Even in the era of novel targeted agents, switching to a second-line nonsteroidal antiandrogen (NSAA) is still widely used in treating metastatic castration-resistant prostate cancer (mCRPC), especially in undeveloped countries. However, whether prior treatment with a second-line NSAA would impact the efficacy of abiraterone acetate (Abi) remains uncertain. In the current study, 87 mCRPC patients treated with Abi were analyzed. Among them, 21 were treated with a second-line NSAA (from bicalutamide to flutamide) before receiving abiraterone, while the remaining 66 received Abi directly. Therapeutic efficacy of Abi was compared between those with and without prior second-line NSAA using Kaplan-Meier curves, log-rank test, and Cox regression models. The therapeutic efficacy of Abi was similar between those with or without the prior switching treatment of flutamide, in terms of either prostate-specific antigen progression-free survival (PSA-PFS, 5.5 vs 5.6 months, P = 0.967), radiographic progression-free survival (rPFS, 12.8 vs 13.4 months, P = 0.508), overall survival (OS, not reached vs 30.6 months, P = 0.606), or PSA-response rate (71.4% [15/21] vs 60.6% [40/66], P = 0.370). This is the first time that the impact of prior switching of treatment to a second-line NSAA on the efficacy of Abi in mCRPC patients has been addressed. Our data support that, use of prior sequential bicalutamide and flutamide does not seem to preclude response to abiraterone, although larger cohort studies and, ideally, a randomized controlled trial are needed. These findings will facilitate doctors' decision-making in the treatment of mCRPC patients, especially for those with previous experience of switching NSAA second-line treatments in the clinic.
Abiraterone Acetate/therapeutic use* ; Aged ; Aged, 80 and over ; Androgen Antagonists/therapeutic use* ; Anilides/therapeutic use* ; Antineoplastic Agents, Hormonal/therapeutic use* ; Disease-Free Survival ; Female ; Flutamide/therapeutic use* ; Humans ; Kaplan-Meier Estimate ; Male ; Nitriles/therapeutic use* ; Nonsteroidal Anti-Androgens/therapeutic use* ; Prostate-Specific Antigen/analysis* ; Prostatic Neoplasms, Castration-Resistant/drug therapy* ; Retrospective Studies ; Survival Analysis ; Tosyl Compounds/therapeutic use* ; Treatment Outcome

OBJECTIVETo study the changes in the mRNA expression of insulin-like factor 3 (INSL-3) in the testis of mouse models of flutamide-induced cryptorchidism.

METHODSWe randomized pregnant BALB/c mice to groups A (control) , B, C, D and E to receive continuous gavage of flutamide at 0, 150, 300, 500 and 700 mg/kg body weight, respectively, from gestation day 12 to 21. We detected the expression of INSL-3 mRNA in the testis of the neonates by real-time PCR at 4 and 8 postnatal weeks.

RESULTSNo cryptorchidism was found in group A; unilateral cryptorchidism was seen in groups B (10.0%) and C (25.0%); and bilateral cryptorchidism was observed in groups D (21.1%) and E (40.0%). The expression of INSL-3 mRNA was reduced with the increased dose of flutamide, not significantly changed in groups B and C (P > 0.05) but remarkably decreased in D and E as compared with A (P < 0.05).

CONCLUSIONAdministration of flutamide to pregnant mice can induce unilateral cryptorchidism at 150 and 300 mg/kg and bilateral cryptorchidism at 500 and 700 mg/kg in their male offspring, which may be related with its reducing effect on the expression of INSL-3 in the testis of the mice.

Animals ; Cryptorchidism ; chemically induced ; metabolism ; Female ; Flutamide ; toxicity ; Insulin ; metabolism ; Male ; Maternal Exposure ; adverse effects ; Mice ; Mice, Inbred BALB C ; Pregnancy ; Proteins ; metabolism ; RNA, Messenger ; genetics ; Testis ; metabolism

OBJECTIVETo observe the effects of flutamide (Flu) on the development of testicular germocytes in SD rats, and to establish a rat model for further researches on the maldevelopment of cryptorchidism gonocytes (Go).

METHODSPregnant SD rats were subcutaneously injected with Flu from gestational day (GD) 12 to 21 to establish a model of cryptorchidism. The testes of the newborns were harvested on postnatal day (PD) 1, 10, 20 and 80 for observation of their morphological and histological changes by HE staining and detection of the expression of neural cell adhesion molecules (NCAM) by immunohistochemistry and RT-PCR.

RESULTSFlu induced 43.9% (29/66) of cryptorchidism in the exposed rats. Significant differences were found in the testicular weight and organ coefficient between the Flu and the control groups on PD 20 and 80. Gos remained in the center of seminiferous tubules of the Flu-induced testis on PD 10, and in the center of seminiferous tubules in the cryptorchids' testicular tissues on PD 20 and 80. Immunohistochemistry showed the expression of NCAM on the membrane of the remaining Gos, and RT-PCR revealed significantly up-regulated expression of NCAM mRNA in the Flu-induced testes on PD 10 and 20 as compared with the controls (P < 0.05).

CONCLUSIONA rat model of Flu-induced cryptorchidism with remaining Gos was successfully established, which could be used to study the mechanism and management of the maldevelopment of cryptorchidism gonocytes.

Animals ; Cryptorchidism ; chemically induced ; pathology ; Female ; Flutamide ; adverse effects ; Male ; Neural Cell Adhesion Molecules ; metabolism ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Testis ; drug effects ; metabolism ; pathology

OBJECTIVE: To investigate the timing of reaching maximum improvement of the lower urinary tract symptoms (LUTS) in patients with advanced prostate cancer treated with maximal androgen blockade(MAB), and to provide guidelines for the treatment program. METHODS: We collected the data of 45 advanced prostate cancer patients complicated with lower urinary tract symptoms who were treated by MAB. The international prostate symptom score (IPSS) and maximum urinary flow rate (Qmax) were selected as indicators reflecting the degree of lower urinary tract symptoms and were observed before the MAB, 3, 6, and 9 months after the patients received MAB. We also observed the changes of prostate volume and analyzed the role of MAB in improving LUTS in patients with prostate cancer. RESULTS: The IPSS and Qmax had significant difference between the 3rd month after the patients received MAB and before the MAB (P<0.05). No significant difference was found between the 3rd month and the 6th month after the patients received MAB (P>0.05). The prostate volume had significant difference in the 3rd month and the 6th month (P<0.05), but no significant difference in the 6th month and the 9th month (P>0.05). CONCLUSION MAB for patients with advanced prostate cancer can improve their lower urinary tract symptoms, whose main effect is presented in the 3rd months after the androgen deprivation therapy.
Aged ; Aged, 80 and over ; Androgen Antagonists ; therapeutic use ; Anilides ; therapeutic use ; Flutamide ; therapeutic use ; Humans ; Male ; Middle Aged ; Neoplasm Staging ; Nitriles ; therapeutic use ; Prostatic Neoplasms ; complications ; drug therapy ; Tosyl Compounds ; therapeutic use ; Urination Disorders ; drug therapy ; etiology

Androgen deprivation therapy, which is the standard treatment for metastatic prostate cancer, includes nonsteroidal antiandrogenic drugs, such as flutamide, nilutamide and bicalutamide. Of them, bicalutamide rarely induces interstitial pneumonia. We report a case of bicalutamide-induced interstitial pneumonia. A 68-year old male diagnosed with prostate cancer and multiple bone metastases presented with dry cough and low grade fever for 3 days. He had taken bicalutamide (50 mg/day) for 13 months. High resolution computed tomography revealed ground glass opacity in his right upper lung. The laboratory studies showed no eosinophilia in the serum and bronchoalveolar lavage fluid. Despite the use of antimicrobial agents for 2 weeks, the extent of the lung lesions increased to the left upper and right lower lung. He had no environmental exposure, collagen vascular disease and microbiological causes. Under the suspicion of bicalutamide-induced interstitial pneumonia, bicalutamide was stopped and prednisolone (1 mg/kg/day) was initiated. The symptoms and radiologic abnormalities were resolved with residual minimal fibrosis.
Anilides ; Anti-Infective Agents ; Bronchoalveolar Lavage Fluid ; Collagen ; Cough ; Environmental Exposure ; Eosinophilia ; Fever ; Fibrosis ; Flutamide ; Glass ; Humans ; Imidazolidines ; Lung ; Lung Diseases, Interstitial ; Male ; Neoplasm Metastasis ; Nitriles ; Prednisolone ; Prostatic Neoplasms ; Tosyl Compounds ; Vascular Diseases

The purpose of this study is to evaluate the therapeutic effect of radical prostatectomy combined with preoperative neoadjuvant hormonal ablation therapy for prostate cancer (PCa). In this study, a total of 31 patients with local PCa underwent radical prostatectomy; of these, 12 patients underwent preoperative hormonal deprivation with a combination of goserelin and flutamide for a period of 5.6 months. Data regarding clinical characteristics were compared between the neoadjuvant therapy and radical prostatectomy groups. A total of 31 patients received pelvic lymph node clearance, and the rate of positive lymph nodes was 12.9% (4/31). Serum prostate-specific antigen (PSA) was 8.9 +/- 1.2 microg L(-1) after the neoadjuvant therapy and 0.4 +/- 0.3 microg L(-1) one month after the radical prostatectomy. There were significant differences in the positive surgical margins, seminal vesicle invasion and lymph node metastasis between the neoadjuvant therapy group (n = 12) and the radical prostatectomy group (n = 19, P < 0.01). The resulsts indicates that preoperative hormonal deprivation induced by goserelin and flutamide can decrease clinical and pathological staging, but assessment of its influence on long-term prognosis requires further study.
Aged ; Antineoplastic Agents, Hormonal ; therapeutic use ; Combined Modality Therapy ; Dose-Response Relationship, Drug ; Flutamide ; therapeutic use ; Goserelin ; therapeutic use ; Humans ; Male ; Middle Aged ; Neoadjuvant Therapy ; methods ; Prostate-Specific Antigen ; blood ; Prostatectomy ; methods ; Prostatic Neoplasms ; blood ; drug therapy ; surgery ; Retrospective Studies ; Treatment Outcome

PURPOSE: Flutamide (4-nitro-3-t-trifluoromethyl-isobutyranilide) is an androgen-receptor antagonist with typical antiandrogenic effect, used to treat androgen-dependent disorders such as prostate cancer. However, some reports noted that flutamide has direct effects to neuronal cells. It has been shown to retard the development of electrical kindling in rats. METHODS: We used the chemoconvulsant 4-aminopyridine (4-AP) and picrotoxin (PTX) in the in vitro hippocampal slice model to determine of flutamide for the suppression of epileptiform discharges. Extracellular field potential recordings were obtained from the CA3 pyramidal layer of hippocampus. RESULTS: The concentration of 30 and 100 micrometer flutamide suppressed the whole mean number of epileptiform discharges to 57.8% and 66.8% each compared with the 4-AP only slices. In 100 micrometer PTX, 10 and 30 micrometer flutamide suppressed the whole mean number of epileptiform discharges to 56.6% and 82.5% each. Intermixed with flumazenil, the anticonvulsant effect of flutamide was decreased. CONCLUSIONS: Flutamide suppressed epileptiform discharges induced by 4-AP and PTX in vitro seizure model. It suggests that flutamide influence to anti-epileptic activity by benzodiazepine site of the GABAA receptor.
4-Aminopyridine ; Benzodiazepines ; Flumazenil ; Flutamide ; Neurons ; Picrotoxin ; Prostatic Neoplasms ; Seizures

Cells, Cultured ; Flutamide ; pharmacology ; Human Umbilical Vein Endothelial Cells ; cytology ; drug effects ; metabolism ; Humans ; Proto-Oncogene Proteins c-myb ; metabolism ; Sp1 Transcription Factor ; metabolism ; Testosterone ; antagonists & inhibitors ; physiology ; Transcription Factors ; metabolism ; Tumor Suppressor Protein p53 ; metabolism

AIMTo determine whether testosterone is involved in morphine withdrawal syndrome (WS).

METHODSIn order to induce dependency, rats were treated with subcutaneous injection of morphine (days 1-2, 5 mg/kg; days 3-5, 7.5 mg/kg; days 6-8, 10 mg/kg), and after the last dose of morphine (day 8) WS was induced by intraperitoneal injection of naloxone (1 mg/kg). Wet dog shake (WDS), abdomen writhing (AW), and jumps (J) were recorded as indicators of WS.

RESULTSThe severity of WDS, AW, and J in male rats was greater than that in females. Accordingly, in 4-week castrated and flutamide-treated (10 mg/kg/day for 8 days, i.p.) male rats, WDS, AW, and J were significantly decreased compared to male control rats. Testosterone replacement therapy (10 mg/kg/day for 8 days, i.m.) in 4-week castrated rats restored the severity of WDS, AW, and J behaviors to the level of non-castrated male rats, whereas testosterone potentiated the WDS behavior in non-castrated male rats.

CONCLUSIONIt can be concluded that testosterone might be effectively involved in morphine WS.

Androgen Antagonists ; pharmacology ; Androgens ; pharmacology ; physiology ; Animals ; Behavior, Animal ; Female ; Flutamide ; pharmacology ; Male ; Morphine ; pharmacology ; Morphine Dependence ; physiopathology ; Naloxone ; pharmacology ; Narcotic Antagonists ; pharmacology ; Narcotics ; pharmacology ; Orchiectomy ; Rats ; Rats, Wistar ; Severity of Illness Index ; Substance Withdrawal Syndrome ; physiopathology ; Testosterone ; pharmacology ; physiology

AIMTo identify flutamide regulated genes in the rat ventral prostate.

METHODSTotal RNA from ventral prostates of control and flutamide treated rats were isolated. Differentially expressed transcripts were identified using differential display reverse transcriptase polymerase chain reaction. The effect of castration on the expression of flutamide-regulated transcripts was studied.

RESULTSWe have identified beta2-microglobulin, cytoplasmic FMR1 interacting protein 2 and pumilio 1 as flutamide induced and spermine binding protein and ribophorin II as flutamide repressed targets in the rat ventral prostate. Although flutamide treatment caused an induction of pumilio 1 mRNA, castration had no effect.

CONCLUSIONCastration and flutamide treatments exert differential effects on gene expression. Flutamide might also have direct AR independent effects, which might have implications in the emergence of androgen independent prostate cancer and the failure of flutamide therapy.

Adaptor Proteins, Signal Transducing ; drug effects ; metabolism ; Androgen Antagonists ; pharmacology ; Animals ; Flutamide ; pharmacology ; Gene Expression Regulation ; drug effects ; Intracellular Signaling Peptides and Proteins ; genetics ; metabolism ; Male ; Membrane Proteins ; genetics ; metabolism ; Orchiectomy ; Prostate ; drug effects ; metabolism ; RNA-Binding Proteins ; metabolism ; Rats ; Rats, Wistar ; beta 2-Microglobulin ; drug effects ; metabolism