Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
1.
Mol Oncol ; 14(10): 2455-2470, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32734688

RESUMEN

Resistance of castration-resistant prostate cancer (CRPC) to enzalutamide and abiraterone involves the expression of constitutively active, truncated androgen receptor (AR) splice variants (AR-Vs) that lack a C-terminal ligand-binding domain (LBD). Both full-length AR and truncated AR-Vs require a functional N-terminal domain (NTD) for transcriptional activity thereby providing rationale for the development of ralaniten (EPI-002) as a first-in-class antagonist of the AR-NTD. Here, we evaluated the antitumor effect of a next-generation analog of ralaniten (EPI-7170) as a monotherapy or in combination with enzalutamide in prostate cancer cells that express AR-V7 that were resistant to enzalutamide. EPI-7170 had 8-9 times improved potency compared to ralaniten. Enzalutamide increased levels of AR-V7 and expression of its target genes. Knockdown of AR-V7 restored sensitivity to enzalutamide, indicating a role for AR-V7 in the mechanism of resistance. EPI-7170 inhibited expression of genes transcriptionally regulated by full-length AR and AR-V7. A combination of EPI-7170 and enzalutamide resulted in synergistic inhibition of proliferation of enzalutamide-resistant cells that was consistent with results from cell cycle and clonogenic assays. In addition, this drug enhanced the antitumor effect of enzalutamide in enzalutamide-resistant CRPC preclinical models. Thus, a combination therapy targeting both the NTD and LBD of AR, and thereby blocking both full-length AR and AR-Vs, has potential for the treatment of enzalutamide-resistant CRPC.

2.
Asian J Endosc Surg ; 2020 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-32602220

RESUMEN

INTRODUCTION: Bilateral renal tumors accounts for approximately 3% of renal tumors. However, surgical treatment methods for bilateral renal tumors have not yet been established. It is imperative to balance the need for curative surgery with the goal of maximal functional preservation in patients with bilateral synchronous renal tumors. Therefore, partial nephrectomy may be the optimal surgical treatment for bilateral synchronous renal tumors. METHODS: We conducted a retrospective, observational study to analyze the clinical outcome of simultaneous robotic-assisted partial nephrectomy (RAPN) for bilateral renal tumors at our institution between 2016 and 2019. A total of eight patients were enrolled and the number of renal masses in the 16 kidneys was 18. RESULTS: There was no positive surgical margin after RAPN in our case series and no local recurrence or metastasis during the follow-up period. The only complication of simultaneous RAPN in the present case series was that one patient experienced acute kidney injury after operation without need for dialysis therapy. CONCLUSION: Our study suggests that simultaneous RAPN for bilateral renal tumors might be feasible both for the preservation of renal function and for oncological outcome such as negative surgical margin.

3.
Cancers (Basel) ; 12(7)2020 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-32708219

RESUMEN

Blocking androgen receptor (AR) transcriptional activity by androgen deprivation therapy (ADT) improves the response to radiotherapy for intermediate and high risk prostate cancer. Unfortunately, ADT, antiandrogens, and abiraterone increase expression of constitutively active splice variants of AR (AR-Vs) which regulate DNA damage repair leading to resistance to radiotherapy. Here we investigate whether blocking the transcriptional activities of full-length AR and AR-Vs with ralaniten leads to enhanced sensitivity to radiotherapy. Combination therapies using ralaniten with ionizing radiation were evaluated for effects on proliferation, colony formation, cell cycle, DNA damage, and Western blot analyses in human prostate cancer cells that express both full-length AR and AR-Vs. Ralaniten and a potent next-generation analog (EPI-7170) decreased expression of DNA repair genes whereas enzalutamide had no effect. FACS analysis revealed a dose-dependent decrease of BrdU incorporation with increased accumulation of γH2AX with a combination of ionizing radiation with ralaniten. An additive inhibitory effect on proliferation of enzalutamide-resistant cells was achieved with a combination of ralaniten compounds with ionizing radiation. Ralaniten and EPI-7170 sensitized prostate cancer cells that express full-length AR and AR-Vs to radiotherapy whereas enzalutamide had no added benefit.

4.
J Clin Med ; 7(11)2018 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-30453546

RESUMEN

Expression of androgen receptor (AR) splice variant 7 (AR-V7) has been identified as the mechanism associated with the development of castration-resistant prostate cancer (CRPC). However, a potential link between AR-V7 expression and resistance to taxanes, such as docetaxel or cabazitaxel, has not been unequivocally demonstrated. To address this, we used LNCaP95-DR cells, which express AR-V7 and exhibit resistance to enzalutamide and docetaxel. Interestingly, LNCaP95-DR cells showed cross-resistance to cabazitaxel. Furthermore, these cells had increased levels of P-glycoprotein (P-gp) and their sensitivity to both docetaxel and cabazitaxel was restored through treatment with tariquidar, a P-gp antagonist. Results generated demonstrated that P-gp mediated cross-resistance between docetaxel and cabazitaxel. Although the LNCaP95-DR cells had increased expression of AR-V7 and its target genes (UBE2C, CDC20), the knockdown of AR-V7 did not restore sensitivity to docetaxel or cabazitaxel. However, despite resistance to docetaxel and carbazitaxel, EPI-002, an antagonist of the AR amino-terminal domain (NTD), had an inhibitory effect on the proliferation of LNCaP95-DR cells, which was similar to that achieved with the parental LNCaP95 cells. On the other hand, enzalutamide had no effect on the proliferation of either cell line. In conclusion, our results suggested that EPI-002 may be an option for the treatment of AR-V7-driven CRPC, which is resistant to taxanes.

6.
Cancer Sci ; 108(3): 331-337, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28004470

RESUMEN

Rat bladder cancer is nearly always papillary non-invasive urothelial carcinoma (UC). To establish an animal model mimicking invasive UC that arises from papillary non-invasive UC in the bladder, male human c-Ha-ras proto-oncogene transgenic rats (Hras128) were treated with 0.05% N-butyl-N-(hydroxybutyl)nitrosameine (BBN) in their drinking water and/or 0.1% phenylethyl isothiocyanate (PEITC) in their diet as follows: BBN (8 weeks)→PEITC (8 weeks); PEITC (8 weeks)→BBN (8 weeks); BBN alone (16 weeks); PEITC alone (16 weeks); and no treatment. At the end of week 16, the highest incidence of invasive UC was observed in the BBN→PEITC group. Therefore, we used Hras128 rats treated with BBN followed by PEITC as a model of invasive bladder cancer to identify invasion-associated proteins. Proteome analysis was performed to compare the protein profiles of invasive and non-invasive UC in Hras128 rats. We identified 49 proteins that were either overexpressed or underexpressed in invasive UC but not in non-invasive UC. Immunohistochemical analysis of carbonic anhydrase 2 (CA2), an overexpressed protein, showed that the relative number of CA2-positive UC was significantly higher for invasive UC compared to non-invasive UC in rats. Moreover, the incidence of CA2-positive cancers was also significantly higher for human muscle-invasive bladder cancer (MIBC) compared to non-MIBC (NMIBC) and was positively associated with the progression of NMIBC. Our findings indicate that CA2 is an invasion-associated factor and suggest that it could serve as a potential therapeutic molecular target for bladder cancers.


Asunto(s)
Anhidrasa Carbónica II/metabolismo , Genes ras/genética , Invasividad Neoplásica/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias de la Vejiga Urinaria/patología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Animales Modificados Genéticamente , Carcinógenos/toxicidad , Modelos Animales de Enfermedad , Femenino , Humanos , Isotiocianatos/toxicidad , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/genética , Nitrosaminas/toxicidad , Ratas , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/inducido químicamente
7.
Cancer Sci ; 107(12): 1736-1744, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27712020

RESUMEN

Immunotherapy based on blockade of the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has shown promising clinical activity for renal cell carcinoma (RCC) patients; however, the most effective use of these agents in combination with conventional targeted therapy remains to be resolved. Here we evaluated the therapeutic efficacy of the combination of the mTOR inhibitor everolimus (EVE) and anti-PD-L1 using an immunocompetent mouse model of RCC. We first assessed the in vitro effect of EVE on PD-L1 expression in the human 786-O and mouse RENCA RCC cell lines and found that EVE upregulated PD-L1 expression in these RCC cell lines. We then treated RENCA tumor-bearing mice with EVE and found that PD-L1 expression was also increased in tumor cells after EVE treatment. To determine the antitumor effects of EVE alone, anti-PD-L1 alone, and EVE in combination with anti-PD-L1, we evaluated their antitumor effects on RENCA tumor-bearing mice. A significant decrease in the tumor burden was observed in the EVE alone but not in the anti-PD-L1 alone treatment group compared with the control group. Importantly, the combination of EVE with anti-PD-L1 significantly reduced tumor burden compared with the EVE alone treatment, increasing tumor infiltrating lymphocytes (TILs) and the ratio of cytotoxic CD8+ T cells to TILs. The results of the present study demonstrated that anti-PD-L1 treatment enhanced the antitumor effect of EVE in a mouse model, supporting a direct translation of this combination strategy to the clinic for the treatment of RCC.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Everolimus/farmacología , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Animales , Antígeno B7-H1/metabolismo , Biomarcadores , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/inmunología , Línea Celular Tumoral , Membrana Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/inmunología , Masculino , Ratones , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Cancer Sci ; 107(2): 123-32, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26663681

RESUMEN

The role of cells expressing stem cell markers deltaNp63 and CD44v has not yet been elucidated in peripheral-type lung squamous cell carcinoma (pLSCC) carcinogenesis. Female A/J mice were painted topically with N-nitroso-tris-chloroethylurea (NTCU) for induction of pLSCC, and the histopathological and molecular characteristics of NTCU-induced lung lesions were examined. Histopathologically, we found atypical bronchiolar hyperplasia, squamous metaplasia, squamous dysplasia, and pLSCCs in the treated mice. Furthermore, we identified deltaNp63(pos)CD44v(pos)CK5/6(pos)CC10(pos) clara cells as key constituents of early precancerous atypical bronchiolar hyperplasia. In addition, deltaNp63(pos)CD44v(pos) cells existed throughout the atypical bronchiolar hyperplasias, squamous metaplasias, squamous dysplasias, and pLSCCs. Overall, our findings suggest that NTCU induces pLSCC through an atypical bronchiolar hyperplasia-metaplasia-dysplasia-SCC sequence in mouse lung bronchioles. Notably, Ki67-positive deltaNp63(pos)CD44v(pos) cancer cells, cancer cells overexpressing phosphorylated epidermal growth factor receptor and signal transducer and activator of transcription 3, and tumor-associated macrophages were all present in far greater numbers in the peripheral area of the pLSCCs compared with the central area. These findings suggest that deltaNp63(pos)CD44v(pos) clara cells in mouse lung bronchioles might be the origin of the NTCU-induced pLSCCs. Our findings also suggest that tumor-associated macrophages may contribute to creating a tumor microenvironment in the peripheral area of pLSCCs that allows deltaNp63(pos)CD44v(pos) cancer cell expansion through activation of epidermal growth factor receptor signaling, and that exerts an immunosuppressive effect through activation of signal transducer and activator of transcription 3 signaling.


Asunto(s)
Carcinoma de Células Escamosas/patología , Neoplasias Pulmonares/patología , Células Madre Neoplásicas/patología , Lesiones Precancerosas/patología , Microambiente Tumoral/inmunología , Animales , Carcinógenos/toxicidad , Carcinoma de Células Escamosas/inmunología , Carmustina/análogos & derivados , Carmustina/toxicidad , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Receptores de Hialuranos/biosíntesis , Receptores de Hialuranos/inmunología , Tolerancia Inmunológica/inmunología , Inmunohistoquímica , Neoplasias Pulmonares/inmunología , Macrófagos/patología , Ratones , Fosfoproteínas/biosíntesis , Fosfoproteínas/inmunología , Transactivadores/biosíntesis , Transactivadores/inmunología , Escape del Tumor/inmunología
9.
Gan To Kagaku Ryoho ; 38(3): 485-7, 2011 Mar.
Artículo en Japonés | MEDLINE | ID: mdl-21403461

RESUMEN

A 66-year-old man was referred to our outpatient clinic for an elevated serum prostatic-specific antigen (PSA 4,319 ng/ mL). Magnetic resonance imaging (MRI) showed multiple metastatic lesions in the bones. The patient had received androgen deprivation therapy, but six months after treatment, he was diagnosed as having prostate cancer refractory to hormones. Combined treatment with docetaxel (DOC 30 mg/m²/week )and estramustine phosphate (EMP 560 mg/day) was initiated as first-line chemotherapy, but the treatment was discontinued because of side effects. Then, treatment with zoledronic acid was started(4 mg/4 weeks)and the PSA level decreased dramatically from 457.2 ng/mL to 5.5 ng/mL. Seven months after the diagnosis of CRPC, MRI showed a decrease ofbone metastases, and the PSA levels continued to decrease, eventually reaching 0.3 ng/mL. Zoledronic acid appears to not only show efficacy in preventing skeletal-related events, but has a potential antitumor effect in patients with metastatic CRPC.


Asunto(s)
Difosfonatos/uso terapéutico , Estramustina/uso terapéutico , Imidazoles/uso terapéutico , Prednisolona/uso terapéutico , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Castración , Difosfonatos/administración & dosificación , Estramustina/administración & dosificación , Resultado Fatal , Humanos , Imidazoles/administración & dosificación , Imagen por Resonancia Magnética , Masculino , Prednisolona/administración & dosificación , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Ácido Zoledrónico
10.
Osaka City Med J ; 56(2): 37-45, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21466128

RESUMEN

Small bowel obstruction caused by an internal hernia involving the sigmoid mesocolon is rare, and this condition is difficult to diagnose clinically. We herein report a case of small bowel obstruction due to an intramesosigmoid hernia that was diagnosed by a 64-row multidetector computed tomography and surgically treated.


Asunto(s)
Colon Sigmoide/diagnóstico por imagen , Hernia/complicaciones , Hernia/diagnóstico por imagen , Obstrucción Intestinal/diagnóstico por imagen , Obstrucción Intestinal/etiología , Colon Sigmoide/cirugía , Femenino , Herniorrafia , Humanos , Obstrucción Intestinal/cirugía , Persona de Mediana Edad , Tomografía Computarizada Espiral , Resultado del Tratamiento
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...