Raloxifene, an oestrogen-receptor-beta-targeted therapy, inhibits androgen-independent prostate cancer growth: results from preclinical studies and a pilot phase II clinical trial.
OBJECTIVE
To determine, in preclinical in vivo animal and in clinical studies, whether raloxifene (a selective oestrogen-receptor (ER) modulator that targets ER-beta and induces apoptosis in vitro in androgen-independent prostate cancer, AIPC cells) affects prostate cell differentiation, proliferation and carcinogenesis, and in the pilot phase II clinical trial, the response rate and duration of patients with AIPC treated with a daily oral dose of raloxifene.


METHODS
Tumour proliferation rate in response to raloxifene treatment, and molecular markers of cell cycle and apoptosis, were evaluated in established ER-beta-positive androgen-dependent (AD) CWR22 and AI CWRSA9 human xenograft prostate cancer models. Twenty-one patients with AIPC and evidence of disease progression were enrolled into the clinical trial and given daily oral raloxifene.


RESULTS
There was significant growth inhibition by raloxifene in the ADPC and AIPC xenograft models (CWR22 68%, P < 0.010; CWRSA9 64%, P < 0.001), with no tumour regression. There was evidence of G1 arrest by increased p27kip1 expression in the raloxifene-treated group. Eighteen patients comprised the efficacy analysis, as three withdrew before the first evaluation. At the first evaluation, five men had stable disease and continued on the study for a median of five cycles. The longest response was 17 cycles. Drug related toxicity was minimal.


CONCLUSIONS
Raloxifene has activity in xenograft models, slowing disease progression. This translated to possible disease stabilization in patients with AIPC. Further studies are warranted.
Louis Warschaw Prostate Cancer Center, Cedars-Sinai Medical Center, 8631 West Third Street, Los Angeles, CA 90048, USA.
Ronald L
RL
Shazer
Anjali
A
Jain
Anna V
AV
Galkin
Nadya
N
Cinman
Koo N
KN
Nguyen
Ronald B
RB
Natale
Mitchell
M
Gross
Leland
L
Green
Leon I
LI
Bender
Stuart
S
Holden
Leslie
L
Kaplan
David B
DB
Agus
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008875:Middle Aged; D010865:Pilot Projects; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D020849:Raloxifene Hydrochloride / Q000627:therapeutic use*; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*; D016896:Treatment Outcome
D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D017430:Prostate-Specific Antigen