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5-aminolevulinic acid (ALA) is used for tumor-targeting phototherapy because it is converted to protoporphyrin IX (PPIX) upon excitation and induces phototoxicity. However, the effect of ALA on malignant cells under unexcited conditions is unclear. This information is essential when administering ALA systemically. We used sarcoma cell lines that usually arise deep in the body and are rarely exposed to light to examine the effects of ALA treatment under light (daylight lamp irradiation) and dark (dark room) conditions. ALA-treated human SW872 liposarcoma cells and human MG63 osteosarcoma cells cultured under light exhibited growth suppression and increased oxidative stress, while cells cultured in the dark showed no change. However, sphere-forming ability increased in the dark, and the expression of stem-cell-related genes was induced in dark, but not light, conditions. ALA administration increased heme oxygenase 1 (HO-1) expression in both cell types; when carbon monoxide (CO), a metabolite of HO-1, was administered to sarcoma cells via carbon-monoxide-releasing molecule 2 (CORM2), it enhanced sphere-forming ability. We also compared the concentration of biliverdin (BVD) (a co-product of HO-1 activity alongside CO) with sphere-forming ability when HO-1 activity was inhibited using ZnPPIX in the dark. Both cell types showed a peak in sphere-forming ability at 60-80 µM BVD. Furthermore, a cell death inhibitor assay revealed that the HO-1-induced suppression of sphere formation was rescued by apoptosis or ferroptosis inhibitors. These findings suggest that in the absence of excitation, ALA promotes HO-1 expression and enhances the stemness of sarcoma cells, although excessive HO-1 upregulation induces apoptosis and ferroptosis. Our data indicate that systemic ALA administration induces both enhanced stemness and cell death in malignant cells located in dark environments deep in the body and highlight the need to pay attention to drug delivery and ALA concentrations during phototherapy.
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Ácido Aminolevulínico , Sarcoma , Humanos , Linhagem Celular , Ácido Aminolevulínico/farmacologia , Ácido Aminolevulínico/uso terapêutico , Apoptose , Morte Celular , Sarcoma/tratamento farmacológico , Heme Oxigenase-1/metabolismo , Protoporfirinas/farmacologiaRESUMO
BACKGROUND/AIM: Life expectancy is considered in treatment decision-making for non-metastatic prostate cancer (PCa). We explored the factors related to overall survival (OS) and investigated the association between OS and life expectancy in patients with non-metastatic PCa according to various treatment modalities. PATIENTS AND METHODS: This retrospective study included 714 patients with non-metastatic PCa between 2006 and 2010 at our institute. The treatment modalities were classified as follows: radical prostatectomy (RP), androgen deprivation therapy (ADT), brachytherapy (BT) and external beam radiation therapy (EBRT). We defined life expectancy according to an abridged life table published by the Ministry of Health, Labour and Welfare in Japan. RESULTS: The median age and initial prostate-specific antigen levels at treatment were 71 years and 8.8 ng/mL, respectively. Advanced age, Charlson comorbidity index (CCI) ≥1, cT3a stage and ADT were independent poor prognostic factors for OS. OS and life expectancy did not significantly differ in all patients (p=0.32) and in the National Comprehensive Cancer Network (NCCN) high-risk group (p=0.059). In patients with a life expectancy of <10 years, the OS was significantly shorter than life expectancy (p<0.001). CONCLUSION: Patients with non-metastatic PCa may live beyond their life expectancy regardless of the type of therapy and NCCN risk classification, and patients with a life expectancy of <10 years may benefit from BT rather than ADT and EBRT.
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Braquiterapia , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Antagonistas de Androgênios/uso terapêutico , Expectativa de Vida , ProstatectomiaRESUMO
We aimed to evaluate the effects of a soluble guanylate cyclase (sGC) activator, BAY 60-2770, on neurogenic lower urinary tract dysfunction in mice with spinal cord injury (SCI). Mice were divided into the following three groups: spinal cord intact (group A), SCI + vehicle (group B), and SCI + BAY 60-2770 (group C). SCI mice underwent Th8-Th9 spinal cord transection and treatment with BAY 60-2770 (10 mg/kg/day) once daily for 2-4 wk after SCI. We evaluated urodynamic parameters using awake cystometry and external urethral sphincter electromyograms (EMG); mRNA levels of mechanosensory channels, nitric oxide (NO)-, ischemia-, and inflammation-related markers in L6-S1 dorsal root ganglia, the urethra, and bladder tissues; and protein levels of cGMP in the urethra at 4 wk after SCI. With awake cystometry, nonvoiding contractions, postvoid residual, and bladder capacity were significantly larger in group B than in group C. Voiding efficiency (VE) was significantly higher in group C than in group B. In external urethral sphincter EMGs, the duration of notch-like reductions in intravesical pressure and reduced EMG activity time were significantly longer in group C than in group B. mRNA expression levels of transient receptor potential ankyrin 1, transient receptor potential vanilloid 1, acid-sensing ion channel (ASIC)1, ASIC2, ASIC3, and Piezo2 in the dorsal root ganglia, and hypoxia-inducible factor-1α, VEGF, and transforming growth factor-ß1 in the bladder were significantly higher in group B than in groups A and C. mRNA levels of neuronal NO synthase, endothelial NO synthase, and sGCα1 and protein levels of cGMP in the urethra were significantly lower in group B than in groups A and C. sGC modulation might be useful for the treatment of SCI-related neurogenic lower urinary tract dysfunction.NEW & NOTEWORTHY This is the first report to evaluate the effects of a soluble guanylate cyclase activator, BAY 60-2770, on neurogenic lower urinary tract dysfunction in mice with spinal cord injury.
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Traumatismos da Medula Espinal , Bexiga Urinária , Animais , Benzoatos , Compostos de Bifenilo , Hidrocarbonetos Fluorados , Camundongos , Óxido Nítrico Sintase/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/tratamento farmacológico , Bexiga Urinária/metabolismoRESUMO
OBJECTIVES: This study aimed to determine whether Dahl salt-sensitive rats fed a high-salt diet would show features of nocturia due to nocturnal polyuria and to examine the efficacy of choreito (CRT) on nocturnal polyuria. METHODS: Dahl salt-sensitive rats were divided into three groups. Group A was fed a 4% salt diet, group B a 2% salt diet, and group C a normal 0.3% salt diet. In groups α and ß, other rats were further divided into two groups: The rats in group α were fed a 2% salt plus 3% CRT diet, and those in group ß, were fed a 2% salt diet. Each rat was placed in an individual metabolic cage for 24 hours every week for 6 weeks. Water intake, urine production, voiding frequency, and voided volume per micturition were recorded. RESULTS: The systolic blood pressure increased in the group fed a 4% salt diet compared to groups fed with a 2% and 0.3% salt diet. The urinary volume was higher in the groups fed with 4% and 2% salt than in the group fed with 0.3% salt. Further, water intake in the group fed a 2% salt plus 3% CRT diet was significantly lower than that in the group fed with a 2% salt diet. CONCLUSIONS: Dahl salt-sensitive rats fed a 2% salt diet were candidates for a model of nocturnal polyuria. Using this model, we suggest that CRT reduces water intake in the active phase and contributes to water restriction in the treatment of nocturnal polyuria.
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Hipertensão , Noctúria , Animais , Pressão Sanguínea , Medicamentos de Ervas Chinesas , Hipertensão/complicações , Noctúria/etiologia , Poliúria/complicações , Ratos , Ratos Endogâmicos DahlRESUMO
INTRODUCTION: Hypoparathyroidism, sensorineural deafness, and renal dysplasia syndrome is an autosomal dominant rare genetic disease. Some patients with hypoparathyroidism, sensorineural deafness, and renal dysplasia syndrome may present with renal calcification (nephrocalcinosis) and disorder. We report the first case of living-donor kidney transplantation for a patient with hypoparathyroidism, sensorineural deafness, and renal dysplasia syndrome. CASE PRESENTATION: This case pertains to a 26-year-old woman who was diagnosed with congenital hypoparathyroidism 1 month after birth, following which vitamin D supplementation was initiated. In 20XX, she developed nephrocalcinosis and was confirmed to have a GATA3 mutation; hence, she was diagnosed with hypoparathyroidism, sensorineural deafness, and renal dysplasia syndrome. In 20XX + 7, ABO-incompatible living-donor kidney transplantation was performed. Her renal function improved, and graft calcification was not observed. CONCLUSION: Over intake of vitamin D caused nephrocalcinosis. The renal function was improved after living-donor kidney transplantation and the patient's serum calcium levels normalized without vitamin D supplementation. Therefore, kidney transplantation should be considered a treatment option for patients with hypoparathyroidism, sensorineural deafness, and renal dysplasia syndrome.
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BACKGROUND: Radiotherapy is one of the most frequently selected treatment options for patients with prostate cancer. However, adverse effects related to the irradiated surrounding normal organs are significant clinical concerns. Specifically, genitourinary and gastrointestinal toxicities can lead to a dramatically reduced quality of life. The aim of this clinical trial is to determine the efficacy of oral 5-aminolevulinic acid (ALA) phosphate with sodium ferrous citrate (SFC) in patients treated with low-dose-rate brachytherapy (LDR-BT) using an iodine-125 seed source. METHODS: The AMBER study is a prospective, single-center trial in patients with localized prostate cancer undergoing LDR-BT. Patients who undergo supplementary extra-beam radiotherapy are excluded, whereas those who undergo pre-implantation short-term (4-6 months) androgen deprivation therapy to decrease the prostate volume and/or improve oncological outcomes are included. After the screening and registration, the patients will be instructed to take capsules of ALA-SFC twice a day (200 mg and 229.42 mg per day) for 6 months from the day of seed implantation (prescribed radiation dose of 160 Gy). Patient data will be collected before the implantation; during oral ALA-SFC treatment; and 1, 3, 6, 9, and 12 month(s) after seed implantation. The primary endpoint of this trial is the urinary frequency 3 months after seed implantation. At each visit, the 24-h urinary frequency, total voided volume, and mean voided volume on a frequency volume chart and other patient-reported outcomes are recorded. The data of the trial cases will be compared with those of historical controls, who are consecutive patients undergoing LDR-BT without supplementary extra-beam radiotherapy between January 2016 and January 2019. The number of subjects has been set to be 50 for trial cases and 150 for the historical control cases. Pre- and post-treatment clinicopathologic factors are compared between two groups. DISCUSSION: The goal of this trial is to determine the potential benefit of ALA-SFC in patients who undergo LDR-BT. To the best of our knowledge, this is the first study investigating the potential clinical benefit of oral ALA-SFC after radiotherapy. More evidence from a further randomized controlled trial is needed to change the standard of care and lead to better post-radiotherapy management. TRIAL REGISTRATION: This clinical trial was prospectively registered with the Japan Registry of Clinical Trials on 5 December 2019. The reference number is jRCTs051190077, nara0013 (Certified Review Board of Nara Medical University).
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We examined extracellular signalregulated kinase (ERK), 4Ebinding protein 1 (4EBP1) and p70 ribosomal S6 kinase (p70) as potential biomarkers for pretreatment prediction of the prognosis of patients with metastatic renal cell carcinoma (RCC) treated with sorafenib, sunitinib or everolimus. 786O and 769P cells were treated with sorafenib, sunitinib and everolimus. The expression of phosphorylated/total ERK, phosphorylated/total 4EBP1 and phosphorylated/total p70 was evaluated using western blotting. ERK, 4EBP1 and p70 were knocked down by siRNA in 786O and 769P cells. Then, the viability after treatment with each drug was assessed. Expression of phosphorylated (phospho)ERK, -4EBP1 and -p70 was immunohistochemically evaluated in radical nephrectomy specimens and correlated with progressionfree survival during treatment with each molecular targeting agent. Sorafenib inhibited the expression of phospho-ERK and -4EBP1 in 769P cells; sunitinib, phospho-ERK and -4EBP1 in 786O and 769P cells; and everolimus, phospho-p70 in 786O and 769P cells. Knockdown of ERK reduced sensitivity to sorafenib in both cell lines, knockdown of ERK and 4EBP1 reduced sensitivity to sunitinib in 769P cells, and knockdown of 4EBP1 and p70 reduced sensitivity to everolimus in 786O cells. High expression of phospho-ERK, -4EBP1 and -p70 correlated with better progressionfree survival in patients treated with sorafenib, sunitinib and everolimus, respectively. Our results indicate that phospho-ERK, -4EBP1 and/or -ERK, and phospho-p70 can be used as biomarkers for the therapeutic efficacy of sorafenib, sunitinib and everolimus, respectively.
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Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Everolimo/farmacologia , Indóis/farmacologia , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Pirróis/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/mortalidade , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Intervalo Livre de Doença , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Niacinamida/farmacologia , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Sorafenibe , Sunitinibe , Resultado do TratamentoRESUMO
BACKGROUND: COX-2 inhibitors have an antitumor potential and have been verified by many researchers. Treatment of cancer cells with external stressors such as irradiation can stimulate the over-expression of COX-2 and possibly confer radiation resistance. In this study, we tested if topical diclofenac, which inhibits both COX-1 and COX-2, administration rendered prostate tumor cells sensitize to the effects of radiation. METHODS: LNCaP-COX-2 and LNCaP-Neo cells were treated with 0 to 1000 µM diclofenac. Next, a clonogenic assay was performed in which cells were subjected to irradiation (0 to 4 Gy) with or without diclofenac. COX-2 expression and other relevant molecules were measured by real-time PCR and immunohistochemistry after irradiation and diclofenac treatment. In addition, we assessed the tumor volumes of xenograft LNCaP-COX-2 cells treated with topical diclofenac with or without radiation therapy (RT). RESULTS: LNCaP-COX-2 and LNCaP-Neo cell lines experienced cytotoxic effects of diclofenac in a dose related manner. Clonogenic assays demonstrated that LNCaP-COX-2 cells were significantly more resistant to RT than LNCaP-Neo cells. Furthermore, the addition of diclofenac sensitized LNCaP-COX-2 not but LNCaP-Neo cells to the cytocidal effects of radiation. In LNCaP-COX-2 cells, diclofenac enhanced radiation-induced apoptosis compared with RT alone. This phenomenon might be attributed to enhancement of RT-induced TRAIL expression as demonstrated by real-time PCR analysis. Lastly, tumor volumes of LNCaP-COX-2 cells xenograft treated with diclofenac or RT alone was >4-fold higher than in mice treated with combined diclofenac and radiation (p<0.05). CONCLUSIONS: These in vitro and in vivo findings suggest that conventional COX inhibitor, diclofenac enhances the effect of RT on prostate cancer cells that express COX-2. Thus, diclofenac may have potential as radiosensitizer for treatment of prostate cancer.
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Adenocarcinoma/tratamento farmacológico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Ciclo-Oxigenase 2/efeitos dos fármacos , Diclofenaco/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/uso terapêutico , Ligante Indutor de Apoptose Relacionado a TNF/efeitos dos fármacos , Adenocarcinoma/metabolismo , Adenocarcinoma/radioterapia , Administração Tópica , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimioterapia Adjuvante , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/radioterapia , Reação em Cadeia da Polimerase em Tempo Real , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVES: To evaluate the safety, diagnostic potential and therapeutic efficacy of cystoscopy with hydrodistension under local anesthesia in patients with suspected painful bladder syndrome/interstitial cystitis (PBS/IC). METHODS: Thirty-six patients with frequency, urgency or bladder pain for > or = 6 months and an average voided volume of <200 mL were enrolled in the study. Hydrodistension was carried out 10 min after instillation of 10 mL of 4% lidocaine. The instilled saline volume for hydrodistension was determined based on each patient's level of tolerance of urinary sensation and symptoms. RESULTS: Overall, 30 patients (median age 54 years, range 25-76) were evaluated. The median instilled saline volume was 450 mL (250 to 580 mL). No patients were admitted to hospital due to adverse events associated with hydrodistension. Glomerulation was found in 23 patients and two had Hunner's ulcers. Therapeutic efficacy at one month after hydrodistension was shown in 21/30 patients (71%). A median efficacy period of 20 + or = 3.7 weeks was determined by Kaplan-Meier analysis. Factors with an independent influence on therapeutic efficacy of hydrodistension were not identified, but patients with an instilled volume greater than the median volume had significantly longer efficacy periods (P < 0.022). CONCLUSIONS: Cystoscopy with hydrodistension under local anesthesia provides a simple and safe method for differential diagnosis and has some therapeutic efficacy in patients with suspected PBS/IC.
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Cistite Intersticial/diagnóstico , Cistite Intersticial/terapia , Cistoscopia/métodos , Dilatação/métodos , Administração Intravesical , Adulto , Idoso , Anestesia Local , Anestésicos Locais/administração & dosagem , Cistoscopia/efeitos adversos , Diagnóstico Diferencial , Feminino , Humanos , Lidocaína/administração & dosagem , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Transtornos Urinários/diagnóstico , Transtornos Urinários/terapia , Água , Adulto JovemRESUMO
BACKGROUND: UFT is an anticancer agent consisting of 1-(2-tetrahydrofuryl)-5-fluorouracil (5-FU) combined with uracil in a molar ratio of 1: 4. Its mechanisms of action are, presumably, inhibition of deoxyribonucleic acid (DNA) synthesis by thymidylate synthetase (TS) and impairment of ribonucleic acid (RNA) function by the incorporation of 5-fluorouridine-5'-triphosphate into RNA. This study was conducted to examine the TS inhibition rate (TS-IR) and the concentration of 5-FU incorporated in RNA per milligram of tissue treated with UFT (F-RNA). METHODS: We administered UFT to 12 patients with bladder cancer. We also administered UFT to 20 rats bearing bladder tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), and to 10 BBN-untreated control rats. We then determined the total TS concentration, TS-IR, and F-RNA in the human bladder tumor and normal tissues and in the BBN-treated and BBN-untreated rat organs, including the urinary bladder. RESULTS: In the bladder cancer patients, the mean F-RNAs in the bladder tumor and normal tissue were 0.133 +/- 0.137 and 0.056 +/- 0.062 ng/mg, respectively, without a significant difference (P < 0.1). The mean TS-IR was 35.3 +/- 19.6% in the tumor tissue and 38.0 +/- 16.6% in the normal bladder tissue, and this difference was also not significant. In the rat bladder cancer model, the total TS concentration and F-RNA in the tumor after the administration of UFT were 15.32 pmol/g and 0.780 ng/mg, respectively, being markedly higher than the corresponding values (1.22 pmol/g and 0.129 ng/mg) in the control normal bladder tissue. CONCLUSION: The impairment of RNA metabolism by F-RNA incorporated in RNA did not seem to be the critical mechanism of the antitumor effect of UFT at the usual clinical dose, as neither TS-IR nor F-RNA (as antitumor parameters) seemed to increase significantly after a clinical dose of UFT. However, the inhibition of DNA synthesis and the impairment of RNA were independent mechanisms of the action of high-dose UFT in the experimental rat bladder tumors, as both total is concentration and F-RNA were increased significantly.
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Fluoruracila/metabolismo , Tegafur/uso terapêutico , Uracila/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Neoplásico/metabolismo , Ratos , Ratos Endogâmicos F344 , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Transurethral needle ablation (TUNA) is less invasive than other therapies for benign prostatic hyperplasia (BPH) and produces coagulative necrosis within selected adenoma lesions. The action mechanism of TUNA is still obscure, even though many early studies have demonstrated good clinical results of TUNA. It is of interest and importance to know how TUNA influences the volume of the intraprostatic region responsible for bladder outlet obstruction in order to elucidate the anatomical action mechanism of TUNA. METHODS: We retrospectively investigated postoperative variations in volumetric parameters of whole prostate volume (PV), transition zone volume (TZV) and transition zone index (TZI = TZV/PV) in 41 patients with symptomatic BPH who were treated with TUNA. The data were analyzed statistically in relation to the preoperative overall severity and postoperative therapeutic efficacy. RESULTS: Both PV and TZV showed a significant decrease at 3 months after TUNA (P < 0.01) as did the symptom score, quality of life (QOL) score and functional variables, and a decreased level of PV and TZV was sustained until 12 months of follow-up when compared to the baseline (P < 0.01 at 6 months, not significant at 12 months). TZI also showed a similar pattern with a significantly decreased level until the postoperative 6th month (P < 0.05 at 6 months, not significant at 12 months). In 'moderate' cases, TZI achieved the minimum value (0.44 +/- 0.13, P < 0.05 compared to the baseline) at 3 months of follow-up, but the level immediately increased, while in 'severe' cases, TZI gradually decreased and achieved the minimum value (0.44 +/- 0.08, P < 0.05 compared to the baseline) at 12 months of follow-up. In the evaluation by postoperative therapeutic efficacy, there were no significant differences in PV, TZV and TZI between 'excellent and good' cases (E/G group) and 'fair and poor/worse' cases (F/P group) at the baseline or 3 months of follow-up. Both of the efficacy groups showed a significant decrease in PV, TZV and TZI at 3 months when compared to the baseline (P < 0.05). The mean decrease in TZI was significantly larger in the E/G group than in the F/P group (0.064 +/- 0.13 vs 0.027 +/- 0.12, P < 0.05). CONCLUSION: Therapeutic efficacy of TUNA did not depend on the baseline value of PV, TZV and TZI, but on variation of a decrease in TZI during follow-up. Moreover, a slow and lasting decrease in TZI seemed to influence durability of the therapeutic efficacy of TUNA, which was clearly observed in 'severe' cases with a larger prostatic volume than in 'moderate' cases.