Expression of multidrug resistance related proteins and proliferative activity is increased in advanced clinical prostate cancer.
OBJECTIVE
Advanced disseminated prostate cancer is highly resistant to cytotoxic chemotherapy. We identified proteins that may be involved in multidrug resistance in clinical prostate cancer. Expression of these proteins was examined in the context of tumor progression.


METHODS
Paraffin embedded, formalin fixed prostate cancer specimens from archival sources of 3 distinct patient groups were examined. These groups were clearly distinct with regard to pathological stage and responsiveness to antihormonal therapy. Group 1 consisted of patients with organ confined prostate cancer treated with radical prostatectomy (early pathological stage T2N0M0). Group 2 patients had disseminated, early advanced prostate cancer and were treated with transurethral prostatic resection for urinary obstruction before receiving antihormonal therapy. Group 3 patients had disseminated prostate cancer with relapse despite antihormonal treatment (late advanced prostate cancer) and they underwent transurethral prostatic resection to relieve the symptoms of urinary obstruction. Immunohistochemical study was done to detect P-glycoprotein, multidrug resistance associated protein, lung resistance protein, glutathione-S-transferase pi, p53, Bcl-2, Bax, topoisomerase I, IIalpha and IIbeta, and Ki-67.


RESULTS
Advanced tumors were distinguished from locally confined tumors because they exhibited significantly higher histological grade and proliferative activity. The expression of multidrug resistance associated protein, p53, topoisomerase IIalpha, Ki-67 and topoisomerase IIbeta was significantly related to a higher Gleason sum score. The number of cases expressing multidrug resistance associated protein, lung resistance protein, glutathione-S-transferase pi, p53, Bcl-2, topoisomerase IIalpha and Ki-67 was significantly increased in the group with advanced disseminated prostate cancer. Topoisomerase I and IIbeta were homogeneously and highly expressed at all stages 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 multidrug 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 progressive prostate cancer to chemotherapy. As shown by the up-regulation of Ki-67 and topoisomerase IIalpha, increased proliferation reflects the aggressiveness of metastatic prostate cancer. Research on agents that counteract multidrug resistance mechanisms and may sensitize prostate carcinoma to cytotoxic chemotherapy may possibly lead to more effective treatment of progressive disseminated prostate cancer.
Van Brussel
J P
JP
Departments of Experimental Urology and Pathology, Erasmus University Rotterdam, The Netherlands.
Jan Van Steenbrugge
G
G
Van Krimpen
C
C
Bogdanowicz
J F
JF
Van Der Kwast
T H
TH
Schröder
F H
FH
Mickisch
G H
GH
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000368:Aged; D016022:Case-Control Studies; D002455:Cell Division; D018432:Drug Resistance, Multiple; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
D018528:ATP-Binding Cassette Transporters; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins