Pendyala L, Velagapudi S, Toth K, Zdanowicz J, Glaves D, Slocum H, Perez R, Huben R, Creaven P J, Raghavan D
Departments of Investigational Therapeutics, Urologic Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Clin Cancer Res. 1997 May;3(5):793-8.
Glutathione (GSH) levels were measured in 13 human tumor cell lines derived from carcinomas of the bladder, ovary, and colon and from melanoma and glioblastoma. High levels were found in four of five bladder cell lines. The average GSH concentration in the bladder cell lines was approximately 6-fold higher than in the non-bladder cell lines. Because this difference suggested the possibility of elevation of GSH in urothelial neoplasia, we measured GSH in bladder tumor tissue from patients with transitional cell carcinoma (TCC) of the bladder (Group I, n = 17). GSH was also measured in two types of control tissues: (a) nontumor bladder tissue from patients with TCC or a history of TCC of the bladder (Group II, n = 23); and (b) bladder tissue from patients without bladder cancer (Group III, n = 14). Thirteen sets of paired specimens of tumor and nontumor bladder tissue from the same patient were evaluated. The tissues were flash-frozen, and GSH was measured after histological assessment of the same samples. Free and total GSH (free + mixed disulfides) were measured by a high-performance liquid chromatography assay with fluorescence detection and expressed as nanomoles/mg protein. The mean free GSH (+/- SD) for groups I, II, and III was 32.0 +/-18.7, 17.3 +/- 11.4, and 9.3 +/- 4.0, respectively, and the mean total GSH was 45.9 +/- 32.5, 23.7 +/- 17.1, and 12.2 +/- 6.7. The respective differences between groups (I and II, I and III, and II and III) were statistically significant for both free and total GSH (Ps ranging from <0.0001 to </=0.05). Free and total GSH were higher in tumor than in nontumor tissue in 11 of 13 paired specimens (free, 29.5 +/- 20.4 versus 18.7 +/- 11.7, P = 0.017; total, 41.7 +/- 33.8 versus 24.9 +/- 18.4, P = 0.005). No correlation was found between GSH levels and the proportion of tumor cells in the tissue. Influence of smoking on GSH expression could not be assessed because 81% of the patients with TCC had a smoking history. Similarly, because only 11% had prior cytotoxic chemotherapy, the influence of prior cytotoxic exposure on GSH could not be assessed. The results indicate: (a) significantly higher levels of GSH in TCC compared to tumor-free bladder tissue; and (b) higher GSH levels in nontumor bladder tissue from patients with bladder cancer than from patients without TCC. The clinical implications of this work include the possibility that GSH may play a role in the resistance of bladder cancer to chemotherapy and may be associated with bladder carcinogenesis.
在源自膀胱癌、卵巢癌、结肠癌、黑色素瘤和胶质母细胞瘤的13种人类肿瘤细胞系中检测了谷胱甘肽（GSH）水平。在5种膀胱癌细胞系中的4种中发现GSH水平较高。膀胱癌细胞系中的平均GSH浓度比非膀胱癌细胞系高约6倍。由于这种差异提示尿路上皮肿瘤中GSH可能升高，我们检测了膀胱移行细胞癌（TCC）患者（第一组，n = 17）膀胱肿瘤组织中的GSH。还在两种类型的对照组织中检测了GSH：（a）患有TCC或有膀胱TCC病史的患者的非肿瘤膀胱组织（第二组，n = 23）；以及（b）无膀胱癌患者的膀胱组织（第三组，n = 14）。评估了来自同一患者的13组肿瘤和非肿瘤膀胱组织的配对标本。组织经速冻处理，在对相同样本进行组织学评估后检测GSH。通过具有荧光检测的高效液相色谱法测定游离和总GSH（游离+混合二硫化物），并以纳摩尔/毫克蛋白表示。第一组、第二组和第三组的平均游离GSH（±标准差）分别为32.0±18.7、17.3±11.4和9.3±4.0，平均总GSH分别为45.9±32.5、23.7±17.1和12.2±6.7。游离和总GSH在组间（第一组和第二组、第一组和第三组以及第二组和第三组）的各自差异在统计学上均具有显著性（P值范围从<0.0001至≤0.05）。在13对配对标本中的11对中，肿瘤组织中的游离和总GSH高于非肿瘤组织（游离，29.5±20.4对18.7±11.7，P = 0.017；总，41.7±33.8对24.9±18.4，P = 0.005）。未发现GSH水平与组织中肿瘤细胞比例之间存在相关性。由于81%的TCC患者有吸烟史，因此无法评估吸烟对GSH表达的影响。同样，由于只有11%的患者曾接受过细胞毒性化疗，因此无法评估先前的细胞毒性暴露对GSH的影响。结果表明：（a）与无肿瘤的膀胱组织相比，TCC中的GSH水平显著更高；以及（b）膀胱癌患者的非肿瘤膀胱组织中的GSH水平高于无TCC患者的非肿瘤膀胱组织。这项工作的临床意义包括GSH可能在膀胱癌对化疗的耐药性中起作用并且可能与膀胱癌发生相关的可能性。
