1.Apalutamide for metastatic castration-sensitive prostate cancer: final analysis of the Asian subpopulation in the TITAN trial.
Byung Ha CHUNG ; Jian HUANG ; Hiroji UEMURA ; Young Deuk CHOI ; Zhang-Qun YE ; Hiroyoshi SUZUKI ; Taek Won KANG ; Da-Lin HE ; Jae Young JOUNG ; Sabine D BROOKMAN-MAY ; Sharon MCCARTHY ; Amitabha BHAUMIK ; Anildeep SINGH ; Suneel MUNDLE ; Simon CHOWDHURY ; Neeraj AGARWAL ; Ding-Wei YE ; Kim N CHI ; Hirotsugu UEMURA
Asian Journal of Andrology 2023;25(6):653-661
The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial showed improvement in overall survival (OS) and other efficacy endpoints with apalutamide plus androgen deprivation therapy (ADT) versus ADT alone in patients with metastatic castration-sensitive prostate cancer (mCSPC). As ethnicity and regional differences may affect treatment outcomes in advanced prostate cancer, a post hoc final analysis was conducted to assess the efficacy and safety of apalutamide in the Asian subpopulation. Event-driven endpoints were OS, and time from randomization to initiation of castration resistance, prostate-specific antigen (PSA) progression, and second progression-free survival (PFS2) on first subsequent therapy or death. Efficacy endpoints were assessed using the Kaplan-Meier method and Cox proportional-hazards models without formal statistical testing and adjustment for multiplicity. Participating Asian patients received once-daily apalutamide 240 mg ( n = 111) or placebo ( n = 110) plus ADT. After a median follow-up of 42.5 months and despite crossover of 47 placebo recipients to open-label apalutamide, apalutamide reduced the risk of death by 32% (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.42-1.13), risk of castration resistance by 69% (HR: 0.31; 95% CI: 0.21-0.46), PSA progression by 79% (HR: 0.21; 95% CI: 0.13-0.35) and PFS2 by 24% (HR: 0.76; 95% CI: 0.44-1.29) relative to placebo. The outcomes were comparable between subgroups with low- and high-volume disease at baseline. No new safety issues were identified. Apalutamide provides valuable clinical benefits to Asian patients with mCSPC, with an efficacy and safety profile consistent with that in the overall patient population.
Male
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Humans
;
Prostatic Neoplasms/pathology*
;
Androgen Antagonists/therapeutic use*
;
Prostate-Specific Antigen
;
Castration
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Prostatic Neoplasms, Castration-Resistant/drug therapy*
2.Recent advances in treatment of patients with castration-resistant prostate cancer after docetaxel failure.
Bi-de CHEN ; Shi-cheng YU ; Gong-hui LI
Journal of Zhejiang University. Medical sciences 2014;43(1):115-118
The standard first-line treatment of castration-resistant prostate cancer (CRPC) is docetaxel-based chemotherapy. However, CRPC may not respond to docetaxel due to drug resistance or other causes. Several new therapeutic agents have been developed, some of which are approved by FDA or on clinical trials. The mechanisms of action of these agents include stabilizing microtubules, inhibiting hormone synthesis, blocking androgen receptor, bone targeting or immune regulation. In this article we review the novel therapeutic options for CPRC after docetaxel failure.
Bone Neoplasms
;
drug therapy
;
secondary
;
Drug Resistance, Neoplasm
;
Humans
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Male
;
Prostatic Neoplasms, Castration-Resistant
;
drug therapy
;
pathology
;
Taxoids
;
therapeutic use
3.A case of metastatic castration-resistant prostate cancer by abiraterone treatment.
Liuxun LI ; Zhi LONG ; Leye HE
Journal of Central South University(Medical Sciences) 2015;40(6):688-692
We reviewed and analyzed the clinical data for a patient with metastatic castration-resistant prostate cancer (mCRPC) from September, 2009 to December, 2014. After the treatment with abiraterone, patient's performance status improved, pain relieved, total prostate specific antigen (tPSA) and free prostate specific antigen (fPSA) markedly decreased. tPSA or fPSA fluctuated between
30 and 50 ng/mL or between 10 and 20 ng/mL. MRI showed the left peripheral zone reduced. MRI and bone single photon emission computed tomography (SPECT) scan showed no new metastasis. These results indicated that application of abiraterone for patient with mCRPC not only decreased prostate specific antigen (PSA) levels and tumor volume, but also blocked bone metastasis progression and enhanced pain relief.
Androstenes
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therapeutic use
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Bone Neoplasms
;
drug therapy
;
secondary
;
Disease Progression
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Humans
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Male
;
Prostate-Specific Antigen
;
blood
;
Prostatic Neoplasms, Castration-Resistant
;
drug therapy
;
pathology
4.Scaffold protein MAPK8IP2 expression is a robust prognostic factor in prostate cancer associated with AR signaling activity.
Jian HUANG ; Wang LIU ; Bi-Yun LIN ; Jean C LI ; Jane LU ; Ben-Yi LI
Asian Journal of Andrology 2023;25(2):198-207
Mitogen-activated protein kinase-8-interacting protein 2 (MAPK8IP2) is a scaffold protein that modulates MAPK signal cascades. Although MAPK pathways were heavily implicated in prostate cancer progression, the regulation of MAPK8IP2 expression in prostate cancer is not yet reported. We assessed MAPK8IP2 gene expression in prostate cancer related to disease progression and patient survival outcomes. MAPK8IP2 expression was analyzed using multiple genome-wide gene expression datasets derived from The Cancer Genome Atlas (TCGA) RNA-sequence project and complementary DNA (cDNA) microarrays. Multivariable Cox regressions and log-rank tests were used to analyze the overall survival outcome and progression-free interval. MAPK8IP2 protein expression was evaluated using the immunohistochemistry approach. The quantitative PCR and Western blot methods analyzed androgen-stimulated MAPK8IP2 expression in LNCaP cells. In primary prostate cancer tissues, MAPK8IP2 mRNA expression levels were significantly higher than those in the case-matched benign prostatic tissues. Increased MAPK8IP2 expression was strongly correlated with late tumor stages, lymph node invasion, residual tumors after surgery, higher Gleason scores, and preoperational serum prostate-specific antigen (PSA) levels. MAPK8IP2 upregulation was significantly associated with worse overall survival outcomes and progression-free intervals. In castration-resistant prostate cancers, MAPK8IP2 expression strongly correlated with androgen receptor (AR) signaling activity. In cell culture-based experiments, MAPK8IP2 expression was stimulated by androgens in AR-positive prostate cancer cells. However, MAPK8IP2 expression was blocked by AR antagonists only in androgen-sensitive LNCaP but not castration-resistant C4-2B and 22RV1 cells. These results indicate that MAPK8IP2 is a robust prognostic factor and therapeutic biomarker for prostate cancer. The potential role of MAPK8IP2 in the castration-resistant progression is under further investigation.
Male
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Humans
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Androgens/therapeutic use*
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Receptors, Androgen/genetics*
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Prognosis
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Mitogen-Activated Protein Kinase 8/therapeutic use*
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Cell Line, Tumor
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Prostatic Neoplasms/pathology*
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Prostatic Neoplasms, Castration-Resistant/drug therapy*
;
Gene Expression Regulation, Neoplastic
5.The effect of continuous androgen deprivation treatment on prostate cancer patients as compared with intermittent androgen deprivation treatment.
Ja Yoon KU ; Jeong Zoo LEE ; Hong Koo HA
Korean Journal of Urology 2015;56(10):689-694
PURPOSE: To investigate the efficacy of androgen deprivation treatment (ADT) between continuous and intermittent ADT. MATERIALS AND METHODS: Between January 2006 and May 2015, 603 patients were selected and divided into continuous ADT (CADT) (n=175) and intermittent ADT (IADT) (n=428) groups. The median follow-up in this study was 48.19 (1.0-114.0) months. The primary end point was time to castration resistant prostate cancer (CRPC). The types of ADT were monotherapy and maximal androgen blockade (i.e., luteinizing hormone-releasing hormone agonist and antiandrogen). RESULTS: The characteristics of patients showed no significant differences between the CADT and IADT groups, except for the Gleason score (p<0.001). The median time to CRPC of all enrolled patients with ADT was 20.60±1.60 months. The median time to CRPC was 11.20±1.31 months in the CADT group as compared with 22.60±2.08 months in the IADT group. In multivariate analysis, percentage of positive core (p=0.047; hazard ratio [HR], 0.976; 95% confidence interval [CI], 0.953-1.000), Gleason score (p=0.007; HR, 1.977; 95% CI, 1.206-3.240), lymph node metastasis (p=0.030; HR, 0.498; 95% CI, 0.265-0.936), bone metastasis (p=0.028; HR, 1.921; 95% CI, 1.072-3.445), and CADT vs. IADT (p=0.003; HR, 0.254; 95% CI. 0.102-0.633) were correlated with the duration of progression to CRPC. The IADT group presented a significantly longer median time to CRPC compared with the CADT group. Additionally, patients in the IADT group showed a longer duration in median time to CRPC in subgroup analysis according to the Gleason score. CONCLUSIONS: This study found that IADT produces a longer duration in median time to CRPC than does CADT.
Adenocarcinoma/*drug therapy/pathology/secondary
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Aged
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Aged, 80 and over
;
Androgen Antagonists/*administration & dosage/therapeutic use
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Antineoplastic Agents, Hormonal/*administration & dosage/therapeutic use
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Disease Progression
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Drug Administration Schedule
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Follow-Up Studies
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Humans
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Lymphatic Metastasis
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Male
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Middle Aged
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Neoplasm Grading
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Prostatic Neoplasms/*drug therapy/pathology
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Prostatic Neoplasms, Castration-Resistant/drug therapy/pathology
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Retrospective Studies
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Treatment Outcome
6.Effects of statin use on the response duration to androgen deprivation therapy in metastatic prostate cancer.
Jaeyoon JUNG ; Chunwoo LEE ; Chanwoo LEE ; Taekmin KWON ; Dalsan YOU ; In Gab JEONG ; Jun Hyuk HONG ; Hanjong AHN ; Choung Soo KIM
Korean Journal of Urology 2015;56(9):630-636
PURPOSE: To determine whether statin use delays the development of castration-resistant prostate cancer (CRPC) in patients with metastatic prostate cancer treated with androgen deprivation therapy (ADT). MATERIALS AND METHODS: A total of 171 patients with metastatic prostate cancer at the time of diagnosis who were treated with ADT between January 1997 and December 2013 were retrospectively analyzed. The patients were classified into two groups: the nonstatin use group (A group) and the statin use group (B group). Multivariate analysis was performed on statin use and other factors considered likely to have an effect on the time to progression to CRPC. RESULTS: The mean patient age was 67.1+/-9.1 years, and the mean follow-up period was 52 months. The mean initial prostate-specific antigen (PSA) level was 537 ng/mL. Of the 171 patients, 125 (73%) were in group A and 46 (27%) were in group B. The time to progression to CRPC was 22.7 months in group A and 30.5 months in group B, and this difference was significant (p=0.032). Blood cholesterol and initial PSA levels did not differ significantly according to the time to progression to CRPC (p=0.288, p=0.198). Multivariate analysis using the Cox regression method showed that not having diabetes (p=0.037) and using a statin (p=0.045) significantly increased the odds ratio of a longer progression to CRPC. CONCLUSIONS: Statin use in metastatic prostate cancer patients appears to delay the progression to CRPC. Large-scale, long-term follow-up studies are needed to validate this finding.
Adenocarcinoma/drug therapy/*secondary
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Adult
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Aged
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Aged, 80 and over
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Androgen Antagonists/therapeutic use
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Antineoplastic Combined Chemotherapy Protocols/therapeutic use
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Body Mass Index
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Diabetes Mellitus/drug therapy
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Disease Progression
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use
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Male
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Middle Aged
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Neoplasm Grading
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Prostatic Neoplasms, Castration-Resistant/drug therapy/*pathology/*prevention & control
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Protective Factors
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Retrospective Studies
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Survival Rate
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Time Factors
7.Indirubin inhibits the proliferation of prostate cancer PC-3 cells.
Yun-fei WEI ; Jian SU ; Zhong-lei DENG ; Chen ZHU ; Lin YUAN ; Zi-jie LU ; Qing-yi ZHU
National Journal of Andrology 2015;21(9):788-791
OBJECTIVETo explore the antitumoral effect of indirubin on androgen-independent prostate cancer PC-3 cells and its possible mechanisms.
METHODSWe measured the inhibitory effect of indirubin on the proliferation of prostate cancer PC-3 cells using MTT assay, detected their cell cycles by flow cytometry, and determined the expressions of the cell cycle regulatory protein cyclin D1 and its related downstream gene c-myc by Western blot.
RESULTSThe viability of the PC-3 cells was significantly decreased by indirubin in a concentration-dependent manner, reduced to 52. 2% and 13. 6% at 5 and 10 µmol/L, respectively. The cell cycle of the PC-3 cells was markedly inhibited by indirubin at 5 µmol/L, with the cells remarkably increased in the G0 and G1 phases and decreased in the S and G2/M phases. Meanwhile, indirubin also inhibited the expressions of cyclin D1 and c-myc in the Wnt signaling pathway.
CONCLUSIONIndirubin can suppress the proliferation of androgen-independent prostate cancer PC-3 cells, which may be associated with its inhibitory effect on the cell cycle and Wnt signaling pathway.
Antibiotics, Antineoplastic ; administration & dosage ; pharmacology ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cell Survival ; drug effects ; Coloring Agents ; Cyclin D1 ; metabolism ; Dose-Response Relationship, Drug ; Genes, myc ; Humans ; Indoles ; administration & dosage ; pharmacology ; Male ; Prostatic Neoplasms, Castration-Resistant ; drug therapy ; pathology ; Proto-Oncogene Proteins c-myc ; metabolism ; Tetrazolium Salts ; Thiazoles
8.Survival Outcomes of Concurrent Treatment with Docetaxel and Androgen Deprivation Therapy in Metastatic Castration-Resistant Prostate Cancer.
Ho Seong JANG ; Kyo Chul KOO ; Kang Su CHO ; Byung Ha CHUNG
Yonsei Medical Journal 2016;57(5):1070-1078
PURPOSE: Docetaxel-based chemotherapy (DTX) improves overall survival (OS) of men with metastatic castration-resistant prostate cancer (mCRPC). Considering the potential existence of androgen receptors that remain active at this stage, we aimed to assess the impact of the combined use of androgen deprivation therapy (ADT) with DTX for mCRPC. MATERIALS AND METHODS: We performed a single-institutional retrospective analysis of patients with mCRPC who received either DTX alone (DTX group, n=21) or concurrent DTX and ADT (DTX+ADT group, n=26) between August 2006 and February 2014. All patients received DTX doses of 75 mg/m2 every three weeks for at least three cycles. In the DTX+ADT group, all patients used luteinizing hormone releasing hormone agonist continuously as a concurrent ADT. RESULTS: The median follow-up period was 24.0 months (interquartile range 12.0-37.0) for the entire cohort. The median radiographic progression-free survival (rPFS) was 9.0 months and 6.0 months in the DTX+ADT and DTX groups, respectively (log-rank p=0.036). On multivariable Cox regression analysis, concurrent administration of ADT was the only significant predictor of rPFS [hazard ratio (HR)=0.525, 95% confidence intervals (CI) 0.284-0.970, p=0.040]. The median OS was 42.0 and 38.0 months in the DTX+ADT and DTX groups, respectively (log-rank p=0.796). On multivariable analysis, hemoglobin level at the time of DTX initiation was associated with OS (HR=0.532, 95% CI 0.381-0.744, p<0.001). CONCLUSION: In chemotherapy-naive patients with mCRPC, the combined use of ADT with DTX improved rPFS. Our result suggests that the concurrent administration of ADT and DTX is superior to DTX alone.
Adenocarcinoma/blood/*drug therapy/secondary
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Aged
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Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
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Disease-Free Survival
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Gonadotropin-Releasing Hormone/administration & dosage/agonists
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Hemoglobins/metabolism
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Humans
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Male
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Middle Aged
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Prostatic Neoplasms, Castration-Resistant/blood/*drug therapy/pathology
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Retrospective Studies
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Survival Rate
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Taxoids/administration & dosage
9.Inhibitory effect of polyphyllin Ⅰ on the proliferation of prostate cancer PC3 cells via ERK1/2/P65/DNMT1 and its molecular mechanism.
Pei-Liang ZOU ; Qiu-Hong ZHANG ; Jian-Fu ZHOU ; Rong-Wu LIN ; Zhi-Qiang CHEN ; Song-Tao XIANG
National Journal of Andrology 2018;24(3):199-205
ObjectiveTo explore the inhibitory effect of polyphyllin Ⅰ (PPⅠ) on the proliferation of castration-resistant prostate cancer PC3 cells and its molecular mechanism.
METHODSWe cultured human prostate cancer PC3 cells in vitro and treated them with PPⅠ at the concentrations of 0 (blank group), 0.4, 0.8, 1.2, 1.6, 2.0, and 2.4 μmol/L for 24, 48, and 72 hours, respectively. Then we detected the proliferation of the cells by MTT assay, measured their apoptosis by flow cytometry, and determined the expressions of p-ERK1/2, ERK1/2, NF-κB/p65 and DNMT1 proteins as well as the level of NF-κB/p65 in the cells additionally treated with the ERK1/2 inhibitor SP600125 by Western blot.
RESULTSCompared with the blank control group, the PPⅠ-treated PC3 cells showed a concentration- and time-dependent reduction of the survival rate (1.00 ± 0.00 vs 0.85 ± 0.05, P < 0.01) at 0.4 μmol/L after 48 hours of intervention, concentration-dependent early apoptosis at 0.8 μmol/L (4.83 ± 0.95 vs 13.83 ± 2.97, P < 0.01), time-dependent increase of the expressions of p-ERK1/2 (1.00 ± 0.00 vs 1.73 ± 0.17, P < 0.01) and ERK1/2 (1.00 ± 0.00 vs 1.36 ± 0.12, P < 0.01) at 2 hours, and concentration-dependent decrease of the expressions of NF-κB/p65 and DNMT1 at 1.2 μmol/L (1.00 ± 0.00 vs 0.78 ± 0.10 and 0.63 ± 0.06, P < 0.01) and 1.6 μmol/L (1.00 ± 0.00 vs 0.67 ± 0.11 and 0.52 ± 0.09, P<0.01). Inhibition of ERK1/2 phosphorylation with PD98059 markedly reversed PPⅠ-induced decrease of the NF-κB/p65 expression as compared with that in the PPⅠ group (0.86 ± 0.18 vs 0.43 ± 0.09, P < 0.05).
CONCLUSIONSPPⅠ induces the early apoptosis and suppresses the proliferation of PC3 cells, probably by activating the ERK1/2 pathway and inhibiting the expressions of the NF-κB/p65 and DNMT1 proteins.
Apoptosis ; Cell Proliferation ; drug effects ; DNA (Cytosine-5-)-Methyltransferase 1 ; metabolism ; Diosgenin ; analogs & derivatives ; pharmacology ; Flavonoids ; metabolism ; Humans ; MAP Kinase Signaling System ; Male ; Mitogen-Activated Protein Kinase 1 ; metabolism ; Mitogen-Activated Protein Kinase 3 ; metabolism ; NF-kappa B ; metabolism ; PC-3 Cells ; Phosphorylation ; Prostatic Neoplasms, Castration-Resistant ; drug therapy ; metabolism ; pathology ; Signal Transduction ; Transcription Factor RelA ; metabolism
10.Exponential Rise in Prostate-Specific Antigen (PSA) during Anti-Androgen Withdrawal Predicts PSA Flare after Docetaxel Chemotherapy in Patients with Castration-Resistant Prostate Cancer.
Kyung Seok HAN ; Sung Joon HONG
Yonsei Medical Journal 2015;56(2):368-374
PURPOSE: To investigate the relationship between rising patterns of prostate-specific antigen (PSA) before chemotherapy and PSA flare during the early phase of chemotherapy in patients with castration-resistant prostate cancer (CRPC). MATERIALS AND METHODS: This study included 55 patients with CRPC who received chemotherapy and in whom pre-treatment or post-treatment PSA levels could be serially obtained. The baseline parameters included age, performance, Gleason score, PSA level, and disease extent. PSA doubling time was calculated using the different intervals: the conventional interval from the second hormone manipulation following the nadir until anti-androgen withdrawal (PSADT1), the interval from the initial rise after anti-androgen withdrawal to the start of chemotherapy (PSADT2), and the interval from the nadir until the start of chemotherapy (PSADT3). The PSA growth patterns were analyzed using the ratio of PSADT2 to PSADT1. RESULTS: There were two growth patterns of PSA doubling time: 22 patients (40.0%) had a steady pattern with a more prolonged PSADT2 than PSADT1, while 33 (60.0%) had an accelerating pattern with a shorter PSADT2 than PSADT1. During three cycles of chemotherapy, PSA flare occurred in 11 patients (20.0%); of these patients, 3 were among 33 (9.1%) patients with an accelerating PSA growth pattern and 8 were among 22 patients (36.4%) with a steady PSA growth pattern (p=0.019). Multivariate analysis showed that only PSA growth pattern was an independent predictor of PSA flare (p=0.034). CONCLUSION: An exponential rise in PSA during anti-androgen withdrawal is a significant predictor for PSA flare during chemotherapy in CRPC patients.
Aged
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Aged, 80 and over
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Androgen Antagonists
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Antineoplastic Agents/*therapeutic use
;
Follow-Up Studies
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Humans
;
Karnofsky Performance Status
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Male
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Middle Aged
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Neoplasm Grading
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Predictive Value of Tests
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Prostate-Specific Antigen/*blood
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Prostatic Neoplasms, Castration-Resistant/*blood/*drug therapy/pathology
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Taxoids/*therapeutic use
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Tumor Markers, Biological/blood