Expression of multidrug resistance related proteins and proliferative activity is increased in advanced clinical prostate cancer

Purpose: Advanced disseminated prostate cancer is highly resistant to cytot oxic chemotherapy. We identified proteins that may be involved in multidrug resistance in clinical prostate cancer. Expression of these proteins was e xamined in the context of tumor progression. Materials and Methods: Paraffin embedded, formalin fixed prostate cancer sp ecimens from archival sources of 3 distinct patient groups were examined. T hese groups were clearly distinct with regard to pathological stage and res ponsiveness to antihormonal therapy. Group 1 consisted of patients with org an confined prostate cancer treated with radical prostatectomy (early patho logical stage T2N0M0). Group 2 patients had disseminated, early advanced pr ostate cancer and were treated with transurethral prostatic resection for u rinary obstruction before receiving antihormonal therapy. Group 3 patients had disseminated prostate cancer with relapse despite antihormonal treatmen t (late advanced prostate cancer) and they underwent transurethral prostati c resection to relieve the symptoms of urinary obstruction. Immunohistochem ical study was done to detect P-glycoprotein, multidrug resistance associat ed protein, lung resistance protein, glutathione-S-transferase pi, p53, Bcl -2, Bax, topoisomerase I, II alpha and II beta, and Ki-67. Results: Advanced tumors were distinguished from locally confined tumors be cause they exhibited significantly higher histological grade and proliferat ive activity. The expression of multidrug resistance associated protein, p5 3, topoisomerase II alpha, Ki-67 and topoisomerase II beta was significantl y related to a higher Gleason sum score. The number of cases expressing mul tidrug resistance associated protein, lung resistance protein, glutathione- S-transferase pi, p53, Bcl-2, topoisomerase II alpha and Ki-67 was signific antly increased in the group with advanced disseminated prostate cancer. To poisomerase I and II beta were homogeneously and highly expressed at all st ages of prostate cancer progression, while P-glycoprotein was not expressed in any tumors regardless of the patient group. Conclusions: Up-regulation of the expression of the drug transporters multi drug resistance associated protein and lung resistance protein, detoxifying enzyme glutathione-S-transferase pi, and apoptosis inhibiting proteins Bcl -2 and p53 may be an explanation of the resistance of disseminated progress ive prostate cancer to chemotherapy. As shown by the up-regulation of Ki-67 and topoisomerase II alpha, increased proliferation reflects the aggressiv eness of metastatic prostate cancer. Research on agents that counteract mul tidrug resistance mechanisms and may sensitize prostate carcinoma to cytoto xic chemotherapy may possibly lead to more effective treatment of progressi ve disseminated prostate cancer.