Effect
of Bicalutamide Therapy on Prolactin Response to
L-dopa in Metastatic Prostate Cancer Patients
by Paolo Lissoni (1),
Fabio Malugani,(1),
Marilena Casu (2),
Roberta Bukovec (1)
Remo Egardi (3),
Veronica Bordin (1),
Elena Fumagalli (1),
Susan Mengo (1)
Gianstefano Gardani (1)
Submitted:
August 17, 2001
Accepted: September 3, 2001
1. U.O. di Oncologia Medica e Radioterapia, San Gerardo Hospital,
20052 Monza (MI), Italy.
2. Divisione di Urologia, San Gerardo Hospital, 20052 Monza
(MI), Italy.
3. Astra-Zeneca, Milan, Italy.
Key
words:
anti-androgens, bicalutamide, L-dopa, prolactin, prostate
cancer
Abstract
OBJECTIVES: The secretion of prolactin (PRL), which is a growth
factor for prostate cancer cell proliferation, has been proven
to present profound alterations in advanced prostate cancer
patients, consisting of abnormally elevated baseline levels
and paradoxical response to L-dopa. Moreover, the efficacy
of standard therapies for prostate cancer may be mediated
at least in part by changes in PRL secretion. The present
study was carried out to analyze the effects of the new antiandrogen
agent bicalutamide on basal levels of PRL and on its response
to L-dopa in metastatic prostate cancer patients.
MATERIAL
& METHODS: The study included 10 metastatic prostate cancer
patients. They were treated with bicalutamide at a dose of
50 mg/day orally. They were investigated with L-dopa test
before therapy and after one month of treatment. L-dopa was
given orally at 500 mg, by collecting blood samples before
and at 60, 120 and 180 minutes after L-dopa administration.
Serum levels of PRL were measured by the RIA method.
RESULTS:
Abnormally basal levels of PRL were seen in 4/10 (40%) patients.
Mean PRL basal levels decreased after bicalutamide therapy,
without, however, significant differences. Before therapy,
a paradoxical increase in PRL levels after L-dopa occurred
in 4 patients, 3 of them showed basal concentrations of PRL
within the normal range. Moreover, bicalutamide therapy significantly
reduced PRL increase in response to L-dopa.
CONCLUSIONS:
This study would suggest that the measurement of the only
basal levels is not sufficient to define as normal the secretion
of PRL in advanced prostate cancer, because of the possible
existence of altered response to the dynamic tests for PRL
secretion. Moreover, the study shows that the antitumor therapy
with the new anti-adrogen bicalutamide may reduce PRL secretion
and improve its paradoxical secretion in response to L.-Dopa.
Further studies will be required to better define the possible
prognostic impact of changes in PRL secretion on the efficacy
of treatments for metastatic prostate cancer.
Introduction
It is known that prolactin (PRL) is a growth factor for prostate
cancer [1]. In particular, PRL has appeared to induce a stimulatory
effect independent of testosterone on prostate cancer cells.
More in detail, PRL has been shown to modulate the proliferation
of androgen-insensitive human prostate cancer cell lines [3].
Moreover, abnormally high levels of PRL have been described
in the blood of patients with advanced prostate cancer [4].
Finally, the evidence of high blood concentrations of PRL
has been proven to be generally associated with poor prognosis
and lack of response to the conventional treatments [4]. However,
few studies only have been performed up to now to evaluate
the effects of the various oncological therapies on PRL secretion
in prostate cancer, in an attempt to establish whether a modulation
of PRL production may influence the efficacy of the conventional
therapies. Radical prostatectomy has appeared to induce a
significant increase in testosterone, estradiol, LH and FSH,
and a significant decline in dihydrotestosterone, whereas
PRL levels were not influenced [5]. Moreover, blood hormone
levels did not correlate with pathological stage or histological
grade [5]. LHRH-analogues have appeared to determine controversial
results on PRL secretion. In fact, the LHRH analogue buserelin
has appeared to enhance PRL levels, even though for a transient
period of time, whereas the chronic therapy does not seem
to influence PRL levels [6]. In contrast, a small decrease
in PRL levels has been described on therapy with another LHRH-analogue,
goserelin [7]. These results, even though still preliminary,
would suggest that the various LHRH- analogues available up
to now for the treatment of prostate cancer may deserve different
effects on PRL secretion, which could explain possible differences
in their therapeutic efficacy.
Moreover, it has to be remarked that most studies carried
out to evaluate PRL secretion in prostate cancer patients
have been limited to the analysis of PRL blond levels in baseline
conditions, rather than in dynamic conditions by the various
endocrine clinical tests, such as L-Dopa test, which represents
the main commonly used inhibitory test for PRL secretion.
0ur previous preliminary studies have shown a paradoxical
stimulatory response of PRL to L-Dopa in a considerable number
of patients with advanced prostate cancer [8]. In contrast,
low-dose bromocriptine, a long-acting dopaminergic agonist,
has been shown to suppress the abnormally high PRL production
in advanced prostate cancer patients [4].
The impact of the association of antiprolactinemic drugs on
the therapeutic efficacy of the commonly used endocrine therapies
of prostate cancer has-still to be better investigated. The
preliminary results available up to now seem to suggest that
a combined suppression of PRL by bromocriptine may improve
the efficacy of the conventional therapies with respect to
orchiectomy alone or orchiectomy plus the antiandrogen flutamide
[9], while no clear data are available about the association
between antiprolactinemic drugs and LHRH-analogues.
Bicalutamide is a new anti-androgen drug [10], with efficacy
superior to that of the most commonly used anti-androgen flutamide
in the treatment of advanced prostate cancer, at least in
terms of survival time [11]. As far as the endocrine effects
of bicalutamide, very few data are available, in particular
those concerning PRL secretion. Preliminary results would
suggest that PRL secretion may increase on bicalutamide therapy
[12]. The present study was performed to evaluate the effect
of bicalutamide on PRL secretion, either in baseline conditions,
or in response to L-Dopa in advanced prostate cancer.
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