Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Cancer. Author manuscript; available in PMC 2010 December 1.
Published in final edited form as:
PMCID: PMC2917101

Vorinostat in Advanced Prostate Cancer Patients Progressing on Prior Chemotherapy (NCI Trial # 6862): Trial results and IL-6 analysis. A study by the DOD Prostate Cancer Clinical Trial Consortium and University of Chicago Phase II Consortium



This phase II trial was designed to evaluate the efficacy of vorinostat in chemotherapy pretreated patients with metastatic castrate resistant prostate cancer.

Patients and Methods

Patients with disease progression on one prior chemotherapy, a PSA ≥ 5ng/ml, and adequate organ function were treated with 400 mg vorinostat orally daily. The primary endpoint was the six month progression rate. Secondary endpoints included safety, rate of PSA decline, objective response, overall survival, and effects of vorinostat on serum IL-6 levels.


Twenty-seven eligible patients were accrued. Median number of cycles delivered was 2 (range 1–7). All patients were taken off therapy before six months. The best objective response in the eligible patients was stable disease in 2 (7%) patients. No PSA decline of ≥ 50% was observed. There was one grade 4 adverse event (AE) and 44% of patients experienced grade 3 AEs. Most common AEs were: fatigue (81%), nausea (74%), anorexia (59%), vomiting (33%), diarrhea (33%), and weight loss (26%). Median time to progression and overall survival were 2.8 and 11.7 months respectively. Median IL-6 levels (pg/ml) were higher in patients removed from protocol for toxicity vs. progression at all time points, including baseline (5.2 vs 2.1, p=0.02), Day 15-Cycle 1 (9.5 vs 2.2, p=0.01), Day 1-Cycle 2 (9.8 vs 2.2, p=0.01), and end of study (11.0 vs 2.9, p=0.09)


Vorinostat at this dose was associated with significant toxicities limiting efficacy assessment in this patient population. The significant association between IL-6 levels and removal from study for toxicities warrants further investigation.

Keywords: prostate cancer, metastatic, HDAC inhibitors, IL-6, SAHA, vorinostat, Zolinza


With the establishment of docetaxel as standard first line chemotherapy for castrate resistant prostate cancer (CRPC) 1, 2, a clinical research priority in this disease is to identify second line therapy. Histone deacetylases (HDACs) regulate cell signaling and gene transcription through removal of acetyl groups from histone and non-histone proteins 35. Inhibition of HDAC activity leads to accumulation of acetylated proteins, which in turn lead to alterations in transcription, mitosis, and protein stability with resultant inhibition of tumor cell proliferation and survival 36. In preclinical studies, HDAC inhibitors have been shown to induce tumor cell cytostasis, differentiation, and apoptosis, and to inhibit tumor angiogenesis in various hematologic and solid malignancies, In prostate cancer, HDAC inhibition has resulted in decreased proliferation in cell lines79, and decreased tumor growth in preclinical models 915 suggesting that HDAC inhibition is of a potential therapeutic benefit in this disease.

Vorinostat is a small molecule inhibitor of class I and II HDACs that has been approved by the Food and Drug Administration for treatment of cutaneous T-cell lymphoma 1618. In early testing, vorinostat showed significant antitumor activity in a broad range of cancers 1922 including preclinical activity in prostate cancer 23, 24. Specifically, vorinostat suppressed the growth of the LNCaP, PC-3, and TSU-Pr1 cell lines at micromolar concentrations 23. In mice with transplanted CWR222 human prostate tumors, vorinostat treatment at 50 mg/kg/day resulted in significant suppression of tumor growth. At this dose, there was no detectable toxicity as evaluated by change in weight and necropsy examination 23. Kulp and colleagues have similarly shown growth inhibition of PC-3, DU-145, and LNCaP human prostate cancer cell lines and suppression of PC-3 xenograft tumors with vorinostat treatment 9. These biologic, preclinical and phase I data collectively provided the rational for testing vorinostat in patients with CRPC failing prior chemotherapy.

Interleukin-6 (IL-6) is a pleiotropic cytokine that stimulates the progression of a variety of cancers. Multiple studies have demonstrated that IL-6 is elevated in the sera of patients with metastatic prostate cancer 2527. Drachenberg and colleagues 28 reported elevated serum IL-6 levels in men with hormone-refractory prostate cancer compared to normal controls, benign prostatic hyperplasia, prostatitis, and localized or recurrent disease suggesting that IL-6 may be a surrogate marker of the androgen independent phenotype. IL-6 has also been associated with disease progression and has been implicated as a potential marker of response to therapy 2931. HDAC inhibition has also been shown to be associated with decreased expression of IL-6 and other pro-inflammatory mediators3234 These findings, along with the observations that vorinostat can down-regulate the IL-6 signaling cascade 35 portends a possible role for the evaluation of IL-6 as an indicator of response to vorinostat. We hypothesized that vorinostat-mediated down regulation of IL-6 activity would be associated with a favorable outcome.

Patients and Methods

This Cancer Therapy Evaluation Program (CTEP) sponsored trial was conducted by the Department of Defense (DOD) Prostate Cancer Clinical Trials Consortium (PCCTC) and the National Cancer Institute (NCI)-sponsored University of Chicago Phase II Consortium. The protocol was reviewed and approved by the institutional review board at each participating institution and all patients provided informed consent prior to initiation of any study procedures. Eligible patients had metastatic prostate cancer with measurable and/or bony disease that had progressed despite androgen deprivation therapy and one prior chemotherapy regimen for CRPC. All patients were required to have prostate-specific antigen (PSA) progression defined as at least two rises in PSA documented over a reference value, no less than 7 days apart, with a minimum value of 5ng/ml. Patients had to have an Eastern Oncology Cooperative Group (ECOG) performance status of 0–2, adequate hematological, renal, and hepatic function defined by a white blood count of ≥ 3,000/μl, absolute neutrophil count ≥ 1,500/μl, platelet count ≥ 100,000/μl, creatinine < 2mg/dl, bilirubin within normal limits, aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 2.5 X the upper limits of normal. Patients with significant cardiovascular disease including congestive heart failure (New York Heart Association Class III or IV), active angina pectoris or recent myocardial infarction (within the last 6 months) were excluded. Patients requiring diuretics for reasons other than hypertension, digoxin for reasons other than atrial fibrillation, or with a history of mild to moderate congestive heart failure, or patients with the following electrocardiogram (EKG) results: (a) significant q waves, (b) ST elevation or depressions of greater than 2 mm, (c) the absence of a regular sinus rhythm, or (d) the presence of a bundle block were required to undergo additional cardiac testing. Patients with known brain metastases were excluded but those with treated and controlled epidural disease were eligible. Patients on luteinizing hormone-releasing hormone (LHRH) agonists were required to continue therapy Discontinuation of all nonsteroidal antiandrogens (28 days for flutamide and 42 days for bicalutamide) was required. Patients taking valproic acid (a histone deacetylase inhibitor) must have stopped therapy at least two weeks prior to registration. No investigational or commercial agents (other than LHRH analogues) or therapies including other hormonal agents such as steroids, megesterol acetate (unless low dose given for hot flashes), antiandrogens or herbal medications were permitted to be administered with the intent to treat the patient’s malignancy. Patients with a “currently active” second malignancy other than non-melanoma skin cancers were not eligible. Patients were not considered to have a “currently active” malignancy if they had completed therapy and were considered by their physician to be with no evidence of disease.

Treatment Plan

Patients received open-label oral vorinostat 400 mg daily continuously. All patients completed a medication diary to monitor compliance. Toxicity was assessed using NCI-common terminology criteria (CTC) version 3.0 and dose reductions to 300 mg/day and 100mg/day were specified for grade 3 or 4 toxicities. Patients were evaluated clinically and by laboratory tests every 21 days. A maximum four week break in treatment for toxicity resolution was permitted.

Duration of Therapy, Monitoring and Response Assessment

Patients were monitored by history and physical exam, toxicity assessment, and PSA every three weeks. Response assessment by bone scan and CT scan and/or other appropriate imaging was performed every 12 weeks. Patients were removed from protocol if there was evidence of progression by PSA or Response Evaluation Criteria in Solid Tumors (RECIST) criteria, or symptomatic progression. Patients with bone scan only progression at first assessment continued treatment with reassessment after 6 additional weeks of therapy. Patients with confirmed progression were removed from protocol. Patients with stable disease or better were permitted to continue protocol therapy. Patients demonstrating progression by bone scan or other measures at the 24 week or subsequent scheduled assessments were considered as having progressive disease and a confirmation of progression was not required. All patients were followed for survival.

Response and Progression Definition

Progression for the purpose of the study was defined by any one or more of the following parameters: 1.) PSA Progression: 25% increase over baseline or nadir whichever is lower and an increase in the absolute value of PSA by 5ng/ml that is confirmed by another PSA at no less than a 4 week interval. 2.) Measurable disease progression: progression of target lesions by RECIST criteria 36 3.) Nonmeasurable disease progression: worsening of bone scan defined as development of ≥2 new lesions, appearance of new metastatic lesions outside of the bone, unequivocal progression of existing non-target lesions, or development of an indication for radiation therapy or other change in cancer therapy based on a change in a disease manifestation while on therapy.

Objective responses were defined using RECIST criteria 36. PSA “response” was defined based on the PSA Working Group Consensus Criteria 37. Bone disease was evaluated by bone scan with disease characterized as complete response if disappearance of all osseous lesions as evaluated by scans, stable or improved defined as no new lesions and no new pain in an area that uptake was previously visualized, and progression as defined by the appearance of two or more new skeletal lesions. An increase in the size or intensity of lesions was not considered progression.

Endpoints and Statistical Design

The primary objective of this phase II trial was to evaluate the activity of oral vorinostat in patients with metastatic prostate cancer that had progressed on one prior chemotherapy regimen. The primary endpoint was the proportion of patients who did not demonstrate disease progression at 6 months. Based on a published retrospective analysis of second-line chemotherapy in men with metastatic CRPC 38, the expected progression rate by criteria used in this protocol in this patient population at six months is 84% (non progression rate of 16%). Therefore, if the progression-free rate was 10% or less, there would be little interest in pursuing this therapy further, whereas, with a progression-free rate of 30% or more, further study would be proposed.

Given the late time point for measuring progression, a single-stage design was used. Using Fisher’s exact test, 29 patients were to be accrued. If seven or more of these 29 patients were progression-free at six months, this agent would be felt to be worthy of further evaluation. This design provided for 80% power at the 5% significance level.

Secondary endpoints were to evaluate the safety of vorinostat and to determine the objective response rate in patients with bidimensionally measurable disease, the rate of PSA decline of ≥50%, progression-free and overall survival.

Correlative Biology Studies

When designing this trial, we hypothesized that vorinostat-mediated down regulation of IL-6 activity would be associated with a favorable outcome. However, since all eligible patients were taken off study before six months, this analysis was not possible. Given that IL-6 is associated with the systemic immune response 39, we performed an exploratory analysis to determine if patients with higher levels of serum IL-6 were more likely to be removed from protocol for toxicity versus progression.

Pre-treatment and on-treatment peripheral blood samples for IL-6 were collected two hours following the most recent dose of vorinostat on day 15 of cycle 1, day 1 of cycle 2, the last week of cycle 4, and at time of removal from study. Quantitative levels of IL-6 were measured using a human IL-6 immunoassay (Quantikine® HS, R&D Systems) according to manufacturers instructions. IL-6 levels were compared between patients removed from protocol for progression vs. toxicity using the Wilcoxon rank-sum test.


Between 5/06 and 2/07, 29 patients were registered to protocol. Two patients were ineligible (due to noncastrate testosterone levels or previous treatment with a radiopharmaceutical). Table 1 lists baseline patient characteristics of the 27 eligible patients. The median age was 68 (range: 54–80). 70% of patients had a performance status of 1. Previous chemotherapy treatment for metastatic CRPC included docetaxel (92%), paclitaxel (4%), and cyclophosphamide (4%). All patients are off protocol therapy with a median number of cycles given of 2 (range 1–7). 70% of patients required dose reduction.

Table 1
Patient Characteristics

Adverse Events

Forty-eight percent of patients experienced grade 3/4 toxicities. There were no grade-5 (treatment-related deaths) adverse events (AEs). Table 2 describes in detail toxicities by type and grade for which 70% of patients required dose reductions. The most common AEs were: fatigue (81%), nausea (74%), anorexia (59%), vomiting (33%), diarrhea (33%), and weight loss (26%). Eleven (41%) patients discontinued therapy due to toxicity (Table 3).

Table 2
Treatment Related Adverse Events
Table 3
Treatment discontinuation by cycle, N=27.

Response and Survival

All eligible patients were off therapy before six months (Table 3); 13 (48%) were removed due to progression, 11 (41%) secondary to toxicity, and 3 (11%) for other reasons. The best objective response obtained was stable disease in two patients (7%). Duration of stable disease was 84 and 135 days, respectively. No PSA declines of ≥ 50% were observed (Figure 1). Median time to progression was 2.8 months (range 0.5–5.3) with a median overall survival of 11.7 months (2.3–14 months with one patient censored at 15.1 months). Of note, the two additional ineligible patients not included in the final analysis also achieved a best stable response of stable disease.

Figure 1
Best Percent PSA Change from Baseline

Correlative Studies

Median IL-6 levels (pg/ml) were higher in patients removed from protocol for toxicity vs. progression at all time points, including baseline (5.2 vs 2.1, p=0.02), Day 15-Cycle 1 (9.5 vs 2.2, p=0.01), Day 1-Cycle 2 (9.8 vs 2.2, p=0.01), and end of study (11.0 vs 2.9, p=0.09) (Figure 2).

Figure 2
Serum IL-6 Values by Reason off Treatment


To date there is no established second line systemic therapy for patients with CRPC. HDAC inhibitors are attractive agents, particularly in prostate cancer, due to demonstrated effect in vitro on proliferation, differentiation, apoptosis, and angiogenesis coupled with anti-tumor effects in preclinical prostate cancer models.

Recognizing that tumor regressions are difficult to quantify objectively in patients with bone metastases, the clinical importance of delaying progression, and the available preclinical data on the anti-tumor effect of vorinostat, this trial was designed with a primary objective of assessing the effect of vorinostat on six month progression rates. Although, the most optimal design would have included a control arm, the progressive nature of this disease and the availability of published historical institutional data, at time of study design, on second-line chemotherapy in a similar population indicating that the expected 6-month progression rate is 84% 38 lead us to chose a single arm design. Although 41% of patients were taken off study due to toxicity thus making it difficult to assess the true efficacy of vorinostat at this dose and schedule, it is reasonable to assume that, had there been clinically meaningful anti-tumor activity, better results would have been expected. There was only one grade 4 AE, and grade 3 AE’s were predominantly constitutional in nature and not significantly different from dose limiting toxicities observed in phase I testing,21. However, despite dose reduction in 70% of patients in this trial, 41% of patients discontinued therapy due to toxicity. Our experience is in contrast with other reports using this agent both as monotherapy and in combination with other systemic therapies in other studies. In the phase I trials, once on a tolerable dose, patients could be treated for prolonged periods of time 21, 22, 40 with chronic adverse effects of fatigue, renal insufficiency, and weight loss reversible upon discontinuation of drug.21 Dose limiting toxicities reported in phase I trials were not related to prior therapy or type of underlying malignancy and remained unpredictable within treatment cohorts.21 They were also rapidly reversible suggesting a readily reversible metabolic process.21

Safety data from 86 patients with cutaneous T-cell lymphoma treated with vorinostat leading to FDA approval of the drug, only 9.3% of patients were removed due to toxicity with 10.5% requiring dose reductions using the same dose/schedule as used in this trial; also in patients who had failed prior systemic therapies.16 Similar results were recently reported on safety data from 476 patients who participated in the vorinostat clinical trial program receiving vorinostat as single agent therapy and in combination with other systemic therapies 41.

The key question is whether our observed results are a function of the patient population studied or lack of significant anti-tumor activity or both. Given the toxicity seen in this trial leading to dose reductions in 70% of patients, it is possible that suboptimal cell inhibitory plasma concentrations of vorinostat may explain why less clinical activity was seen than expected. Without pharmacokinetic (PK) data and data from other prostate cancer settings, it is difficult to conclude whether the preclinical models were poor predictors of clinical activity or whether this agent would be more efficacious in an alternative patient population or dosing schedule. One interesting observation from this population is that patients that came off study due to toxicity had significantly higher serum IL-6 levels at all time points (baseline, Day 15-Cycle 1, Day 1-Cycle, and end of study) as compared to patients removed from study for progression. It is possible that since IL-6 is associated with the inflammatory response and regulation of the systemic immune response 39, that higher levels of serum IL-6 at baseline that were not modulated by the drug, predisposed patients to adverse side-effects leading to treatment discontinuation. IL-6 has been associated with non-responsiveness to drug therapy 2931. However, of the 11 patients taken off protocol due to toxicity in this study, nine patients recovered suggesting drug effect and not disease progression.

Toxicities were also prominent with no significant clinical activity in the only other reported clinical trial of HDAC inhibition in prostate cancer 42. In this phase II trial (n=31) investigating romidepsin, a bicyclic depsipeptide that inhibits HDAC, as front line therapy for patients with metastatic CRPC, constitutional toxicities were common, with a 6 month disease control rate of 14% and PSA response rate of 7%. Observations from this and our trial raise questions regarding the impact of an androgen suppressed state as it relates to predisposing to toxicities to this class of drugs.

It is not clear why outcomes from clinical investigation of HDAC inhibitors in metastatic CRPC have not matched the promising preclinical activity and scientific rationale. However, based on the current data, further investigation of vorinostat at this dose and schedule is not recommended. Given the lack of significant clinical activity in this trial coupled with comparable outcome reported with romidepsin 42 raise concerns regarding further study of this class of drugs as single agent therapy for treatment of CRPC unless newer agents with a more favorable toxicity profile with substantial supportive preclinical data are introduced. Our observation of the association of IL-6 levels and removal from study for toxicities warrants further investigation.


CTEP, PC051382, PC051375, N01-CM-62201, PCF N008367 D.A.B is supported by NIH grant T32CA009357, UL1RR024986.


Authors of the DOD Prostate Cancer Clinical Trial Consortium and Phase II consortium also included George Wilding4, Susan Slovin2, Kathleen A. Cooney1, June Escara-Wilke1and Evan Keller1.

This study was presented in part at the 2008 ASCO Genitourinary Cancers Symposium


1. Petrylak DP, Tangen CM, Hussain MH, Lara PN, Jr, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004. pp. 1513–20. Available from [PubMed]
2. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004. pp. 1502–12. Available from [PubMed]
3. Xu WS, Parmigiani RB, Marks PA. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007. pp. 5541–52. Available from [PubMed]
4. Dokmanovic M, Clarke C, Marks PA. Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res. 2007. pp. 981–9. Available from [PubMed]
5. Fantin VR, Richon VM. Mechanisms of resistance to histone deacetylase inhibitors and their therapeutic implications. Clin Cancer Res. 2007. pp. 7237–42. Available from [PubMed]
6. Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst. 2000. pp. 1210–6. Available from [PubMed]
7. Iacopino F, Urbano R, Graziani G, Muzi A, Navarra P, Sica G. Valproic acid activity in androgen-sensitive and -insensitive human prostate cancer cells. Int J Oncol. 2008. pp. 1293–303. Available from [PubMed]
8. Arts J, Angibaud P, Marien A, Floren W, Janssens B, King P, et al. R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies. Br J Cancer. 2007. pp. 1344–53. Available from [PMC free article] [PubMed]
9. Kulp SK, Chen CS, Wang DS, Chen CY. Antitumor effects of a novel phenylbutyrate-based histone deacetylase inhibitor, (S)-HDAC-42, in prostate cancer. Clin Cancer Res. 2006. pp. 5199–206. Available from [PubMed]
10. Kuefer R, Hofer MD, Altug V, Zorn C, Genze F, Kunzi-Rapp K, et al. Sodium butyrate and tributyrin induce in vivo growth inhibition and apoptosis in human prostate cancer. Br J Cancer. 2004. pp. 535–41. Available from [PMC free article] [PubMed]
11. Qian DZ, Kato Y, Shabbeer S, Wei Y, Verheul HM, Salumbides B, et al. Targeting tumor angiogenesis with histone deacetylase inhibitors: the hydroxamic acid derivative LBH589. Clin Cancer Res. 2006. pp. 634–42. Available from [PubMed]
12. Lai MT, Yang CC, Lin TY, Tsai FJ, Chen WC. Depsipeptide (FK228) inhibits growth of human prostate cancer cells. Urol Oncol. 2008. pp. 182–9. Available from [PubMed]
13. Hassig CA, Symons KT, Guo X, Nguyen PM, Annable T, Wash PL, et al. KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther. 2008. pp. 1054–65. Available from [PubMed]
14. Sargeant AM, Rengel RC, Kulp SK, Klein RD, Clinton SK, Wang YC, et al. OSU-HDAC42, a histone deacetylase inhibitor, blocks prostate tumor progression in the transgenic adenocarcinoma of the mouse prostate model. Cancer Res. 2008. pp. 3999–4009. Available from [PubMed]
15. Qian DZ, Wei YF, Wang X, Kato Y, Cheng L, Pili R. Antitumor activity of the histone deacetylase inhibitor MS-275 in prostate cancer models. Prostate. 2007. pp. 1182–93. Available from [PubMed]
16. Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist. 2007. pp. 1247–52. Available from [PubMed]
17. Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL) Blood. 2007. pp. 31–9. Available from [PubMed]
18. Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007. pp. 3109–15. Available from [PubMed]
19. Kelly WK, Richon VM, O’Connor O, Curley T, MacGregor-Curtelli B, Tong W, et al. Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res. 2003. pp. 3578–88. Available from [PubMed]
20. Kelly WK, Marks PA. Drug insight: Histone deacetylase inhibitors--development of the new targeted anticancer agent suberoylanilide hydroxamic acid. Nat Clin Pract Oncol. 2005. pp. 150–7. Available from [PubMed]
21. Kelly WK, O’Connor OA, Krug LM, Chiao JH, Heaney M, Curley T, et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol. 2005. pp. 3923–31. Available from [PMC free article] [PubMed]
22. Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, Wierda WG, et al. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood. 2008. pp. 1060–6. Available from [PubMed]
23. Butler LM, Agus DB, Scher HI, Higgins B, Rose A, Cordon-Cardo C, et al. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res. 2000. pp. 5165–70. Available from [PubMed]
24. Marrocco DL, Tilley WD, Bianco-Miotto T, Evdokiou A, Scher HI, Rifkind RA, et al. Suberoylanilide hydroxamic acid (vorinostat) represses androgen receptor expression and acts synergistically with an androgen receptor antagonist to inhibit prostate cancer cell proliferation. Mol Cancer Ther. 2007. pp. 51–60. Available from [PubMed]
25. Adler HL, McCurdy MA, Kattan MW, Timme TL, Scardino PT, Thompson TC. Elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma. J Urol. 1999. pp. 182–7. Available from [PubMed]
26. Twillie DA, Eisenberger MA, Carducci MA, Hseih WS, Kim WY, Simons JW. Interleukin-6: a candidate mediator of human prostate cancer morbidity. Urology. 1995. pp. 542–9. Available from [PubMed]
27. Hoosein N, et al. Clinical significance of elevation in neuroendocrine factors and interleukin-6 in metastatic prostatic carcinoma. Urol Oncol. 1995;1:246–51. [PubMed]
28. Drachenberg DE, Elgamal AA, Rowbotham R, Peterson M, Murphy GP. Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer. Prostate. 1999. pp. 127–33. Available from [PubMed]
29. Woods Ignatoski KM, Friedman J, Escara-Wilke J, Zhang X, Daignault S, Dunn RL, et al. Change in Markers of Bone Metabolism with Chemotherapy for Advanced Prostate Cancer: Interleukin-6 Response Is a Potential Early Indicator of Response to Therapy. J Interferon Cytokine Res. 2008. Available from [PMC free article] [PubMed]
30. Domingo-Domenech J, Oliva C, Rovira A, Codony-Servat J, Bosch M, Filella X, et al. Interleukin 6, a nuclear factor-kappaB target, predicts resistance to docetaxel in hormone-independent prostate cancer and nuclear factor-kappaB inhibition by PS-1145 enhances docetaxel antitumor activity. Clin Cancer Res. 2006. pp. 5578–86. Available from [PubMed]
31. Smith PC, Hobisch A, Lin DL, Culig Z, Keller ET. Interleukin-6 and prostate cancer progression. Cytokine Growth Factor Rev. 2001. pp. 33–40. Available from [PubMed]
32. Choi Y, Park SK, Kim HM, Kang JS, Yoon YD, Han SB, et al. Histone deacetylase inhibitor KBH-A42 inhibits cytokine production in RAW 264.7 macrophage cells and in vivo endotoxemia model. Exp Mol Med. 2008. pp. 574–81. Available from [PMC free article] [PubMed]
33. Lin HS, Hu CY, Chan HY, Liew YY, Huang HP, Lepescheux L, et al. Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents. Br J Pharmacol. 2007. pp. 862–72. Available from [PMC free article] [PubMed]
34. Leoni F, Fossati G, Lewis EC, Lee JK, Porro G, Pagani P, et al. The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol Med. 2005. pp. 1–15. Available from [PMC free article] [PubMed]
35. Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Hideshima T, et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci U S A. 2004. pp. 540–5. Available from [PubMed]
36. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000. pp. 205–16. Available from [PubMed]
37. Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol. 1999. pp. 3461–7. Available from [PubMed]
38. Beekman KW, Fleming MT, Scher HI, Slovin SF, Ishill NM, Heller G, et al. Second-line chemotherapy for prostate cancer: patient characteristics and survival. Clin Prostate Cancer. 2005. pp. 86–90. Available from [PubMed]
39. Hong DS, Angelo LS, Kurzrock R. Interleukin-6 and its receptor in cancer: implications for Translational Therapeutics. Cancer. 2007. pp. 1911–28. Available from [PubMed]
40. Richardson P, Mitsiades C, Colson K, Reilly E, McBride L, Chiao J, et al. Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma. Leuk Lymphoma. 2008. pp. 502–7. Available from [PubMed]
41. Siegel D, Hussein M, Belani C, Robert F, Rizvi S, Wigginton J, et al. Safety and tolerability of vorinostat--Experience from the vorinostat clinical trial program. J Clin Oncol. 2008:26. abstract 14580. [PubMed]
42. Parker C, Molife R, Karavasilis V, Reid A, Patterson S, Riggs C, et al. Romidepsin (FK228), a histone deacetylase inhibitor: Final results of a phase II study in metastatic hormone refractory prostate cancer (HRPC) J Clin Oncol. 2007;25(18S) abstract 15507.