The Prostate 56:106 ^109 (2003)
`
`Possible Mechanism of DexamethasoneTherapy for
`Prostate Cancer: Suppression of Circulating
`Levelof Interleukin- 6
`
`Koichiro Akakura,* Hiroyoshi Suzuki, Takeshi Ueda, Akira Komiya,
`Tomohiko Ichikawa, Tatsuo Igarashi, and Haruo Ito
`Department of Urology,Graduate Schoolof Medicine,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-dose
`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
`androgen-independent 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: 106–109, 2003. # 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-
`coid 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-
`mone-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) hormone-naı¨ve;
`(ii) androgen-independent and hormone-sensitive; and
`(iii) androgen-independent and hormone-insensitive.
`
`ß 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’s present address is Department of Urology,
`Tokyo Kosei Nenkin Hospital, Tokyo, Japan.
`*Correspondence to: Koichiro Akakura, Department of Urology,
`Tokyo Kosei Nenkin Hospital, 5-1 Tsukudo-cho, Shinjuku-ku, Tokyo
`162-8543, Japan. E-mail: akakurak@tkn-hosp.gr.jp
`Received 8 July 2002; Accepted 9 December 2002
`DOI 10.1002/pros.10231
`
`WCK1093
`Wockhardt Bio AG v. Janssen Oncology, Inc.
`IPR2016-01582
`
`1
`
`

`

`MATERIALS AND METHODS
`
`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
`PSA Assay (Hybritech, Inc., San Diego, CA). The
`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
`
`DexamethasoneTherapy for Prostate Cancer
`
`107
`
`TABLE I. Change of Serum PSA and Clinical Symptoms by
`DexamethasoneTherapy in Prostate Cancer Patients Who
`Showed Biochemical Failure
`
`50%
`PSA decline
`
`Yes
`No
`Total
`
`Pain relief by dexamethasone therapy
`
`Effective
`
`Not
`effective
`
`No
`symptom
`
`8
`1
`9
`
`0
`12
`12
`
`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: 1–8) 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
`
`Factors
`
`Number of patients
`PSA at dexamethasone therapy (ng/ml)
`Duration of endocrine therapy (months)
`Previous antiandrogen withdrawal syndrome
`Yes
`No
`Not evaluable
`
`Respondersa
`
`Non-responders
`
`12 (48%)
`657.6 645.6
`32.3 26.6
`
`13 (52%)
`774.1 1172.3
`23.0 17.2
`
`2
`7
`3
`
`2
`11
`0
`
`aResponders: patients who showed 50% or more decline of serum PSA and/or improvement
`of pain.
`
`2
`
`

`

`108
`
`Akakura et al.
`
`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
`
`Fig. 1. Changeofseruminterleukin-6(IL-6)followingdexametha-
`sone therapy.Each dotrepresents each patient.Responders to dex-
`amethasone therapy (n¼ 8): patients who showed 50% or more
`decline of serum PSA and/orimprovementofpain.
`
`Fig. 2. Change of serum IL-6 following dexamethasone therapy.
`Each dot represents each patient. Non-responders to dexametha-
`sone therapy (n¼ 8).
`
`dexamethasone therapy irrespective of the response
`of dexamethasone therapy. In some of non-responders
`to dexamethasone 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 [10–12].
`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 [13–15]. 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
`
`3
`
`

`

`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.
`
`REFERENCES
`
`1. Scher HI, Kelly WK. Flutamide withdrawal syndrome: Its impact
`on clinical trials in hormone-refractory prostate cancer. J Clin
`Oncol 1993;11:1566–1572.
`Incidence and
`2. Akakura K, Akimoto S, Furuya Y, Ito H.
`characteristics of antiandrogen withdrawal syndrome in pros-
`tate cancer after treatment with chlormadinone acetate. Eur Urol
`1998;33:567–571.
`3. Scher HI, Steineck G, Kelly WK. Hormone-refractory (D3)
`prostate cancer: Refining the concept. Urology 1995;46:142–148.
`4. Stolie JA, Buckner JC, Wiseman GA, Burch PA, Hartmann LC,
`Richardson RL. Prostate specific antigen levels and clinical
`response to low dose dexamethasone for hormone-refractory
`metastatic prostate carcinoma. Cancer 1995;76:96–100.
`5. Nishiyama T, Terunuma M. Hormone/antihormone withdra-
`wal and dexamethasone for hormone-refractory prostate cancer.
`Int J Urol 1998;5:44–47.
`
`DexamethasoneTherapy for Prostate Cancer
`
`109
`
`6. Nishimura K, Nonomura N, Yasunaga Y, Takaha N, Inoue H,
`Sugao H, Yamaguchi S, Ukimura O, Miki T, Okuyama A. Low
`doses of oral dexamethasone for hormone-refractory prostate
`carcinoma. Cancer 2000;89:2570–2576.
`7. Nishimura K, Nonomura N, Satoh E, Harada Y, Nakayama M,
`Tokizane T, Fukui T, Ono Y, Inoue H, Shin M, Tsujimoto Y,
`Takayama H, Aozasa K, Okuyama A. Potential mechanism
`for the effects of dexamethasone on growth of androgen-
`independent prostate cancer. J Natl Cancer Inst 2001;93:1739–
`1746.
`8. Hobisch A, Rogatsch H, Hittmair A, Fuchs D, Bartsch G Jr.,
`Klocker H, Bartsch G, Culig Z.
`Immunohistochemical
`localization of interleukin-6 and its receptor in benign, pre-
`malignant and malignant prostate tissue. J Pathol 2000;191:
`239–244.
`9. Ray A, Zhang D-G, Siegel MD, Ray P. Regulation of Interleukin-6
`gene expression by steroids. In: Mackiewicz A, Koj A, Sehgal PB,
`editors. Interleukin-6-type cytokines. New York: Ann NY Acad
`Sci; 1995. pp 79–88.
`10. Okamoto M, Lee C, Oyasu R. Interleukin-6 as a paracrine and
`autocrine growth factor in human prostatic carcinoma cells
`in vitro. Cancer Res 1997;57:141–146.
`11. Chung TD, Yu JJ, Spiotto MT, Bartkowski M, Simons JW.
`Characterization of the role of IL-6 in the progression of prostate
`cancer. Prostate 1999;38:199–207.
`12. Lou W, Ni Z, Dyer K, Tweardy DJ, Gao AC. Interleukin-6
`induces prostate cancer cell growth accompanied by activation
`of STAT3 signaling pathway. Prostate 2000;42:239–242.
`13. Hobisch A, Eder IE, Putz T, Horninger W, Bartsch G, Klocker H,
`Culig Z. Interleukin-6 regulates prostate-specific protein expres-
`sion in prostate carcinoma cells by activation of the androgen
`receptor. Cancer Res 1998;58:4640–4645.
`14. Chen T, Wang LH, Farrar WL. Interleukin 6 activates androgen
`receptor-mediated gene expression through a signal transducer
`and activator of transcription 3-dependent pathway in LNCaP
`prostate cancer cells. Cancer Res 2000;60:2132–2135.
`15. Ueda T, Bruchovsky N, Sadar MD. Activation of the androgen
`receptor N-terminal domain by interleukin-6 via MAPK and
`STAT3 signal transduction pathways. J Biol Chem 2002;277:
`7076–7085.
`16. Drachenberg DE, Elgamal AA, Rowbotham R, Peterson M,
`Murphy GP. Circulating levels of interleukin-6 in patients with
`hormone refractory prostate cancer. Prostate 1999;41:127–133.
`17. Nakashima J, Tachibana M, Horiguchi Y, Oya M, Ohigashi T,
`Asakura H, Murai M. Serum interleukin-6 as a prognostic
`factor in patients with prostate cancer. Clin Cancer Res 2000;
`6:2702–2706.
`18. Takeda H, Akakura K, Masai M, Akimoto S, Yatani R, Shimazaki
`J. Androgen receptor content of prostate carcinoma cells
`estimated by immunohistochemistry is related to prognosis
`of patients with stage D2 prostate carcinoma. Cancer 1996;77:
`934–940.
`
`4
`
`