Berendsen C L, Peters W H, Scheffer P G, Bouman A A, Boven E, Newling D W
Department of Urology, Free University Hospital, Amsterdam, The Netherlands.
Urology. 1997 Apr;49(4):644-51. doi: 10.1016/s0090-4295(96)00575-4.
Clinical data indicate that drug resistance to chemotherapy may occur in all stages of transitional cell cancer (TCC). Glutathione S-transferases (GSTs) are a family of detoxification enzymes composed of four different classes, denoted alpha (GSTA), mu (GSTM), pi (GSTP), and theta (GSTT), each containing one or more homo- or heterodimeric isoforms (GSTA1-1, GSTA1-2, and so forth), GSTs play a prominent role in drug detoxification and have been associated with resistance of tumor cells to anticancer agents. GST activity and isoenzyme levels were studied in TCC and normal bladder mucosa.
Enzyme activity was studied in samples of TCC (n = 37), adjacent normal bladder mucosa (n = 37), and in bladder mucosa of control patients without TCC (n = 46). GST isoenzyme composition was studied in mucosa and TCC of 14 patients and 11 controls.
The mucosa of patients with TCC showed GST activity (191 +/- 21 nmol/min/mg cytosolic protein), similar to the mucosa of controls (176 +/- 15 nmol/min/mg). GST activity was significantly increased in TCC (666 +/- 157 nmol/min/mg) in comparison with adjacent mucosa (P < 0.003). In mucosa samples, the levels of GSTA (A1-1, A1-2, and A2-2) were below the detection limit in 92% of the samples. GSTM (GSTM1-1) was found in 9 controls and in 7 patients with TCC but not in the other 7 patients, whereas GSTP (GSTP1-1) could be detected in all samples. The levels of GSTM1-1 and GSTP1-1 were similar in mucosa of patients and controls. The mean relative increase of GSTP1-1 levels in TCC was 4.6-fold (P < 0.002). In the 7 patients with GSTM1-1-detectable expression in adjacent normal mucosa, mean GSTM1-1 levels in TCC were increased 2.8-fold compared with mean levels in normal adjacent mucosa (P < 0.02). GSTA was measured in five samples of TCC at relatively low levels.
Overexpression of GSTP1-1 and GSTM1-1 may suggest that in the process of TCC carcinogenesis, a selection pressure occurs, resulting in a tumor with enhanced detoxification properties, including that of therapeutic drugs.
临床数据表明，移行细胞癌（TCC）的各个阶段都可能出现对化疗的耐药性。谷胱甘肽S-转移酶（GSTs）是一类解毒酶家族，由四个不同的类别组成，分别为α（GSTA）、μ（GSTM）、π（GSTP）和θ（GSTT），每类都包含一种或多种同二聚体或异二聚体同工型（如GSTA1-1、GSTA1-2等）。GSTs在药物解毒过程中起重要作用，并与肿瘤细胞对抗癌药物的耐药性有关。本研究对TCC和正常膀胱黏膜中的GST活性及同工酶水平进行了研究。
对37例TCC样本、37例相邻正常膀胱黏膜样本以及46例无TCC的对照患者的膀胱黏膜样本进行了酶活性研究。对14例患者和11例对照的黏膜及TCC样本进行了GST同工酶组成研究。
TCC患者的黏膜显示出GST活性（191±21 nmol/分钟/毫克胞质蛋白），与对照黏膜（176±15 nmol/分钟/毫克）相似。与相邻黏膜相比，TCC中的GST活性显著增加（666±157 nmol/分钟/毫克）（P<0.003）。在黏膜样本中，92%的样本中GSTA（A1-1、A1-2和A2-2）水平低于检测限。GSTM（GSTM1-1）在9例对照和7例TCC患者中被检测到，但在其他7例患者中未检测到，而GSTP（GSTP1-1）在所有样本中均可检测到。患者和对照的黏膜中GSTM1-1和GSTP1-1水平相似。TCC中GSTP1-1水平的平均相对增加为4.6倍（P<0.002）。在7例相邻正常黏膜中可检测到GSTM1-1表达的患者中，TCC中GSTM1-1的平均水平比相邻正常黏膜中的平均水平增加了2.8倍（P<0.02）。在5例TCC样本中检测到相对较低水平的GSTA。
GSTP1-1和GSTM1-1的过表达可能表明，在TCC致癌过程中存在选择压力，导致肿瘤的解毒特性增强，包括对治疗药物的解毒能力。
