有完全反应。反应或复发时间与γ-谷氨酰转肽酶表达之间无统计学显著相关性。然而,肿瘤中高水平的γ-谷氨酰转肽酶与接受顺铂治疗的患者的急性耳毒性之间存在相关性。还发现肿瘤中高水平的γ-谷氨酰转肽酶表达与患者生存期较短相关,这表明γ-谷氨酰转肽酶可能在对二线和三线治疗中使用的药物的耐药性中起作用。
γ-谷氨酰转肽酶在卵巢浆液性乳头状癌或低分化腺癌中的表达对于顺铂的抗肿瘤活性不是必需的。发现肿瘤中高水平的γ-谷氨酰转肽酶与顺铂耳毒性增加和患者生存期缩短均相关。这些数据表明,给予γ-谷氨酰转肽酶活性抑制剂以阻断顺铂的肾毒性不会干扰其治疗效果。