Sullivan G F, Amenta P S, Villanueva J D, Alvarez C J, Yang J M, Hait W N
Department of Pharmacology, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, New Brunswick 08901, USA.
Clin Cancer Res. 1998 Jun;4(6):1393-403.
Prostate cancer progresses from a localized disease to a widely disseminated malignancy. Each step along this progression pathway involves multiple genetic alterations that impart a survival advantage to the tumor cell over its normal counterparts and may confer resistance to therapy. Because metastatic prostate cancer is one of the most therapy-resistant human neoplasms, we studied the expression of certain molecular determinants of drug resistance in the context of tumor progression. Paraffin-embedded formalin-fixed resected prostates were chosen based on Gleason grade and surgical stage. Immunohistochemistry was used to detect the expression of multidrug resistance protein (MRP), topoisomerase II alpha, p53, glutathione S-transferase pi, Bcl-2, and P-glycoprotein in these specimens. We found that all of the proteins were expressed in resected prostate except for P-glycoprotein. The expression of MRP, topoisomerase II alpha, p53, and Bcl-2 increased with the Gleason grade. In addition, the expression of MRP, topoisomerase II alpha, and p53 increased with the surgical stage. In contrast, the glutathione S-transferase pi and Bcl-2 expression decreased with the increasing surgical stage. Stage was the strongest indicator of protein expression. These results suggest that drug resistance gene products are expressed in prostate cancer at the time of surgical resection. Thus, although the emergence of the "pan-resistance" phenotype in prostate cancer may partly be a function of the selection pressure exerted by therapeutic interventions, certain determinants of chemoresistance may be caused by genetic changes accompanying tumorigenesis.
前列腺癌会从局限性疾病发展为广泛播散的恶性肿瘤。在这一进展过程的每一步都涉及多种基因改变，这些改变赋予肿瘤细胞相对于其正常对应细胞的生存优势，并可能导致对治疗产生抗性。由于转移性前列腺癌是人类最难治疗的肿瘤之一，我们在肿瘤进展的背景下研究了某些耐药分子决定因素的表达。根据Gleason分级和手术分期选择福尔马林固定石蜡包埋的切除前列腺组织。采用免疫组织化学法检测这些标本中多药耐药蛋白（MRP）、拓扑异构酶IIα、p53、谷胱甘肽S转移酶π、Bcl-2和P-糖蛋白的表达。我们发现，除了P-糖蛋白外，所有这些蛋白在切除的前列腺组织中均有表达。MRP、拓扑异构酶IIα、p53和Bcl-2的表达随Gleason分级增加而升高。此外，MRP、拓扑异构酶IIα和p53的表达随手术分期增加而升高。相比之下，谷胱甘肽S转移酶π和Bcl-2的表达随手术分期增加而降低。分期是蛋白表达的最强指标。这些结果表明，耐药基因产物在前列腺癌手术切除时就已表达。因此，尽管前列腺癌中“泛耐药”表型的出现可能部分是治疗干预施加的选择压力所致，但某些化疗耐药的决定因素可能是肿瘤发生过程中伴随的基因变化引起的。
