`
`Possible Mechanism of DexamethasoneTherapy for
`
`Prostate Cancer: Suppression of Circulating
`Level of lnter|eukin- 6
`
`Koichiro Al<akura,* Hiroyoshi Suzuki, Takeshi Ueda, Akira Komiya,
`Tomohiko Ichikawa, Tatsuo Igarashi, and Haruo Ito
`
`Department of Urology, Graduate School ofMedicine, Chiba University, Chiba, japan
`
`BACKGROUND. Glucocorticoids may have favorable effects on prostate cancer patients
`showing clinical and/or biochemical failure after androgen ablation. The efficacy and
`mechanisms of dexamethasone therapy as possible alternative endocrine therapy were
`investigated.
`METHODS. Twenty five patients with prostate cancer treated by androgen ablation and
`showing a steady increase in serum prostate specific antigen (PSA) were treated with low-d ose
`dexamethasone.
`
`RESULTS. Of 25 patients, 11 demonstrated 50% or more decline of serum PSA and 9 showed
`improvement of pain on dexamethasone therapy. Of 8 patients who responded to
`dexamethasone thearpy, 5 had 80% or more decrease in serum interleukin-6 (IL-6). In contrast,
`none of 8 non-responders showed remarkable IL-6 suppression. Response of PSA was not
`correlated to the changes in serum dehydroepiandrosterone, dehydroepiandrosterone sulfate,
`or androstendione.
`
`CONCLUSIONS. Significant suppression of serum IL-6, probably through inhibition of
`androgemindependent activation of androgen receptor, may be one of the mechanisms for the
`effect of dexamethasone therapy in prostate cancer patients with progressive disease. Prostate
`56: 105-109, 2003.
`(C) 2003 Wiley-Liss. Inc.
`
`KEY WORDS:
`
`prostate cancer; androgen ablation; glucocorticoid; interleukin-6; prostate
`specific antigen
`
`INTRODUCTION
`
`For the management of advanced prostate cancer,
`endocrine therapy by androgen ablation is generally
`effective as an initial
`treatment. However, when
`
`progression occurs after initial endocrine therapy,
`optimal therapy has not been established. Recently, it
`was demonstrated that antiandrogen withdrawal and
`administration of another antiandrogen or glucocorti-
`Cold might have favorable effects on patients who had
`been treated with androgen ablation and had shown
`clinical and / or biochemical failure [1—6]. Thus, "hor-
`
`rnone-refractory” prostate cancer is thought to include
`patients with a spectrum of diseases. Based on these find-
`ings, Scher et al. [3] advocated new classification of hor-
`monal sensitivity of prostate cancer: (i) horrnone—na'1've,'
`(ii) androgen—incIependent and hormone—sensitive; and
`(iii) androgen—independent and hormone—insensitive.
`
`© 2003 Wiley-Liss, Inc.
`
`In the present study, the efficacy of dexamethasone as
`an alternative endocrine therapy is examined by
`responses in serum prostate specific antigen (PSA)
`and pain relief.
`In addition,
`the mechanisms of
`dexamethasone therapy are investigated.
`
`Grant sponsor: Ministry of Education, Culture, Sports, Science and
`Technology (Grants-in Aid); Grant numbers: 11770882, 11671536,
`13671635.
`
`Koichiro Akakura'5 present address is Department of Urology,
`Tokyo Kosei Nenkin Hospital, Tokyo, Japan.
`‘Correspondence to: Koichiro Akakura, Department of Urology,
`Tokyo Kosei Nenkin Hospital, 51 Tsukudo-cho, Shinjuku-ku, Tokyo
`162-8543, Japan. E-mail: al<aI<ural<@tl<n-hosp.gr.jp
`Received 8 July 2002; Accepted 9 December 2002
`DOI 10.1002/pros.1D231
`
`
`
`
`
`DexamethasoneTherapy for Prostate Cancer [07
`
`
`
`MATERIALS AN D M ETHODS
`
`A total of 25 patients with prostate cancer who had
`been treated with androgen ablation (surgical castra-
`tion or LHRH agonist) and had shown biochemical
`failure (a steady increase in serum PSA) were included
`in the present study. Upon biochemical failure, the
`patients were treated with dexamethasone (initially
`1.5 mg / day, then tapered to 0.5 mg/day). In patients
`treated with surgical or medical castration plus anti-
`androgen, antiandrogen withdrawal syndrome was
`assessed for at least 4—8 weeks by the cessation of the
`antiandrogen before dexamethasone therapy; and
`treatment with LHRH agonist was not discontinued.
`Serum PSA levels were determined with the Tandem-R
`
`Inc., San Diego, CA). The
`PSA Assay (Hybritech,
`clinical effect of dexamethasone therapy was evaluated
`based on improvement of pain. Patients who showed
`50% or more decline of serum PSA and/ or improve-
`ment of pain estimated by decrease in dose or change of
`analgesics were defined as responders to dexametha-
`sone therapy. The changes in serum testosterone,
`dehydroepiandrosterone,
`dehydroepiandrosterone
`sulfate, androstendione, ACTH, cortisol and interleu~
`kin—6 (IL-6) were measured in relation to the effect of
`
`dexamethasone therapy.
`
`Statistical Analysis
`
`Statistical analysis was performed by the Mann-
`Whitney U—test and chi—square test. P<0.05 was
`considered significant.
`
`RESULTS
`
`At initial diagnosis, histological examination of the
`tumor showed 3 well differentiated, 10 moderately
`differentiated, and 10 poorly differentiated adenocar—
`cinomas. Histological grade of the tumor was unknown
`in two patients. The methods of initial endocrine
`
`TABLE I. Change of Serum PSA and Clinical Symptoms by
`Dexametl-IasoneTherapy in Prostate Cancer Patients Who
`Showed Biochemical Failure
`
`250%
`PSA decline
`Yes
`No
`Total
`
`Pain relief by dexamethasone therapy
`
`Effective
`8
`1
`9
`
`Not
`effective
`0
`12
`12
`
`No
`symptom
`3
`1
`4
`
`therapy consisted of surgical or medical castration
`alone in 7, castration plus chlormadinone acetate in 11,
`castration plus flutamide in 6, and castration plus
`bicalutamide in 1. As second or third line endocrine
`
`therapy, alternative antiandrogen was administered;
`chlormadinone acetate in 4, flutamide in 7, and bicalut-
`amide in 12. The duration of endocrine therapy ranged
`from 5 to 81 months with a mean of 27.4 months.
`
`Patients’ ages at the start of dexamethasone therapy
`ranged from 47 to 82 years with a mean of 69 years. The
`median serum PSA level at dexamethasone therapy
`was 262 ng/ ml with a range of 8.4—4,100 ng/ ml.
`Of 25 patients, 11 (44%) demonstrated 50% or
`more decline of serum PSA by dexamethasone therapy.
`The average duration of responding period was 5.1
`(range: l~8) months. Eight patients showing 50% or
`more decline of PSA and one patient without remark-
`able decline of PSA revealed improvement of pain relief
`(Table I). The response of dexamethasone therapy was
`not related to serum PSA levels at the start of therapy,
`the duration of previous endocrine therapy, or the
`previous occurrence of antiandrogen withdrawal syn-
`drome (Table II).
`
`Serum testosterone levels were suppressed to within
`the castrate range in all patients examined (data not
`shown). The response to dexamethasone therapy was
`
`
`
`TABLE II. Comparison of Clinical Characteristics Between Responders and
`Non-Responders to DexamethasoneTherapy in Prostate Cancer Patients Who
`Showed Biochemical Failure
`mm-
`
`Factors
`
`Number of patients
`PSA at dexamethasone therapy (ng/ml)
`Duration of endocrine therapy (months)
`Previous antiandrogen withdrawal syndrome
`Yes
`No
`Not evaluable
`
`Responders“
`
`Non-responders
`
`12 (48%)
`657.6 i 645.6
`32.3 :|: 26.6
`
`13 (52%)
`774.1 d: 1172.3
`23.0 i 17.2
`
`2
`7
`3
`
`2
`11
`
`O a
`
`Responders: patients who showed 50% or more decline of serum PSA and/or improvement
`of pain.
`
`
`
`I03
`
`Akakura at at.
`
`not correlated with the changes in serum dehydroe—
`piandrosterone, dehydroepiandrosterone sulfate, or
`androstendione, although some non—responders did
`not show significant suppression of adrenal androgens
`after dexamethasone therapy (data not shown). The
`change of serum IL-6 during dexamethasone therapy
`was evaluated in 16 patients. As shown in Figure 1, 5 of
`8 responders to dexamethasone therapy demonstrated
`80% or more decrease in serum IL-6 at 1 month from the
`
`start of dexamethasone. On the contrary, none of 8 non-
`responders
`showed remarkable IL-6 suppression
`(Fig. 2). There was an association between the response
`of dexamethasone therapy and 80% or more suppres-
`sion of serum IL-6 (P < 0.05, chi—square test).
`
`DISCUSSION
`
`In the present study, the favorable effect of low—dose
`dexamethasone was demonstrated in a substantial
`
`number of patients who showed PSA failure after
`initial endocrine therapy. Some of the previous studies
`also reported the high rate of PSA response to gluco-
`corticoid therapy in patients with progressive prostate
`cancer after androgen ablation [4—6]. Thus, it may be
`worthwhile to administer dexamethasone after con-
`
`firming the antiandrogen withdrawal syndrome, since
`low-dose dexamethasone therapy does not have severe
`adverse effects.
`
`The mechanism of dexamethasone therapy for
`hormone—refractory prostate cancer has been believed
`to be suppression of adrenal androgens. However, in
`the majority of patients in the present series, serum
`levels of adrenal androgens were suppressed by
`
`interleukin-6
`
`(psfmh
`100
`
`10
`
`1
`
`Before
`
`1 month
`
`3 months
`
`Responders
`
`I. Change ofserum inter|eukin-6(|L- 6)fol|owingdexametha-
`Fig.
`sone therapy. Each dot represents each patient. Responders to dex-
`amethasone therapy (n :8): patients who showed 50% or more
`decline of serum PSA and/or improvement of pain.
`
`Interleukin-6
`
`(P9/ml)
`
`100
`
`n——-——~——n
`
`l0
`
`1
`
`_,,mL...
`Before
`
`l month
`
`3 months
`
`Non—responders
`
`Fig. 2. Change of serum IL-6 following dexamethasone therapy.
`Each clot represents each patient. Non-responders to dexametha-
`sone therapy (n = 8).
`
`dexamethasone therapy irrespective of the response
`of dexamethasone therapy. In some of non-responders
`to dexarnethasone therapy, no marked suppression of
`adrenal androgens was observed, probably due to low
`compliance with dexamethasone administration, since
`serum cortisol was not decreased very much.
`The present
`study suggests another possible
`mechanism of dexamethasone action, that of significant
`suppression of IL-6. The direct effect of dexamethasone
`on prostate cancer cells has been suggested through
`NF-kappaB—IL-6 pathway [7]. However, circulating
`IL-6 is thought to be derived from many different cell
`types including monocytes, fibroblasts, endothelial
`cells, and possibly some of prostate cells [8]. IL-6 is
`known to be suppressed by glucocorticoids [9] and to
`stimulate the growth of the prostate cancer cell lines
`through its receptors in an androgen-independent
`manner [l0—12].
`In addition,
`recent reports have
`shown that IL-6 can activate the androgen receptor
`through a signal transducer and activator of transcrip-
`tion 3 (STAT3)~dependent pathway [l3—l5]. Circulat-
`ing IL-6 levels are high in hormone—refractory prostate
`cancer patients [16], and Serum IL-6 may be a good
`prognostic factor after androgen ablation therapy in
`prostate cancer patients [17], the present study shows
`that remarkable suppression of serum IL-6 is closely
`related to the response to dexamethasone therapy.
`Since serum level of IL-6 was not related to serum PSA
`
`at the start of dexamethasone therapy in the present
`study, and both IL-6 producing and non—producing
`prostatic cancer cells have been reported in the
`literature [10], it seems unlikely that the decline of
`serum IL-6 simply resulted from reduction of IL-6
`
`
`
`producing cancer cells. Therefore, the decrease in cir-
`culating IL-6 by dexamethasone administration may
`reflect inhibition of ligand-independent activation of
`the androgen receptor, resulting in inhibition of ex-
`pression of androgen responsive genes.
`The androgen receptor plays a key role in androgen-
`dependent proliferation of prostate cancer cells.
`Although the content of androgen receptor has been
`shown to be a prognostic indicator in prostate cancer
`patients treated by endocrine therapy, androgen-inde-
`pendent tumors can express the androgen receptor
`[18], suggesting that post—receptor pathways of cell
`proliferation are preserved in a number of prostate
`cancer cells. Therefore, it is likely that expression of
`other androgen—responsive genes which control andro-
`gen-dependent proliferation of cancer cells could be
`similarly inhibited by dexamethasone.
`
`CONCLUSIONS
`
`The favorable effect of low-dose dexamethasone was
`
`demonstrated in prostate cancer patients who showed
`PSA failure after initial endocrine therapy. Significant
`suppression of IL-6 may represent one of the mechan-
`isms for
`the effect of dexamethasone therapy in
`prostate cancer patients showing biochemical failure.
`Since the present study was based on a small number of
`patients and the observation seemed preliminary,
`further investigations would be required to make final
`conclusions.
`
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