[Show abstract][Hide abstract] ABSTRACT: To investigate the levels of testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prostate-specific antigen (PSA) in prostate cancer patients before and after the switch from degarelix to leuprolide treatments.
We enrolled 40 treatment-naïve prostate cancer patients who were treated initially with degarelix and were later switched to leuprolide. The subjects were divided into three groups depending on when they were switched to leuprolide: the 3-month group (3m; switched after 84 days, n=10), the 2-month group (2m; 56 days, n=10), and the 1-month group (1m; 28 days, n=20). Patient symptoms and hormone levels were measured after switching therapy. The castration level was defined as a serum testosterone level ≤50 ng/dl.
Thirty-nine subjects (97.5%) achieved castration levels of testosterone (11±5.8 ng/dl) 2 weeks after degarelix was first administered, and the characteristics of these patients were investigated. Testosterone levels increased and exceeded the castration level in one subject each of the 3m (142 ng/dl), 2m (72 ng/dl), and 1m groups (63 ng/dl). All subjects achieved the castration level by day 5. In contrast to testosterone levels, the LH and FSH surge on day 2 was significantly higher in the 1m group than in the other groups. The clinical symptoms were not exacerbated before or after switching in any patients.
A testosterone surge was observed in 8.3 % of the study patients; however, it was very short-lived and mild. LH and FSH levels were significantly higher 1 month after administration compared with 2 or 3 months after degarelix administration.
[Show abstract][Hide abstract] ABSTRACT: To assess the cognitive and sexual/hormonal functioning of prostate cancer patients treated with a luteinizing hormone-releasing hormone (LH-RH) agonist, and the relationships thereof with adrenal and residual testicular androgen levels.
Materials and methods
Previously, we reported the effect of a luteinizing hormone-releasing hormone (LH-RH) agonist on testicular and adrenal androgen production in patients with prostate cancer. A 6-month treatment with an LH-RH agonist significantly reduced testicular androgens by 90–95% and adrenal androgens by 26–40%. This study evaluated the changes in cognitive and sexual/hormonal functions in the same cohort using the Mini-Mental State Evaluation (MMSE) and Expanded Prostate Cancer Index Composite (EPIC) questionnaire, respectively. In addition, the associations of each function with the serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2), dehydroepiandrosterone-sulfate (DHEA-S), dehydroepiandrosterone (DHEA), androstenedione (A-dione), and cortisol levels were studied.
Cognitive functions did not change significantly during the treatment. Sexual functions were relatively low before treatment and worsened significantly after 6 and 12 months of treatment. Interestingly, sexual bothers were improved with the treatment. The treatment significantly worsened hormonal functions and bothers. Regarding specific items in the hormonal domains, hot flashes and body weight changes were the main effects of worsened hormonal function. Low levels of T and E2 and high levels of A-dione were associated with low MMSE scores at 6 months. Regarding sexual and hormonal functions, A-dione, E2, T, cortisol, and DHEA-S were associated with poorer functioning and bother. Especially, low T levels and high E2 levels were the most significant factors associated with worse sexual and hormonal bothers.
The LH-RH agonist monotherapy worsened sexual and hormonal functions and hormonal bothers, but not sexual bothers or cognitive functions. The changes in these functions were related to the testicular and adrenal androgens levels.
[Show abstract][Hide abstract] ABSTRACT: Orteronel (TAK-700) is a non-steroidal, selective, reversible inhibitor of 17,20-lyase. We evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effect of orteronel with or without prednisolone in Japanese patients with castration-resistant prostate cancer (CRPC).
We conducted a phase 1 study in men with progressive and chemotherapy-naïve CRPC. Patients received orteronel orally at doses of 200-400 mg twice daily (BID) with or without oral prednisolone (5 mg BID). Dose-limiting toxicity (DLT) was assessed during Cycle 1 (28 days). Patients could continue study treatment until any of criteria for treatment discontinuation were met. Gonadotropin-releasing hormone therapy was continued in patients without prior orchidectomy.
Fifteen patients were enrolled and administered at least one dose of orteronel. No DLTs were reported during Cycle 1 in this study. Adverse events (AEs) were reported in all 15 patients. Most common AEs (>30 %) were hyperlipasemia (47 %), hyperamylasemia (40 %), and constipation (33 %). Acute pancreatitis (Grades 2 and 3) and pancreatitis (Grade 1) were complicated in three patients during the study. Dose-dependent increase in plasma orteronel concentrations was indicated over the 200-400 mg BID dose range. Prednisolone coadministered did not alter PK of orteronel. Serum testosterone was rapidly suppressed below the lower limit of quantification across all doses. Of 15 subjects, 13 achieved at least a 50 % reduction from baseline in prostate-specific antigen.
Orteronel at doses up to 400 mg BID was tolerable in Japanese CRPC patients. The present results support further evaluation of orteronel with or without prednisolone.
Cancer Chemotherapy and Pharmacology 12/2014; 75(2). DOI:10.1007/s00280-014-2654-y · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epidemiological studies showed the inverse association between statin use and prostate cancer incidence, especially advanced stages, or mortality. Recent report on association of postdiagnostic use of statin with reduction of prostatic or all-cause mortality strengthened the evidence in this subject. Our basic research findings demonstrated multiple mechanisms of lipid on prostate cancer proliferations. We also showed the mechanism of statin action on prostate cancer cells via IGF1-receptor or LDL receptor cascades. These findings will serve the new strategy for progressive and castration resistant prostate cancer management.
Nippon rinsho. Japanese journal of clinical medicine 12/2014; 72(12):2116-20.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Mammalian target of rapamycin inhibitor has exhibited promising anticancer activity for the treatment of renal cell carcinoma (RCC). However, many patients acquire resistance to therapeutic agents leading to treatment failure. The objective of this study was to determine whether treatment with YM155, a novel small molecule inhibitor of survivin, could reverse rapamycin resistance in a rapamycin-resistant RCC.
We induced a rapamycin-resistant clear cell carcinoma cell line (Caki-1-RapR). We showed that survivin gene expression was significantly up-regulated in Caki-1-RapR compared with that in its parent cells (Caki-1). Therefore, we hypothesized that targeting of survivin in Caki-1-RapR could reverse the resistant phenotype in tumor cells, thereby enhancing the therapeutic efficacy of rapamycin. We used both in vitro and in vivo models to test the efficacy of YM155 either as a single agent or in combination with rapamycin.
In Caki-1-RapR cells, YM155 significantly decreased survivin gene and protein expression levels and cell proliferation in a dose-dependent manner in vitro. In addition, YM155 treatment significantly reversed rapamycin resistance in cancer cells. In a nude mouse tumor xenograft model, YM155 significantly inhibited the growth of Caki-1-RapR tumor. In addition, YM155 significantly enhanced the antitumor effects of rapamycin in Caki-1-RapR tumor.
Our results suggest a potentially novel strategy to use YM155 to overcome the resistance in tumor cells, thereby enhancing the effectiveness of molecular target therapy in RCC.
Journal of Cancer Research and Clinical Oncology 06/2014; 140(10). DOI:10.1007/s00432-014-1734-z · 3.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sunitinib is an oral multi-target tyrosine kinase inhibitor approved for treating metastatic renal cell carcinoma (RCC) that is metabolised mainly by CYP3A4 to the pharmacologically active N-desethyl metabolite SU12662. In a phase I clinical trial, the recommended dose of sunitinib with manageable toxicity was determined to be 50 mg day-1 (4 weeks on, 2 weeks off; 4/2 schedule). Although a single dose of up to 350 mg was well tolerated, a case of sunitinib overdose has never been reported. Here, we report the pharmacokinetic analysis of sunitinib and a life-threatening adverse event in a patient with metastatic RCC who took 450 mg of sunitinib as a single dose together with brotizolam.
British Journal of Clinical Pharmacology 03/2014; 78(4). DOI:10.1111/bcp.12381 · 3.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the clinical efficacy of low-dose chlormadinone acetate (CMA) in prostate cancer patients who suffer from hot flushes that is a major side effect of androgen deprivation therapy.
Our study included 32 prostate cancer patients who had severe hot flush after undergoing hormone therapy for more than 3 months. The average age of the patients was 72.5 years. In the beginning, patients received CMA at 100 mg orally per day. We defined the hot flush as disappeared, improved, or not improved. In patients with disappeared or improved symptoms, we decreased CMA dose to 50 mg per day, and after we reevaluated the effect, we decreased CMA dose to 25 mg per day. When hot flush appeared again at 25 mg per day, we returned the dose of CMA to 50 mg per day. In cases with no change for more than two months, we canceled the treatment of CMA.
Hot flush disappeared in 17 patients, improved in 10 patients, and did not improve in 5 patients (reduction in 84% of hot flush patients). The median time to hot flush reduction was 1.16 months. The effect of CMA was maintained at 25 mg per day in 19 patients and at 50 mg per day in 8 patients. No patients had prostate-specific antigen failure in the treatment of CMA.
When hot flush appears during treatment with luteinizing hormone-releasing hormone agonist for prostate cancer, it seems that CMA can improve it immediately in most patients.
[Show abstract][Hide abstract] ABSTRACT: Inguinal hernias often occur after radical retropubic prostatectomy (RRP). We present a novel and simple technique for preventing inguinal hernias after RRP, which any surgeon can complete within a few minutes.
A total of 230 Japanese prostate cancer patients underwent RRP between January 2007 and September 2011. From July 2009, 115 patients underwent inguinal hernia prevention procedures at the same time as RRP. In this procedure, we released approximately 5 cm of the bilateral vas deferens and spermatic vessels from the peritoneum. In cases in which the processus vaginalis had spread into the abdomen, we ligated it close to the peritoneal cavity and then transected it. The remaining 115 patients who underwent RRP but did not undergo the hernia prevention procedure were used as the control group. The incidence rate of postoperative inguinal hernia was compared between the 2 groups.
Inguinal hernias developed during the postoperative follow-up period in 18 of the 115 control patients (15.7%) (median duration, 50 months). The hernia-free survival rate of this group was 89.6% and 84.1% at 1 and 2 postoperative years, respectively. In contrast, only 1 of the 115 patients (0.87%) who underwent the hernia prevention procedure developed an inguinal hernia during the follow-up period (median duration, 27 months). The hernia-free survival rate of this group was 100% at both 1 and 2 postoperative years (P<0.0001).
We developed a simple method for preventing post-RRP inguinal hernias. The procedure is easy to perform and produces excellent outcomes.
[Show abstract][Hide abstract] ABSTRACT: The β form of p120 is reported to be a strong coactivator of the androgen receptor. We investigated the gene expression profiles of the α and β forms of p120 in prostate cancer cell lines, benign prostatic hyperplasia (BPH), nontreated prostate cancer (NTPC), and prostate cancer after androgen deprivation therapy (PCA-ADT).
We obtained 154 prostate needle biopsy specimens (81 in BPH, 51 in NTPC, and 22 in PCA-ADT). Levels of p120α and β expression were determined by multiplex real-time polymerase chain reaction.
Prostate cancer cell lines, LNCaP, PC-3, DU-145, and LNCaP-LA, which is a derivative of LNCaP under androgen deprivation, expressed both p120α and p120β. p120α expression levels were significantly higher than those of p120β in all cell lines examined. In human prostate tissues, p120α expression was significantly higher than that of p120β in BPH and NTPC. p120α expression in BPH was significantly higher than in other groups. In contrast, p120β expression was significantly higher in NTPC and PCA-ADT than in BPH. Expression of the two forms of p120 was not correlated with age, prostate-specific antigen, or Gleason score.
The expression profiles of p120α and p120β significantly differ in cancerous and benign prostatic tissues.
[Show abstract][Hide abstract] ABSTRACT: Hereditary and familial prostate cancers respectively account for about 5% and 20% of all prostate cancer in the United States. The most striking characteristic of familial prostate cancer is the early-onset of the disease. In the clinical setting, a family history of prostate cancer is recognized as a high risk for developing prostate cancer, and a risk-based prostate cancer screening program for it has been proposed. Genetic analyses for identifying the susceptible genes have been reported, and it appears that multiple genes are involved in the development of prostate cancer. Recently, genome-wide association studies showed that the single nucleotide polymorphisms located at the 8q24 region had an association with prostate cancer development. Familial prostate cancer, although its incident rate is relatively rare, must be treated as a high-risk group. Further clinical and basic research is warranted to explore the mechanism of prostate cancer development.
Gan to kagaku ryoho. Cancer & chemotherapy 02/2013; 40(2):159-63.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
One of the most important issues to address when developing an optimal screening system for prostate cancer is investigating appropriate biopsy indications following serum prostate-specific antigen (PSA) measurements in order to maintain high sensitivity and avoid unnecessary biopsy.
Between April 2004 and December 2007, 239 consecutive men with total PSA levels of 2.0-10.0 ng/mL underwent measurements of PSA, free PSA, and [-2]pro-PSA. We assessed the significance of laboratory-based PSA-related indices including free PSA/total PSA (%f-PSA), p2PSA/free PSA (%p2PSA), p2PSA/%f-PSA, Prostate Health Index (phi, an index combining PSA, free PSA, and p2PSA), total prostate volume (TPV)-adjusted PSA-related indices, including PSA density, %p2PSA density, p2PSA/%f-PSA density, and phi density, and transition zone (TZ) prostate volume-adjusted PSA-related indices such as PSA TZ density (PSATZD), %p2PSA TZD, p2PSA/%fPSA TZD, and phi TZD.
The positive biopsy rate was 22.2%. When sensitivity was fixed at 95 %, unnecessary biopsies could be avoided in 28% of men when phi was used as a biopsy indication. In cases where total and transition zone prostate volumes were available, the use of %p2PSA density, phi density, p2PSA/%f-PSA TZD, and phi TZD resulted in the avoidance of 48, 47, 54, and 54 % of unnecessary biopsies, respectively, while maintaining a high sensitivity of 90%.
At 90 and 95 % sensitivity, laboratory-based indices containing p2PSA, particularly phi, showed significantly greater specificity for prostate cancer as compared with %f-PSA. The diagnostic accuracy of prostate volume-adjusted p2PSA-related indices could be excellent, particularly the transition zone volume-adjusted indices at fixed sensitivities of 95 and 90%.
World Journal of Urology 08/2012; 31(2). DOI:10.1007/s00345-012-0927-9 · 2.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:We previously conducted a genome-wide linkage analysis of Japanese nuclear families affected with prostate cancer and showed that the susceptibility to prostate cancer was closely linked to D8S550 at 8p23. The role of farnesyl diphosphate farnesyltransferase (FDFT1), which is located under the peak marker D8S550 at 8p23, and squalene synthase, the enzyme encoded by FDFT1, in prostate cancer was studied.Methods:The association among common variants of FDFT1 with prostate cancer risk, the promoter activities of FDFT1 with different genotypes and the effects of inhibition of squalene synthase were studied, and the FDFT1 transcript levels of human prostate samples were quantified.Results:The A allele of rs2645429 was significantly associated with prostate cancer risk in a Japanese familial prostate cancer population. Rs2645429 was located in the promoter region of FDFT1, and the AA genotype showed significantly increased promoter activity. The knockdown of FDFT1 mRNA expression or squalene synthase inhibition led to a significant decrease in prostate cancer cell proliferation. Additionally, human prostate cancer specimens expressed significantly higher levels of FDFT1 mRNA compared with noncancerous specimens. Finally, aggressive cancers showed higher transcript levels.Conclusions:FDFT1 and its encoded enzyme, squalene synthase, may play an important role in prostate cancer development and its aggressive phenotypes.Prostate Cancer and Prostatic Diseases advance online publication, 1 May 2012; doi:10.1038/pcan.2012.14.
Prostate cancer and prostatic diseases 05/2012; 15(4). DOI:10.1038/pcan.2012.14 · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives: Recently, adrenal androgens have been targeted as key hormones for the development of castration-resistant prostate cancer therapeutics. While circulating adrenal androgens originate mainly from the adrenal glands, the testes also supply about 10%. Although widely used in androgen deprivation medical castration therapy, the effect of luteinizing-hormone (LH)-releasing hormone (RH) agonist on adrenal androgens has not been fully studied. In this study, changes in testicular and adrenal androgen levels were measured and compared to adrenocorticotropic hormone (ACTH) levels. To assess the possible role of LH in the adrenal glands, immunohistochemical studies of the LH receptor in normal adrenal glands were performed. Findings: Forty-seven patients with localized or locally progressive prostate cancer were treated with LH-RH agonist with radiotherapy. Six months after initiation of treatment, testosterone, dihydrotestosterone and estradiol levels were decreased by 90-95%, and dehydroepiandrosterone-sulfate (DHEA-S), DHEA, and androstendione levels were significantly decreased by 26-40%. The suppressive effect of LH-RH agonist at 12 months was maintained. ACTH levels showed an increasing trend at 6 months and a significant increase at 12 months. LH receptors were positively stained in the cortex cells of the reticular layer of the adrenal glands. Conclusions: The long-term LH-RH agonist treatment reduced adrenal-originated adrenal androgens. LH receptors in the adrenal cortex cells of the reticular layer might account for the underlying mechanism of reduced adrenal androgens.
Journal of Andrology 04/2012; 33(6). DOI:10.2164/jandrol.112.016493 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Docetaxel is a first-line treatment choice in castration-resistant prostate cancer (CRPC). However, the management of CRPC remains an important challenge in oncology. There have been many reports on the effects of rapamycin, which is an inhibitor of the mammalian target of rapamycin (mTOR), in the treatment of carcinogenesis. We assessed the cytotoxic effects of the combination treatment of docetaxel and rapamycin in prostate cancer cells. Furthermore, we examined the relationship between these treatments and survivin, which is a member of the inhibitory apoptosis family.
Prostate cancer cells were cultured and treated with docetaxel and rapamycin. The effects on proliferation were evaluated with the MTS assay. In addition, we evaluated the effect on proliferation of the combination treatment induced knockdown of survivin expression by small interfering RNA transfection and docetaxel. Protein expression levels were assayed using western blotting. PC3 cells and xenograft growth in nude mice were used to evaluate the in vivo efficacy of docetaxel and its combination with rapamycin.
In vitro and in vivo, the combination of rapamycin with docetaxel resulted in a greater inhibition of proliferation than treatment with rapamycin or docetaxel alone. In addition, in vitro and in vivo, rapamycin decreased basal surviving levels, and cotreatment with docetaxel further decreased these levels. Transfection siRNA against survivin enhanced the cytotoxicity of docetaxel in PC3 cells.
The rapamycin-dependent enhancement of the cytotoxic effects of docetaxel was associated with the downregulation of survivin expression. Our results suggest that the combination of docetaxel and rapamycin is a candidate for the improved treatment of advanced prostate cancer.
Biochemical and Biophysical Research Communications 02/2012; 419(3):584-9. DOI:10.1016/j.bbrc.2012.02.089 · 2.30 Impact Factor