Prolonging androgen sensitivity in prostate cancer - a role for COX inhibitors?
BACKGROUND
Advanced prostate cancer has long been known to respond to androgen deprivation, but disease inevitably progresses to become androgen independent. Lengthening the responsive period is an important, yet underinvestigated, clinical goal. This study aims to determine whether cyclooxygenase-2 (COX-2) inhibitors are potentially useful agents in prolonging androgen sensitivity.


METHODS
The expression of COX-2 in human prostate surgical specimens, both benign and malignant, androgen dependent and independent, was determined by immunohistochemistry. Nude mice, in which prostate cancer xenografts had been established, were castrated and randomized to receive either COX-2 inhibitor or vehicle for 8 weeks. Time to androgen independence (AIPC), growth rate and rate of PSA rise were compared between groups. COX-2 expression, at the mRNA and protein level, was determined in the native xenograft cell line and in tissues of varying androgen sensitivity derived from the xenografts.


RESULTS
In human tissues, COX-2 protein was expressed in prostate epithelium and was upregulated in prostate cancer and remained upregulated after androgen ablation and in the androgen-independent state. Tissue obtained from the LNCaP xenograft model showed variable COX-2 expression, with some evidence of downregulation in AIPC. The addition of a COX-2 inhibitor to castration does not lengthen the time to AIPC (P= 0.53), rate of tumour growth (P= 0.59) or rate of PSA rise (P= 0.34) in the LNCaP xenograft model.


CONCLUSIONS
This study does not support a role for COX-2 inhibitors in prolonging androgen responsiveness in prostate cancer.
Richards
Andrew
A
Department of Urology, Royal Prince Alfred Hospital, Australia. office@drandrewrichards.com.au
McGeechan
Kevin
K
Niknam
Marzieh
M
Salomon
Robert
R
Kurek
Caroline
C
Dong
Qihan
Q
Patel
Manish I
MI
D000728:Androgens / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009919:Orchiectomy; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000628:therapy*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D000728:Androgens; D052246:Cyclooxygenase 2 Inhibitors; D051546:Cyclooxygenase 2