Therapy resistance is a significant challenge for prostate cancer treatment in clinic. Although targeted therapies such as androgen deprivation and androgen receptor (AR) inhibition are effective initially, tumor cells eventually evade these strategies through multiple mechanisms. Lineage reprogramming in response to hormone therapy represents a key mechanism that is increasingly observed. The studies in this area have revealed specific combinations of alterations present in adenocarcinomas that provide cells with the ability to transdifferentiate and perpetuate AR-independent tumor growth after androgen-based therapies. Interestingly, several master regulators have been identified that drive plasticity, some of which also play key roles during development and differentiation of the cell lineages in the normal prostate. Thus, further study of each AR-independent tumor type and understanding underlying mechanisms are warranted to develop combinational therapies that combat lineage plasticity in prostate cancer.
Androgen Antagonists/therapeutic use* ; Androgen Receptor Antagonists/therapeutic use* ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Prostatic Neoplasms/genetics* ; Prostatic Neoplasms, Castration-Resistant/genetics* ; Receptors, Androgen/drug effects*

BACKGROUNDThe failure of endocrine treatment for advanced prostate cancer might be related to aberrant activation of androgen receptor (AR). Prostate cancer cell line LNCaP contains AR that can be activated by androgen, estrogen and progesterone. This study was set to investigate the effects of antisense AR RNA on growth of LNCaP cultured in medium containing varied concentrations of R1881, 17beta-estradiol, and progesterone, respectively.

METHODSLNCaP cells transfected with antisense AR RNA retroviral vector pL-AR-SN were designated as LNCaPas-AR. LNCaP cells containing empty vector pLXSN served as LNCaPNeo. LNCaP and LNCaPNeo were taken as controls. In vitro cell growth assay, proliferative cells of LNCaP and tranfected LNCaPs were counted by typan staining when they cultured with synthetic androgen R1881, 17beta-estradiol, and progesterone, respectively.

RESULTSGrowth of LNCaPas-AR was inhibited significantly (P < 0.05) compared with that of LNCaP and LNCaPNeo at 1 nmol/L R1881, 10 nmol/L 17beta-estradiol, and 1 nmol/L progesterone, respectively. No difference was seen between LNCaP and LNCaPNeo (P > 0.05). Microscopic observation showed that LNCaP and LNCaPNeo cells grew well, but only few LNCaPas-AR cells were alive.

CONCLUSIONSOur observations indicate that antisense AR RNA retroviral vector pL-AR-SN could change androgen-independent characteristics of LNCaP cells, which might shed some novel insights into the treatment of androgen-independent prostate cancer.

Androgen Receptor Antagonists ; Cell Division ; drug effects ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Estradiol ; pharmacology ; Humans ; Male ; Metribolone ; antagonists & inhibitors ; pharmacology ; Progesterone ; antagonists & inhibitors ; pharmacology ; Prostatic Neoplasms ; pathology ; therapy ; RNA, Antisense ; therapeutic use ; Receptors, Androgen ; genetics

BACKGROUNDThe failure of hormone treatment for advanced prostate cancer might be related to aberrant activation of the androgen receptor. We have shown that (125)I labeled triple-helix forming oligonucleotide (TFO) against the androgen receptor gene inhibits androgen receptor expression and cell proliferation of LNCaP prostate cancer cells in vitro. This study aimed at exploring the effects of the (125)I-TFO on prostate tumor growth in vivo using a nude mouse xenograft model.

METHODSTFO was labeled with (125)I by the iodogen method. Thirty-two nude mice bearing LNCaP xenograft tumors were randomized into 4 groups and were intratumorally injected with (125)I-TFO, unlabeled TFO, Na(125)I and normal saline. Tumor size was measured weekly. The tumor growth inhibition rate (RI) was calculated by measurement of tumor weight. The expression of the androgen receptor gene was performed by RT-PCR and immunohistochemical study. The prostate specific antigen (PSA) serum levels were measured by enzyme linked immunosorbent assay. The tumor cell apoptosis index (AI) was detected by TUNEL assay.

RESULTSTumor measurements showed that tumor development was significantly inhibited by either (125)I-TFO or TFO, with tumor RIs of 50.79% and 32.80% respectively. (125)I-TFO caused greater inhibition of androgen receptor expression and higher AIs in tumor tissue than TFO. Both the tumor weight and the PSA serum levels in (125)I-TFO treated mice ((0.93 +/- 0.15) g and (17.43 +/- 1.85) ng/ml, respectively) were significantly lower than those ((1.27 +/- 0.21) g and (28.25 +/- 3.41) ng/ml, respectively) in TFO treated mice (all P < 0.05). Na(125)I did not significantly affect tumor growth and androgen receptor expression in tumor tissue.

CONCLUSIONSThe (125)I-TFO can effectively inhibit androgen receptor expression and tumor growth of human prostate cancer xenografts in vivo. The inhibitory efficacy of (125)I-TFO is more potent than that of TFO, providing a reference for future studies of antigen radiotherapy.

Androgen Receptor Antagonists ; Animals ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Enzyme-Linked Immunosorbent Assay ; Humans ; Immunohistochemistry ; Iodine Radioisotopes ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Oligonucleotides ; chemistry ; pharmacology ; therapeutic use ; Prostate-Specific Antigen ; blood ; Prostatic Neoplasms ; drug therapy ; metabolism ; pathology ; Receptors, Androgen ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Burden ; drug effects ; Xenograft Model Antitumor Assays ; methods

PURPOSE: Few data are available concerning the clinical outcome of abiraterone acetate treatment in patients with metastatic castration-resistant prostate cancer (mCRPC) in terms of the duration of androgen deprivation therapy (ADT) before diagnosis of CRPC. We investigated the clinical efficacy of abiraterone acetate according to the duration of ADT. MATERIALS AND METHODS: We reviewed the medical records of 20 patients with mCRPC who received abiraterone acetate after failure of docetaxel chemotherapy from May 2012 to March 2014 at Seoul National University Bundang Hospital. Clinical factors including prostate-specific antigen (PSA) nadir level, time to PSA nadir, PSA doubling time, PSA response, and modes of progression (PSA, radiologic, clinical) were analyzed. Disease progression was classified according to the Prostate Cancer Working Group 2 criteria. RESULTS: The mean age and PSA value of the entire cohort were 76.0+/-7.2 years and 158.8+/-237.9 ng/mL, respectively. The median follow-up duration was 13.4+/-6.7 months. There were no statistically significant differences in clinical characteristics between patients who received abiraterone acetate with ADT duration<35 months and those who received abiraterone acetate with ADT duration> or =35 months. There were also no significant differences in terms of PSA progression-free survival, radiologic progression-free survival, and clinical progression-free survival between patients with ADT duration<35 months and those with ADT duration > or =35 months. CONCLUSIONS: Although this was a retrospective study with a small sample size, we did not observe any statistically significant differences in the clinical response to abiraterone acetate between mCRPC patients with long ADT duration and those with short ADT duration in terms of disease progression-free survival.
Abiraterone Acetate/administration & dosage ; Aged ; Aged, 80 and over ; Androgen Receptor Antagonists/administration & dosage ; Antineoplastic Agents/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Disease Progression ; Drug Administration Schedule ; Humans ; Kallikreins/blood ; Male ; Neoplasm Metastasis ; Prostate-Specific Antigen/blood ; Prostatic Neoplasms, Castration-Resistant/*drug therapy ; Retrospective Studies ; Taxoids/administration & dosage ; Treatment Outcome