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1.
Anticancer Res ; 41(9): 4271-4276, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475046

RESUMO

BACKGROUND/AIM: The anticancer mechanism of itraconazole remains unsolved; therefore, we studied itraconazole-induced alterations in specialized pro-resolving mediators (SPMs) in cancer cells. MATERIALS AND METHODS: The human cervical squamous carcinoma cell line CaSki was cultured with or without 1 µM itraconazole. Liquid chromatography/mass spectrometry analysis was conducted to identify SPMs that were influenced by itraconazole. Cell growth experiments were conducted using itraconazole and inhibitors targeting the metabolic pathways of candidate SPMs. RESULTS: Resolvin E3, resolvin E2, prostaglandin J2 (PGJ2), delta-12-PGJ2, and maresin 2 were identified as candidate SPMs. The 12/15-lipoxygenase inhibitor, which is involved in the conversion of 18-hydroxy-eicosapentaenoic acid to resolvin E3, attenuated the inhibitory effect of itraconazole. Inhibition of the PGJ2 metabolic pathway did not interfere with itraconazole treatment. CONCLUSION: The metabolic pathway of SPMs, including resolving E3, could be proposed as an anticancer target of itraconazole.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Ácidos Graxos Insaturados/metabolismo , Itraconazol/farmacologia , Inibidores de Lipoxigenase/farmacologia , Neoplasias do Colo do Útero/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Espectrometria de Massas , Redes e Vias Metabólicas/efeitos dos fármacos , Neoplasias do Colo do Útero/tratamento farmacológico
2.
Gynecol Oncol Rep ; 32: 100563, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32300630

RESUMO

A germline pathogenic variant in BRCA2 was secondarily found through genomic sequencing of uterine serous carcinoma. Clinical response to olaparib was observed in recurrent uterine serous carcinoma with a germline BRCA2 mutation. Here, we report, for the first time, a long-term clinical response to olaparib in a patient with uterine serous carcinoma and a germline pathogenic BRCA2 variant.

3.
Anticancer Res ; 40(2): 991-997, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014944

RESUMO

AIM: To evaluate the efficacy of chemotherapy with itraconazole for advanced or recurrent gastric cancer. PATIENTS AND METHODS: Patients with human epidermal growth factor receptor 2 (HER2) negative unresectable gastric cancer referred to our hospital were included. The regimen comprised 160 mg/m2 nab-paclitaxel i.v. and 100 mg/m2 oxaliplatin i.v. on day 1, 60 mg/m2 S-1 orally on days 1-3, and 400 mg itraconazole orally on days -2 to 2, repeated every 2 weeks for 6-8 cycles. RESULTS: Twenty-three patients aged 40-80 years (median age=68 years) were enrolled, of whom 21 had stomach cancer and two gastroesophageal junction cancer. Regarding stage, two, one, and 20 patients had stage IIIA, IIIB, and IV, respectively. Among patients with liver metastases, 2/10 had simultaneous lung metastases. Nine patients had peritoneal dissemination, and five patients with stage IV disease developed recurrence after primary surgery followed by adjuvant S-1. The other 18 patients had no history of surgery or chemotherapy. The response rate was 70% (complete response in two; partial response in 14). Among 12 patients (67%) who underwent conversion surgery, R0 resection was conducted in eight, and no residual tumour was observed in two. For the population overall, the median overall survival was 24 months (95% confidence intervaI=21 months-not reached) and the 1-year overall survival rate was 95% (95% confidence intervaI=67-98%). Grade 3/4 neutropenia and grade 2 peripheral sensory neuropathy occurred in five (22%) and six (26%) patients, respectively, while no patient developed grade 3/4 thrombocytopenia. CONCLUSION: Chemotherapy with itraconazole is promising for patients with unresectable gastric cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gastrostomia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Combinação de Medicamentos , Feminino , Gastrostomia/efeitos adversos , Gastrostomia/métodos , Humanos , Itraconazol/administração & dosagem , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Oxaliplatina/administração & dosagem , Ácido Oxônico/administração & dosagem , Paclitaxel/administração & dosagem , Neoplasias Gástricas/mortalidade , Tegafur/administração & dosagem , Resultado do Tratamento
4.
Obstet Gynecol Int ; 2019: 4365754, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31263500

RESUMO

Aim: To reveal current problems and challenges faced by our gynecologic services department in managing patients with hereditary cancers. Methods: We collected clinical data of patients with hereditary cancers, identified via genetic testing (or clinically diagnosed in cases of Cowden syndrome or Peutz-Jeghers syndrome), and treated in our gynecological department from 2012 to 2018. Results: Fifteen patients had hereditary breast and ovarian cancer (HBOC), 6 had Lynch syndrome, 2 had Cowden syndrome, and 2 had Peutz-Jeghers syndrome. Five patients diagnosed with HBOC were younger than 40 years at diagnosis. Risk-reducing salpingo-oophorectomy (RRSO) was performed on 1 patient with a BRCA1 mutation at age 38 years. Seven patients overall underwent RRSO, and none had malignancies on pathological examinations. Peritoneal washing cytology (PWC) was suspicious for malignancy in one patient; however, subsequent PWC at 6 months after RRSO was negative. A patient with endometrial cancer and Lynch syndrome and a patient with atypical endometrial hyperplasia (AEH) and Cowden syndrome strongly desired fertility preservation. They achieved remission after medroxyprogesterone acetate treatment and multiple dilations and curettages, respectively. One patient with Lynch syndrome developed AEH after 11 years of surveillance. Laparotomy revealed adjacent low-grade and high-grade serous ovarian cancer with positive ascites cytology. She had no recurrence during 7-year follow-up after laparotomy. Conclusion: Managing patients with hereditary cancer, positive or false-positive ascites cytology discovered during RRSO, and desired preservation of fertility is highly challenging.

5.
J Obstet Gynaecol Res ; 45(1): 203-209, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30117238

RESUMO

AIM: To investigate the effects of leuprorelin using a self-administered quality-of-life (QOL) questionnaire in patients with recurrent gynecological cancer. METHODS: Records of patients who received 3.75 mg leuprorelin every 4 weeks for the treatment of recurrent gynecological cancer were retrospectively reviewed. The physical domain of the QOL questionnaire, Care Notebook, was used to assess physical symptoms. Symptom deterioration was defined as a ≥10-point increase in baseline score; otherwise, symptoms were defined as controlled. Radiological and serological responses were evaluated according to the 2011 Gynecological Cancer Intergroup criteria. RESULTS: From 2007 to 2015, 25 patients were administered leuprorelin for the treatment of epithelial ovarian cancer, granulosa cell tumor, endometrial cancer, endometrial stromal sarcoma and clear cell cervical cancer (in 13, 3, 6, 2 and 1 patients, respectively). Twenty patients had received a median of three lines (range 1-12 lines) of chemotherapy. Ten patients had progressive disease during their previous round of chemotherapy. Twenty patients completed the questionnaire every 4 weeks. Following leuprorelin treatment for 8 weeks, the symptom and disease control rates were 65% (13/20) and 44% (11/25), respectively. Two patients, one each with granulosa cell tumor and endometrial cancer, had stable disease at 6 months. Among the 20 patients who completed the QOL questionnaire, symptom control and disease control at 8 weeks showed a significant correlation (P = 0.016). CONCLUSION: Leuprorelin had minimal anticancer activity. The physical domain of the QOL questionnaire could be used to assess effects of hormonal treatment.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias dos Genitais Femininos/tratamento farmacológico , Leuprolida/farmacologia , Recidiva Local de Neoplasia/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/administração & dosagem , Feminino , Humanos , Leuprolida/administração & dosagem , Pessoa de Meia-Idade , Estudos Retrospectivos , Inquéritos e Questionários
6.
J Obstet Gynaecol Res ; 45(3): 671-678, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30575239

RESUMO

AIM: A multi-institutional phase II trial was conducted to determine the efficacy and toxicity of neoadjuvant chemotherapy with irinotecan and nedaplatin followed by radical hysterectomy and adjuvant chemotherapy for locally advanced, bulky stage IB2-IIB cervical cancer. METHODS: Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB2-II, bulky type (>4 cm in diameter) squamous cell carcinoma of the uterine cervix were enrolled. Irinotecan (60 mg/m2 ) was administered intravenously on days 1 and 8 and nedaplatin (80 mg/m2 ) was also administered on day 1 of every 21-day cycle. After two cycles of chemotherapy, a radical hysterectomy was performed. Until 6 weeks after the surgery, three to five cycles of the regimen were added as adjuvant chemotherapy. The primary endpoint was the 2-year relapse-free survival rate. The response rates and toxicities were evaluated as secondary endpoints. RESULTS: Thirty-two patients from seven institutions were enrolled in this study. The median age was 48 years (range 25-75 years). The average follow-up period was 37.8 months (15-71 months). Twenty-three patients completed the regimen as planned. The objective response rate (complete response + partial response) for the neoadjuvant chemotherapy regimen was 81.2%. The 2-year and 5-year relapse-free-survival rates were 87.5% and 78.8%, respectively. The incidence of grade 3/4 neutropenia was 6.3% and 34.4% during neoadjuvant and adjuvant treatment, respectively. All other toxicities were well tolerated. CONCLUSION: Our treatment showed efficacy and tolerability for patients with locally advanced, bulky stage IB2-IIB cervical cancer. This suggests that treatment has the potential to improve the prognosis compared to concurrent chemo-radiotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/terapia , Quimioterapia Adjuvante , Irinotecano/uso terapêutico , Terapia Neoadjuvante , Compostos Organoplatínicos/uso terapêutico , Inibidores da Topoisomerase I/uso terapêutico , Neoplasias do Colo do Útero/terapia , Adulto , Idoso , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/cirurgia , Feminino , Humanos , Histerectomia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Resultado do Tratamento , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/cirurgia
7.
J Cancer Res Ther ; 15(6): 1201-1206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31898647

RESUMO

Context: In platinum-resistant ovarian cancer, single-agent chemotherapy is recommended for the reduction of adverse events. However, in clinical practice, some patients can tolerate drug-specific adverse events. Aims: We assessed the safety of pegylated liposomal doxorubicin (PEG-LD) and docetaxel regimen in the first cycle of ovarian cancer. Settings and Design: We performed a phase I study to evaluate the combination therapy of PEG-LD and docetaxel. Materials and Methods: We recruited five patients with recurrent ovarian cancer within 12 months of first-line platinum-based chemotherapy. All patients had measurable disease severity. PEG-LD and docetaxel were intravenously administered on day 1 and every 21 days using three dose levels: 25 mg/m2 PEG-LD and 50 mg/m2 docetaxel; 30 mg/m2 PEG-LD and 50 mg/m2 docetaxel; and 30 mg/m2 PEG-LD and 60 mg/m2 docetaxel. Statistical Analysis Used: We defined the maximum tolerated dose of the combination therapy based on the modified Fibonacci method. Results: Five patients were enrolled in this study. The median treatment-free interval was 5.5 months. Two dose-limiting toxicities (Grade 4 neutropenia) were observed in two patients. One complete response, one partial response, one stable disease, and two progressive disease cases were observed. The overall response rate was 2/5, and the disease control rate was 3/5. The median overall survival was 7.4 months. Conclusions: We determined that 25 mg/m2 of PEG-LD and 50 mg/m2 of docetaxel were safe and effective doses. This preliminary efficacy and safety data should be further investigated in a Phase II trial.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Epitelial do Ovário/diagnóstico , Carcinoma Epitelial do Ovário/mortalidade , Docetaxel/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/mortalidade , Platina/farmacologia , Platina/uso terapêutico , Polietilenoglicóis/administração & dosagem , Retratamento , Resultado do Tratamento
8.
BMC Cancer ; 18(1): 630, 2018 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-29866134

RESUMO

BACKGROUND: Primary malignant melanoma of the vagina is extremely rare, with a poorer prognosis than cutaneous malignant melanoma. Previous studies have explored the repurposing of itraconazole, a common oral anti-fungal agent, for the treatment of various cancers. Here, we describe a patient with metastatic, unresectable vaginal malignant melanoma treated with 200 mg oral itraconazole twice a day in a clinical window-of-opportunity trial. CASE PRESENTATION: A 64-year-old Japanese woman with vaginal and inguinal tumours was referred to our institution. On the basis of an initial diagnosis of vaginal cancer metastatic to the inguinal lymph nodes, we treated her with itraconazole in a clinical trial until the biopsy and imaging study results were obtained. During this period, biopsies were performed three times, and 18F-fluoro-deoxyglucose positron emission tomography (FDG/PET)-computed tomography (CT) was performed twice. Biopsy results confirmed the diagnosis of primary malignant melanoma of the vagina. Imaging studies revealed metastases to multiple sites, including the brain, for which she underwent gamma-knife radiosurgery. During the window period before nivolumab initiation, the patient received itraconazole for 30 days. Within a week of itraconazole initiation, pain in the inguinal nodes was ameliorated. PET-CT on days 6 and 30 showed a reduction in tumour size and FDG uptake, respectively. The biopsied specimens obtained on days 1, 13, and 30 were subjected to cDNA microarray analysis, which revealed a 100-fold downregulation in the transcription of four genes: STATH, EEF1A2, TTR, and CDH2. After 12 weeks of nivolumab administration, she developed progressive disease and grade 3 immune-related hepatitis. Discontinuation of nivolumab resulted in the occurrence of left pelvic and inguinal pain. Following re-challenge with itraconazole, the patient has not reported any pain for 4 months. CONCLUSION: The findings of this case suggest that itraconazole is a potential effective treatment option for primary malignant melanoma of the vagina. Moreover, we identified potential itraconazole target genes, which could help elucidate the mechanism underlying this disease and potentially aid in the development of new therapeutic agents.


Assuntos
Antineoplásicos/uso terapêutico , Itraconazol/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Vaginais/tratamento farmacológico , DNA Complementar/análise , Feminino , Humanos , Melanoma/diagnóstico por imagem , Melanoma/genética , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/genética , Análise Serial de Tecidos , Neoplasias Vaginais/diagnóstico por imagem , Neoplasias Vaginais/genética
9.
Gynecol Oncol Rep ; 24: 54-56, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29915800

RESUMO

Ovarian Sertoli cell tumors (SCTs) are rare sex cord tumors (Oliva et al., 2005). The standard treatment for high-grade SCTs is surgery followed by platinum-based chemotherapy. Although platinum-based chemotherapy is also an option for recurrent SCTs (Sigismondi et al., 2012), there is no established chemotherapy regimen for platinum-resistant recurrent SCTs. The effectiveness of pazopanib in treating epithelial ovarian cancer has recently been reported (du Bois et al., 2014; Pignata et al., 2015). In the case described herein, pazopanib was used to treat the platinum-resistant recurrence of a high-grade Sertoli cell tumor, and the response was evaluated by 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET)-computed tomography (CT). Written informed consent to reporting the case was obtained from the patient.

10.
Gynecol Oncol Rep ; 24: 57-60, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29682600

RESUMO

Standard chemotherapy for women with advanced or recurrent cervical cancer involves a combination of paclitaxel, platinum, and bevacizumab. However, for patients who experience anaphylaxis in response to paclitaxel or platinum, have permanent peripheral neuropathy, or develop early recurrence or progressive disease during first-line chemotherapy, the development of a non-taxane non-platinum regimen is mandatory. Clinical trials using anti-angiogenic treatment demonstrated favorable outcomes in cases of highly vascularized cervical cancer. Metronomic chemotherapy has been considered an anti-angiogenic treatment, although its use in combination with bevacizumab has not been studied in cervical cancer. We treated four patients with recurrent cervical cancer with 50 mg of oral cyclophosphamide daily and 15 mg/kg of intravenous bevacizumab every 3 weeks (CFA-BEV). One patient experienced disease progression after 4 months, whereas the other three patients continued the regimen until their last follow-up at 13, 14, and 15 months, respectively. One patient suffered from grade 3 neutropenia; however, no grade 2 or higher non-hematological toxicities were observed. These cases demonstrate the use of CFA-BEV with minimal toxicity and expected anti-cancer activity and indicate that this regimen should be considered for second-line chemotherapy in advanced recurrent cervical cancer.

11.
Cancer Sci ; 109(5): 1602-1608, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29575254

RESUMO

The purpose of this phase II trial was to assess the efficacy and toxicity of paclitaxel and nedaplatin (TN) as the initial postoperative adjuvant chemotherapy for uterine cervical cancer with lymph node metastases (LNM). Patients with FIGO stage IB1-IIA2 squamous cell carcinoma of the uterine cervix were enrolled. Histological confirmation of LNM was mandatory. Intravenous paclitaxel at 175 mg/m2 and nedaplatin at 80 mg/m2 were administered every 28-day cycle, of which there were 5 cycles after radical hysterectomy. Sixty-two patients were enrolled in the study from November 2011 to July 2015. Their median age was 48.5 years (range 28-64). The median tumor diameter was 37 mm (5-64). Overall, 30 patients (48.4%) had 1 metastatic lymph node, 11 (17.7%) had 2, 3 (4.8%) had 3, 5 (8.1%) had 4, and 13 (21.0%) had 5 or more. With a median follow-up of 45.7 months (range 23.4-69.5), the 2-year relapse-free survival and 2-year overall survival rates were 79.0% (90% CI, 69.0%-86.2%) and 93.5% (95% CI, 83.7%-97.5%), respectively. Almost all adverse events were relatively mild. Grade 3-4 adverse events (NCI-CTC ver. 4.0) that occurred in 5% or more of patients were neutropenia (60.7%) and infection (6.6%). The proportion of patients who completed 5 cycles of treatment was 90.3%. Postoperative adjuvant chemotherapy with TN for cervical cancer with LNM was demonstrated to be an effective and feasible treatment. A phase III trial is warranted to compare this with concurrent chemoradiotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Compostos Organoplatínicos/administração & dosagem , Paclitaxel/administração & dosagem , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Quimiorradioterapia , Quimioterapia Adjuvante , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia
12.
J Cancer Res Ther ; 13(3): 446-450, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28862207

RESUMO

OBJECTIVES: We conducted a retrospective multi-institutional study to evaluate the efficacy and toxicity of intraperitoneal or intrapleural triamcinolone acetonide (TA), a slowly metabolized corticosteroid administration for the management of malignant ascites or pleural effusion. MATERIALS AND METHODS: The medical records of patients with gynecologic cancer who were treated with paracentesis or thoracocentesis followed by administration of 400 mg of TA between 2005 and 2014 were reviewed. RESULTS: The median age of the 74 eligible patients was 59 years. An Eastern Cooperative Oncology Group performance status 3-4 was present in 53 patients (73%), and 52 patients (70%) had ovarian cancer. Paracentesis followed by TA administration was performed in 65 patients (88%), and 37 patients (50%) were treated in a palliative setting. Chemotherapy or surgery after TA administration was performed in 37 patients (50%) in an aggressive setting, of which 14 patients (19%) were treated at the primary phase and 23 patients (31%) were treated at recurrent phase. The time interval of serial drainage was prolonged in 15 of 19 assessable patients, resulting in a response rate of 79% (95% confidence interval [95% CI]: 54-94%). Median overall survival after TA therapy in a palliative setting was 36 days (95% CI: 19-58 days). After TA therapy in a palliative setting, one patient complained of mild abdominal pain, two patients with advanced peritonitis carcinomatosis experienced bowel perforation, and three patients died within 7 days owing to disease progression. CONCLUSIONS: Intraperitoneal and intrapleural TA administration were feasible and effective in symptomatic control of ascites and pleural effusion.


Assuntos
Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Triancinolona Acetonida/administração & dosagem , Adulto , Idoso , Ascite/complicações , Ascite/tratamento farmacológico , Ascite/patologia , Feminino , Neoplasias dos Genitais Femininos/complicações , Neoplasias dos Genitais Femininos/patologia , Humanos , Infusões Parenterais , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Neoplasias Peritoneais/complicações , Neoplasias Peritoneais/patologia , Derrame Pleural Maligno/tratamento farmacológico , Derrame Pleural Maligno/patologia
13.
Oncol Lett ; 14(2): 1240-1246, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28789339

RESUMO

Itraconazole, a common anti-fungal agent, has demonstrated potential anticancer activity, including reversing chemoresistance mediated by P-glycoprotein, modulating the signal transduction pathways of Hedgehog, mechanistic target of rapamycin and Wnt/ß-catenin in cancer cells, inhibiting angiogenesis and lymphangiogenesis, and possibly interfering with cancer-stromal cell interactions. Clinical trials have suggested the clinical benefits of itraconazole monotherapy for prostate cancer and basal cell carcinoma, as well as the survival advantage of combination chemotherapy for relapsed non-small cell lung, ovarian, triple negative breast, pancreatic and biliary tract cancer. As drug repurposing is cost-effective and timesaving, a review was conducted of preclinical and clinical data focusing on the anticancer activity of itraconazole, and discusses the future directions for repurposing itraconazole as an anticancer agent.

14.
Anticancer Res ; 37(7): 3521-3526, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28668841

RESUMO

BACKGROUND/AIM: Repurposing itraconazole as an anticancer agent has been evaluated in several studies. The present study investigated whether itraconazole exerts an anticancer effect on cervical cancer cells. MATERIALS AND METHODS: CaSki and HeLa cells were cultured in itraconazole and vehicle after which colony-forming and cell viability assays were performed. Transcription and protein expression were assessed by cDNA microarray analysis and immunoblotting, respectively. RESULTS: Itraconazole suppressed proliferation of CaSki and HeLa cells in a dose- and time-dependent manner. Furthermore, CaSki cells were more significantly affected by itraconazole than HeLa cells. The microarray analysis showed an 8-fold down-regulation in the expression of GLI1, WNT4 and WNT10A among itraconazole-treated CaSki cells. Moreover, the transcription of sterol carrier protein-2 and ATP-binding cassette transporter-1 was unaffected by itraconazole. Immunoblots showed suppression in ß-catenin expression and Akt phosphorylation. CONCLUSION: Itraconazole is a multi-targeting anticancer agent and a promising therapeutic agent for cervical cancer.


Assuntos
Proliferação de Células/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Itraconazol/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/metabolismo , Proteína Wnt4/metabolismo , Proteína GLI1 em Dedos de Zinco/metabolismo
15.
World J Surg Oncol ; 15(1): 132, 2017 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-28716033

RESUMO

BACKGROUND: This study aimed to evaluate the current status of secondary debulking surgery (SDS) and tertiary debulking surgery (TDS; performed for recurrence after SDS) and to assess the overall survival after recurrence of Müllerian epithelial cancer in Japan. We also evaluated the data of patients who underwent a fourth debulking surgery (i.e., quaternary debulking surgery (QDS)). METHODS: We conducted a retrospective study of 164 patients with recurrent Müllerian epithelial cancers (i.e., ovarian, tubal, and peritoneal cancers). The SDS was performed between January 2000 and September 2014 in 20 Japanese hospitals. Clinicopathological data were collected and analyzed. RESULTS: Of the 164 patients, 66 patients did not have a recurrence or died after SDS. Ninety-eight patients had a recurrence after SDS. Forty-three of the 98 patients underwent TDS; 55 of the 98 patients did not undergo TDS and were classified into the non-TDS group. The overall survival (OS) after SDS was significantly better in the TDS group than in the non-TDS group. The median OS after SDS was 123 and 42 months in the TDS group and non-TDS group, respectively. Of the 43 patients who received TDS, 11 patients were further treated with QDS. The median OS after SDS was 123 months for patients who underwent QDS. CONCLUSIONS: This multicenter study on the prognosis of post-SDS is apparently the first report on QDS in Japan. Patients undergoing TDS have a good prognosis, compared to patients in the non-TDS group. Novel drugs are being evaluated; however, debulking surgery remains a necessary treatment for recurrence.


Assuntos
Procedimentos Cirúrgicos de Citorredução/métodos , Neoplasias das Tubas Uterinas/cirurgia , Recidiva Local de Neoplasia/cirurgia , Neoplasias Ovarianas/cirurgia , Neoplasias Peritoneais/cirurgia , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/cirurgia , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/cirurgia , Adulto , Idoso , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/cirurgia , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Neoplasias das Tubas Uterinas/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
16.
Anticancer Res ; 37(2): 515-519, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28179296

RESUMO

BACKGROUND: Itraconazole is a common antifungal agent that has demonstrated anticancer activity in preclinical and clinical studies. This study investigated whether itraconazole exerts this effect in endometrial cancer (EC) cells. MATERIALS AND METHODS: Cell viability was evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and gene and protein expression were assessed by microarray analysis and immunoblotting, respectively, in five EC cell lines. RESULTS: Itraconazole-suppressed proliferation of AN3-CA, HEC-1A and Ishikawa cells (p<0.05) but not of HEC-50B or SNG-II cells. Itraconazole did not suppress GLI1 or GLI2 transcription but did inhibit the expression of mammalian target of rapamycin (mTOR) signaling components in AN3-CA and HEC-1A cells, while inducing that of microtubule-associated protein 1A/1B-light chain 3-II, a marker of autophagy. ATP-binding cassette transporter A1 gene was down-regulated in Ishikawa, HEC-50B and SNG-II cells. CONCLUSION: Itraconazole treatment suppresses the growth of EC cells by inhibiting AKT/mTOR signalling.


Assuntos
Neoplasias do Endométrio/tratamento farmacológico , Itraconazol/farmacologia , Proteína Oncogênica v-akt/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Proteína Oncogênica v-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
17.
Gynecol Oncol Rep ; 17: 60-4, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27617285

RESUMO

A 48-year-old woman underwent a total abdominal hysterectomy after preoperative diagnosis of multiple uterine leiomyomas. The histopathological diagnosis was leiomyosarcoma (LMS). After 47 months, multiple lung metastases were detected and resected. The patient was also diagnosed with pelvic bone metastasis and received six cycles of adjuvant chemotherapy with gemcitabine plus docetaxel and local radiation therapy to control the pain. Seventy-seven months from the initial diagnosis, she had a headache and developed left hemiparesis and aphasia. Imaging studies detected a solitary brain metastasis in the right frontal lobe. The patient underwent a craniotomy and resection of the lesion, which was a confirmed metastasis from uterine LMS by histopathology. One month after the craniotomy, the patient experienced lower abdominal pain, and a pelvic metastasis was detected. She was prescribed oral pazopanib (800 mg per day). For twelve months, she remained asymptomatic, but gradually, pelvic pain increased due to pelvic mass growth. After 14 months of pazopanib treatment, pazopanib was discontinued. To date, for 18 months after the brain surgery, she is alive with disease, and the brain metastasis has not recurred.

18.
Gynecol Oncol Rep ; 16: 11-3, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27331128

RESUMO

•An ovarian clear cell carcinoma patient showed malignant pericardial and pleural effusion.•She subsequently experienced pulmonary embolism due to cancer progression.•Pericardial and pleural effusion were successfully treated using bevacizumab.

19.
Eur J Obstet Gynecol Reprod Biol ; 203: 72-7, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27267869

RESUMO

OBJECTIVE: To investigate the localization and function of gremlin-2 during human ovarian folliculogenesis. STUDY DESIGN: Ovarian tissue from a gynecologic cancer patient was cultured in the presence or absence of gremlin-2 and then analyzed histologically. Growing follicles were counted by the microscopic observations of ovarian histological sections. Immunocytochemical staining was carried out to detect the expression of bone morphogenetic protein (BMP) 4 and phosphorylated Smad 1/5/8 (p-Smad 1/5/8). RESULTS: Gremlin-2 was detected in human primordial, primary, and early growing follicles before culture. By day 4 of culture, the follicle growth rate in the presence of gremlin-2 (13.7%; 24/175) was significantly lower than that of the control (54.8%; 92/175; p<0.01). BMP4 expression was similar in the presence and absence of gremlin-2, whereas the p-Smad 1/5/8 signal was noticeably stronger in the absence of gremlin-2 in primordial and early-stage growing follicles. CONCLUSIONS: Gremlin-2 maintains the follicle store as primordial follicles by suppressing Smad 1/5/8 signaling in the human ovary. The data presented here provide potential insight into reproductive medicine for cases of intractable infertility, such as premature ovarian insufficiency and cancer survivors.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Folículo Ovariano/efeitos dos fármacos , Ovário/efeitos dos fármacos , Proteína Morfogenética Óssea 4/metabolismo , Citocinas , Feminino , Humanos , Folículo Ovariano/crescimento & desenvolvimento , Folículo Ovariano/metabolismo , Ovário/crescimento & desenvolvimento , Ovário/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Smad/metabolismo
20.
J Obstet Gynaecol Res ; 42(6): 701-6, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26935489

RESUMO

AIM: The early and precise diagnosis and proper palliative treatment of bone metastasis is important for improving the quality of life of cervical cancer patients. The aim of this study was to clarify the clinical features, treatment modalities and prognosis of bone metastasis in cervical cancer patients in Japan. METHODS: The medical records of 75 cervical cancer patients with bone metastasis who were treated between January 2000 and December 2010 were retrospectively analyzed in a multi-institutional study. RESULTS: Fifty-four patients (72.0%) had a single bone metastasis. Bone metastases were found in the spine (46.7%) and pelvis (42.7%). Forty-three patients (57.3%) also had extra-osseous metastases. Most of the patients received radiotherapy, chemotherapy or both, but 25 patients (33.3%) received palliative care only. Bisphosphonates were given as palliative therapy to 25 patients (33.3%). The median overall survival after the diagnosis of bone metastasis was significantly shorter in patients with extra-osseous metastases than in those without extra-osseous metastases (14 vs 5 months; P < 0.05). The survival of patients who received chemotherapy following radiotherapy or concurrent chemoradiotherapy was significantly longer than that of the patients who received palliative care. On multivariate analysis, the presence of extra-osseous metastasis was an independent predictor of survival in patients with bone metastasis from cervical cancer. CONCLUSIONS: Multidisciplinary treatment might improve the prognosis of patients with bone metastasis who do not have extra-osseous lesions.


Assuntos
Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/secundário , Neoplasias Ósseas/terapia , Neoplasias do Colo do Útero/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia , Tratamento Farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Cuidados Paliativos , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
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