GLUTATHIONE AND RELATED ENZYMES IN TUMOR PROGRESSION AND METASTASES OF HUMAN-MELANOMA
GLUTATHIONE AND RELATED ENZYMES IN TUMOR PROGRESSION AND METASTASES OF HUMAN-MELANOMA
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DOI：
10.1111/1523-1747.ep12313403
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发表时间：
1995-07-01
影响因子：
6.5
通讯作者：
CZARNETSKI, BM
中科院分区：
文献类型：
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作者：
SCHADENDORF, D;JURGOVSKY, K;CZARNETSKI, BM
我们以前已经表明，p-170糖蛋白介导的多药耐药的过表达在赋予人黑素瘤细胞的化学抗性中仅起次要作用。除了膜转运蛋白如p-170之外，代谢酶系统已经涉及改变的药物敏感性。最近，谷胱甘肽和相关酶已经与对烷基化物质的抗性相关，特别是在胃肠道和妇科癌症中。在这项研究中，我们研究了谷胱甘肽和相关酶的水平增加是否在黑色素瘤的化学抗性中起作用。谷胱甘肽、谷胱甘肽S-转移酶（GST）、谷胱甘肽还原酶，和γ-谷氨酰转肽酶在黑色素瘤和非黑色素瘤细胞系中进行了分析，此外，还检查了18个来自皮肤和淋巴结的黑色素瘤转移灶，与非黑色素瘤细胞系和正常细胞相比，来自黑色素细胞肿瘤的细胞中γ-谷氨酰转肽酶的水平在统计学上不同，此外，来自皮肤或淋巴结的转移灶中的GST水平显著低于永久性细胞系中的GST水平。然而，转移灶和细胞系中的谷胱甘肽和相关酶的水平在宽范围内波动，高达40倍，与治疗状态或转移灶的起源无关。在研究的第二部分中，GST同工酶α、μ和β 1的表达，对10例良性痣、29例原发性黑色素瘤和39例转移性黑色素瘤在化疗前和化疗期间进行免疫组织化学研究。GST同工酶表达随肿瘤进展而增加，以GST rr表达最强，但免疫组化检测GST水平与肿瘤进展、化疗前或化疗中转移灶GST水平、临床反应之间均无相关性。这些数据表明，谷胱甘肽代谢和GST的表达的改变并没有发挥重要作用，在黑色素瘤化疗药物的耐药性。
We have shown previously that overexpression of p-170 glycoprotein-mediated multidrug resistance plays only a minor role in conferring chemoresistance to human melanoma cells, In addition to membrane transporters like p-170, metabolizing enzyme systems have been implicated in altered drug sensitivity, Recently, glutathione and associated enzymes have been associated with resistance to alkylating substances, particularly in gastrointestinal and gynecologic cancers, In this study, we investigated whether increased levels of glutathione and related enzymes map play a role in chemoresistance in melanoma, Levels of glutathione, glutathione S-transferase (GST), glutathione reductase, and gamma-glutamyl transpeptidase were analyzed in melanoma and nonmelanoma cell lines, In addition, 18 melanoma metastases derived from skin and lymph nodes were examined, Levels of gamma-glutamyl transpeptidase were statistically different in cells derived from melanocytic tumors compared with non-melanoma cell lines and normal cells, In addition, GST levels in metastases derived from skin or lymph nodes were significantly lower than those in permanent cell lines, However, levels of glutathione and related enzymes in metastases and cell lines fluctuated over a wide range, up to 40-fold, regardless of treatment status or origin of metastases, In a second part of the study, the expression of GST isoenzymes alpha, mu, and pi, was studied by immunohistology in 10 benign nevi, 29 primary melanomas, and 39 melanoma metastases before and during chemotherapy. Expression of GST isoenzymes was increased with tumor progression, and GST rr was the strongest isoform expressed, However, no correlation was found between GST levels by immunohistochemistry and the course of tumor progression, between GST levels in metastases obtained before or during chemotherapy, or between GST levels and clinical response, These data suggest that alterations in glutathione metabolism and the expression of GST do not play a major role in resistance to chemotherapeutic drugs in melanoma.