RESUMO
BACKGROUND: Relugolix is a once-daily, oral, nonpeptide, gonadotropin-releasing hormone receptor antagonist. The aim of this study was to evaluate safety of relugolix over 24 weeks in women with endometriosis-associated pain. METHODS: This phase 2, randomized, open-label, parallel-group extension study was conducted in 101 clinics in Japan. Patients (premenopausal females ≥ 20 years) who completed the preceding 12-week relugolix phase 2 study continued to receive relugolix (10 mg, 20 mg, or 40 mg), placebo, or leuprorelin (3.75 mg) for an additional 12 weeks. Relugolix was administered orally once daily, and leuprorelin subcutaneously once every 4 weeks. The primary outcome was safety, including bone mineral density (BMD) and treatment-emergent adverse events (TEAEs). Secondary endpoints included visual analog scale (VAS) scores for endometriosis-associated pain. Analysis sets were defined as all patients who were administered the study drug. RESULTS: Of 487 randomized patients in the preceding study, 397 enrolled in this extension study and continued to receive placebo (n = 77), relugolix 10 mg (n = 84), relugolix 20 mg (n = 78), relugolix 40 mg (n = 89), or leuprorelin (n = 69). Baseline characteristics were similar between extension study patients and patients in the preceding study. Frequency of TEAEs including metrorrhagia, menorrhagia, and hot flush was similar in the relugolix 40-mg and leuprorelin groups. Mean (SD) change in BMD from baseline at Week 24 was - 0.2 (1.99)% for placebo; - 1.6 (2.34)%, - 2.6 (2.94)%, and - 4.9 (2.91)% for the relugolix 10-mg, 20-mg, and 40-mg groups, respectively; and - 4.4 (2.16)% for leuprorelin. Mean ± SD change from baseline in mean VAS score (mm) for pelvic pain at end of treatment was - 3.2 ± 12.16 for placebo; - 6.8 ± 10.56, - 9.0 ± 11.84, and - 11.9 ± 11.26 for the relugolix 10-mg, 20-mg, and 40-mg groups, respectively; and - 12.7 ± 12.57 for leuprorelin. Estradiol levels decreased with increasing relugolix dose and remained below postmenopausal levels throughout the 24-week relugolix 40-mg treatment period. CONCLUSIONS: Treatment with relugolix for 24 weeks was generally well tolerated and demonstrated similar pain reduction to leuprorelin in women with endometriosis. The dose-dependent loss in BMD observed with relugolix treatment was expected due to an induced hypoestrogenic state. Relugolix demonstrated a similar benefit/risk profile to injectable therapy in this phase 2 study. Trial registration NCT01452685 (ClinicalTrials.gov, registered 17/10/2011).
Assuntos
Endometriose , Método Duplo-Cego , Endometriose/complicações , Endometriose/tratamento farmacológico , Feminino , Humanos , Japão , Leuprolida/uso terapêutico , Dor Pélvica/tratamento farmacológico , Dor Pélvica/etiologia , Compostos de Fenilureia , Pirimidinonas , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the efficacy and safety of three dose levels of relugolix, a gonadotropin-releasing hormone receptor antagonist, compared with placebo and leuprorelin in women with endometriosis-associated pain. DESIGN: Phase 2, multicenter, randomized, double-blind, placebo-controlled study. SETTING: Hospitals and clinics. PATIENT(S): Adult premenopausal women with endometriosis who had dysmenorrhea and endometriosis-associated pelvic pain. INTERVENTION(S): During a 12-week treatment period, patients received relugolix 10 mg (n = 103), 20 mg (n = 100), or 40 mg (n = 103) as a daily oral dose; placebo (n = 97) as a daily oral dose; or leuprorelin 3.75 mg (n = 80) as a monthly subcutaneous injection. MAIN OUTCOME MEASURE(S): Primary endpoint was the change from baseline in mean visual analog scale score for pelvic pain during 28 days before the end of treatment. RESULT(S): The mean changes in mean visual analog scale score for pelvic pain were -3.8 mm in the placebo group; -6.2, -8.1, and -10.4 mm in the relugolix 10-mg, 20-mg, and 40-mg groups; respectively; and -10.6 mm in the leuprorelin group. The major adverse events with relugolix were hot flush, metrorrhagia, menorrhagia, and irregular menstruation, and bone mineral density decrease in a dose-response manner, which were also observed in the leuprorelin group with a frequency comparable with that in the relugolix 40-mg group. CONCLUSION(S): Oral administration of relugolix alleviated endometriosis-associated pain in a dose-response manner and was generally well tolerated. Relugolix 40 mg demonstrated efficacy and safety comparable with those of leuprorelin. CLINICAL TRIAL REGISTRATION NUMBER: NCT01458301.
Assuntos
Antagonistas de Androgênios/administração & dosagem , Endometriose/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Dor Pélvica/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Pirimidinonas/administração & dosagem , Receptores LHRH/antagonistas & inibidores , Administração Oral , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Endometriose/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Medição da Dor/métodos , Dor Pélvica/diagnóstico , Adulto JovemRESUMO
OBJECTIVE: To investigate the clinical features of patients in Japan with malignant transformation of ovarian endometrioma. PATIENTS: Thirty-three patients diagnosed with ovarian cancer presumably arising from endometrioma were recruited retrospectively. These patients had been followed for at least 2 years after the ovarian endometrioma diagnosis, then continued to be followed after they had been found to have malignant transformation. RESULTS: The average age of the patients was 47.7 ± 9.3 years; 75.7% were premenopausal at the time of diagnosis of ovarian cancer. Among the 33 patients, ovarian cancer developed in the ipsilateral ovary of 6 patients with endometrioma after cystectomy. Twenty-eight patients were diagnosed with stage I ovarian cancer, and major histotypes were clear cell in 23 cases and endometrioid in 8. Before surgery for cancer, mural nodules within the endometriomas were detected in 32 patients, and 1 patient had a small 3-mm nodule. In 30 patients, the diameter of the tumor doubled in size 6 months prior to the diagnosis of malignant transformation. The diameter of the endometrioma and the preoperative CA125 value did not significantly correlate. CONCLUSIONS: To detect malignant transformation of ovarian endometrioma early and precisely, the clinician should determine the existence of a mural nodule and assess the rapid growth of the endometrioma.
Assuntos
Adenocarcinoma de Células Claras/patologia , Carcinoma Endometrioide/patologia , Transformação Celular Neoplásica/patologia , Endometriose/patologia , Cistos Ovarianos/patologia , Neoplasias Ovarianas/patologia , Adulto , Idoso , Antígeno Ca-125 , Endometriose/diagnóstico , Endometriose/diagnóstico por imagem , Endometriose/terapia , Feminino , Seguimentos , Humanos , Japão , Imageamento por Ressonância Magnética , Proteínas de Membrana , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Cistos Ovarianos/etiologia , Cistos Ovarianos/cirurgia , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/cirurgia , Estudos Retrospectivos , UltrassonografiaRESUMO
Endometriosis is an estrogen-dependent inflammatory disease. In endometriotic tissues, a high-estrogen environment associated with up-regulation of the aromatase gene has been well documented. There is accumulating evidence supporting a concept that endometriosis is a disease associated with an epigenetic disorder. Epigenetics is one of the most expanding fields in the current biomedical research. The word 'epigenetics' refers to the study of mitotically and/or meiotically heritable changes in gene expression that occur without changes in the DNA sequence. The disruption of such changes (epigenetic aberration or disorder) underlies a wide variety of pathologies. Epigenetic regulation includes DNA methylation and histone modifications, and is responsible for a number of gene transcription associated with chromatin modifications that distinguish the states of diseases. In this review, we summarized our studies as well as recent studies from other laboratories using an epigenetic approach focused on DNA methylation. We also summarized studies using advanced technologies including Genome-Wide (GW) methylation profiling analysis and GW Association Study (GWAS). We reviewed recent monozygotic twins studies in relation to environmental factors since they may provide insight into the epigenetic background of endometriosis. Finally, we referred to a new concept of GW DNA methylation.
Assuntos
Endometriose/genética , Epigênese Genética , Expressão Gênica , Metilação de DNA , Estrogênios/fisiologia , Feminino , Estudo de Associação Genômica Ampla , HumanosRESUMO
OBJECTIVE: The objective of this study was to determine the genes that may be associated with malignant transformation of ovarian endometrioma. METHODS: Endometriotic epithelial cells were isolated from tissues derived from chocolate cyst linings by laser capture microdissection. A Gene Chip Human Genome U133 Plus 2.0 Array was applied to evaluate levels of gene expression in 3 different groups of epithelial cells: epithelial cells of endometrioma, epithelial cells of endometrioma adjacent to clear cell carcinoma, and epithelial cells of clear cell carcinoma. As a validation assay, real-time reverse transcriptase-polymerase chain reaction and immunohistochemical analyses were performed. RESULTS: Gene expression analysis identified differential expressions among the 3 groups of epithelial cells. Using the classification of a signaling pathways database, 9 genes (12 gene probes) were selected from among 39 up-regulated genes indicating more than 2-fold higher expression between any comparisons of the 3 groups in the comprehensive microarray. Enhancement of fibroblast growth factor receptor 2 (FGFR2) gene expression was detected by microarray using 3 distinct probes. Gene and protein expression of FGFR2 differed significantly between epithelial cells of endometrioma and the epithelial component of clear cell carcinoma. CONCLUSIONS: We demonstrated that FGFR2 may play a significant role in the carcinogenesis of endometriosis and thus represents a potential therapeutic target.
Assuntos
Adenocarcinoma de Células Claras/patologia , Transformação Celular Neoplásica/patologia , Endometriose/patologia , Células Epiteliais/patologia , Neoplasias Ovarianas/patologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Endometriose/genética , Endometriose/metabolismo , Células Epiteliais/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
A new cell line of human ovarian clear cell adenocarcinoma (CCC), TU-OC-1, was established and characterized. The cells showed a polygonal-shaped morphology and grew in monolayers without contact inhibition and were arranged like a jigsaw puzzle. The chromosome numbers ranged from 64 to 90. A low rate of proliferation was observed, similar to other CCC cell lines tested (OVTOKO, RMG-I, and OVAS), and the doubling time was 38.4 h. The respective IC50 values of cisplatin and paclitaxel were 12.2 µM and 58.3 nM. Mutational analysis revealed that TU-OC-1 cells harbored a PIK3CA mutation at codon 542 (E542K) in exon 9, which is a mutation hot spot on this gene. We observed that phosphorylated Akt protein was overexpressed in TU-OC-1 cells by western blot analysis. Heterotransplantation to nude mice produced tumors that reflected the original. This cell line may be useful to study the chemoresistant mechanisms of CCC and contribute to novel treatment strategies.
Assuntos
Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patologia , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/genética , Idoso , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Transplante HeterólogoRESUMO
AIMS: We investigated the potential of gonadotropin-releasing hormone (GnRH) agonists and GnRH antagonists to inhibit cell proliferation in endometriotic and endometrial stromal cells. METHODS: Twenty patients with ovarian endometriomas and 18 patients with uterine fibromas were recruited. Endometriotic and endometrial stromal cells were obtained from the ovarian chocolate cyst linings and the eutopic endometria of premenopausal women with uterine fibromas, respectively. RESULTS: GnRH agonist or antagonist treatment attenuated tumor necrosis factor (TNF)-α-induced cell proliferation in the endometrial stromal cells, whereas endometriotic stromal cells did not respond to treatment. The endometriotic stromal cells exhibited a decreased expression of the type I GnRH receptor compared with the endometrial stromal cells. GnRH agonists or antagonists did not repress TNF-α-induced IL-8 production in endometriotic stromal cells. CONCLUSION: GnRH agonists and antagonists have similar effects in slowing the growth of endometrial stromal cells. Endometriotic stromal cells resist the antiproliferative effect of GnRH agonists and antagonists.
Assuntos
Proliferação de Células/efeitos dos fármacos , Endométrio/patologia , Hormônio Liberador de Gonadotropina/farmacologia , Células Estromais/patologia , Adulto , Western Blotting , Busserrelina/farmacologia , Endometriose/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Expressão Gênica , Hormônio Liberador de Gonadotropina/análogos & derivados , Humanos , Interleucina-8/metabolismo , Leiomioma/patologia , Doenças Ovarianas/patologia , Pré-Menopausa , Receptores LHRH/metabolismo , Células Estromais/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Neoplasias Uterinas/patologiaRESUMO
The nuclear factor kappaB (NF-kappaB) is a ubiquitously expressed transcription factor playing vital roles in innate immunity and other processes involving cellular survival, proliferation, and differentiation. This review highlights the importance of NF-kappaB in the pathophysiology of endometriosis. Constitutive activation of NF-kappaB has been shown in endometriotic lesions. Complex interactions of NF-kappaB with steroid receptors and apoptotic molecules in endometriosis resulting in opposing roles of NF-kappaB are discussed. NF-kappaB regulates the expression of cytokines mediating autocrine self-amplifying cycles of cytokine release and NF-kappaB activation, leading to maintenance of inflammatory reactions in endometriosis. NF-kappaB can contribute to the increased ability of endometriotic cells to invade and adhere to the peritoneal surface by regulating the expression of matrix metaloproteinases. We are presenting the role of NF-kappaB to regulate vascularization and oxidative stress in endometriotic cells. Effects of drugs used for the treatment of endometriosis on NF-kappaB pathway are presented and we show how drugs that inhibit the NF-kappaB can mediate the progression of endometriosis. Novel therapeutic strategies involving the NF-kappaB and applied in endometriosis are also discussed.
Assuntos
Endometriose/metabolismo , NF-kappa B/metabolismo , Animais , Endometriose/patologia , Feminino , Humanos , Transdução de SinaisRESUMO
OBJECTIVE: This study was aimed to elucidate the roles of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3'-kinase (PI3K)/Akt pathways in regulating cytotoxicity induced by cisplatin (CDDP) in ovarian carcinoma cells. METHODS: We treated 7 ovarian cancer cell lines with CDDP alone or with CDDP and either a PI3K inhibitor (LY294002), a MEK inhibitor (PD98059), or a MEK/ERK activator (phorbol 12-myristate 13-acetate [PMA]) and assessed cell viability, expression of MEK/ERK and PI3K/Akt, cell cycle distribution, and apoptosis. We also investigated the effect of combination treatment on survival in a xenograft model. RESULTS: The cell lines showed half-maximal inhibitory concentrations (IC50) of CDDP from 2.4 to 26.9 µmol/L. KFr, a CDDP-resistant cell line developed from KF cells, showed an IC50 of CDDP of 9.6 µmol/L. Five of the cell lines with IC50 values of 9.6 µmol/L or greater were defined as CDDP-resistant. Cisplatin and LY294002 had an additive effect on inhibiting cell growth, and CDDP and PD98059 had and antagonistic effect on cell growth in all cell lines. In CDDP-resistant cells, CDDP and PMA dramatically suppressed the cell growth, up-regulated the expression of phosphorylated ERK and cleaved caspase-9, down-regulated the expression of checkpoint kinases, and increased the proportion of cells in the synthesis-phase fraction and apoptotic cells. The treatment of nude mice with CDDP and PMA prolonged survival in an ovarian cancer xenograft model. CONCLUSIONS: The present study indicates that further study is warranted to determine the effectiveness of combination treatment with CDDP and PMA for platinum-resistant ovarian carcinoma.
Assuntos
Adenocarcinoma/tratamento farmacológico , Cromonas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Flavonoides/uso terapêutico , Morfolinas/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Acetato de Tetradecanoilforbol/análogos & derivados , Animais , Antineoplásicos/uso terapêutico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cromonas/farmacologia , Cisplatino/uso terapêutico , Sinergismo Farmacológico , Feminino , Flavonoides/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Nus , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Morfolinas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Fase S/efeitos dos fármacos , Acetato de Tetradecanoilforbol/farmacologia , Acetato de Tetradecanoilforbol/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A new line of human ovarian serous adenocarcinoma cells, TU-OS-4, was established and characterized. The cells showed a short, spindle-shaped morphology and grew in monolayers without contact inhibition while forming an arrangement resembling a jigsaw puzzle. Chromosome numbers ranged from 55 to 73. The proliferation rate was lower than other serous adenocarcinoma cell lines tested (KF, SHIN-3, and SK-OV-3), and the doubling time was 53.3 h. Western blot analysis showed that TU-OS-4 cells overexpressed epidermal growth factor receptor, human epidermal growth factor receptor (HER) 2, and phosphorylated HER2 protein. The IC(50) values to cisplatin, paclitaxel, and lapatinib were 25.8 µM, 686 nM, and 183 nM, respectively. Heterotransplantation in nude mice reflected the original tumor of the cells. These results suggested that this cell line would be useful to study chemoresistant mechanisms and contribute to establishing novel treatment strategies for patients with ovarian cancer.
Assuntos
Antineoplásicos/farmacologia , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Técnicas Citológicas/métodos , Receptores ErbB/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Receptor ErbB-2/metabolismo , Idoso , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lapatinib , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Quinazolinas/farmacologia , Receptor ErbB-2/genética , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: Ovarian clear cell carcinoma (CCC) carries a poor prognosis because of its insensitivity to chemotherapy. We previously found an association between reduced proliferation of CCC and chemoresistance; here we investigated the mechanism of the reduced proliferation. METHODS: We assessed cell cycle function by measuring the activity of cyclin-dependent kinases (CDKs) and the protein expression of cyclins, the CDK inhibitors, and p53 in 22 ovarian cancer cell lines and 60 human ovarian cancer specimens. We examined the cellular location of p27, p27 phosphorylated at threonine 157 (p27(Thr157)), and CDK2 protein by confocal microscopy and western blotting. We tested the effect of the inhibitor of phosphatidylinositol-3-kinase (PI3K) and small interfering RNA against p27 (si-p27) in two CCC cell lines (RMG-I, SMOV-2). RESULTS: CCC cells had lower CDK2 activity and higher p27 expression than serous adenocarcinoma (SA) cells. Low CDK2 activity correlated with high p27 protein expression. p27(Thr157) sequestered CDK2 in the cytoplasm, but PI3K inhibitor or si-p27 maintained CDK2 in the nucleus and restored its activity. In human specimens, CDK2 was mostly in the cytoplasm and was spatially associated with p27; CDK2 activity was lower in the CCC than in the SA specimens. si-p27 enhanced the cytotoxic effect of cisplatin, doxorubicin, and gemcitabine in both RMG-I cells and SMOV-2 cells. CONCLUSIONS: Reduced CDK2 activity via the cytoplasmic sequestration of CDK2 by p27(Thr157) may contribute to suppression of CCC proliferation. A prospective study is needed to determine whether the cytoplasmic sequestration of CDK2 results in the chemoresistance of CCC.
Assuntos
Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/patologia , Quinase 2 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Adenocarcinoma de Células Claras/tratamento farmacológico , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Inibidor de Quinase Dependente de Ciclina p27/deficiência , Inibidor de Quinase Dependente de Ciclina p27/genética , Citoplasma/metabolismo , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Doxorrubicina/farmacologia , Ativação Enzimática/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação , GencitabinaRESUMO
PURPOSE: The mTOR pathway is thought to be a central regulator of proliferation and survival of cells. Rapamycin and its analogs are undergoing clinical trials in patients with epithelial ovarian cancer. This study aimed to assess the potential to use rapamycin and anticancer agents in combination for first- and second-line chemotherapy to treat ovarian cancer. EXPERIMENTAL DESIGN: We used six ovarian serous adenocarcinoma cell lines (KF, KOC-2S, SHIN-3, SK-OV-3, TU-OS-3, and TU-OS-4) in this study. We treated the cells with rapamycin and anticancer agents, then assessed cell viability, apoptosis, and the expression of protein in apoptotic pathways and molecules downstream of the mTOR signaling pathways. We also investigated the effect of these drug combinations on survival in nude mouse xenograft models. RESULTS: Synergistic effects were observed in five cell lines from the combination of etoposide and rapamycin. However, we observed antagonistic effects when rapamycin was combined with gemcitabine, cisplatin, or paclitaxel on more than two cell lines. Rapamycin dramatically enhanced apoptosis induced by etoposide and the expression of cleaved caspase 9. This effect was associated with upregulation of phosphorylated c-Jun and downregulation of Bcl-xL. The synergistic interaction of rapamycin and etoposide was lower when the c-Jun pathway was suppressed by a c-Jun N-terminal kinase inhibitor (SP600125). Finally, treating nude mice with rapamycin and etoposide significantly prolonged survival in the model mice with ovarian cancer xenografts. CONCLUSIONS: Chemotherapy with rapamycin and etoposide combined is worth exploring as a treatment modality for women with epithelial ovarian cancer.
Assuntos
Antineoplásicos/farmacologia , Etoposídeo/farmacologia , Neoplasias Ovarianas/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima/efeitos dos fármacos , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Proteínas Proto-Oncogênicas c-jun/genética , Transdução de Sinais/genética , Sirolimo/farmacologia , Análise de Sobrevida , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To evaluate the efficacy and safety of low-dose oral contraceptives (IKH-01; 0.035 mg ethinyl estradiol and 1 mg norethisterone) for patients with primary dysmenorrhea. DESIGN: Placebo-controlled, double-blind, randomized trial. SETTING: Clinical trial sites in Japan. PATIENT(S): One hundred fifteen patients with primary dysmenorrhea. INTERVENTION(S): Patients randomly assigned to receive IKH-01 or placebo for four cycles. MAIN OUTCOME MEASURE(S): Total dysmenorrhea score, verbal rating scale defining pain according to limited ability to work and need for analgesics, and visual analog scale (VAS). RESULT(S): Reduction in total dysmenorrhea score and VAS before and after treatment was significantly higher in the IKH-01 group than in the placebo group. Total dysmenorrhea score and VAS in the IKH-01 group significantly decreased from cycles 2 to 5. Overall incidence of adverse events was significantly higher in the IKH-01 group. Incidence decreased over time in the IKH-01 group; it was invariable in the placebo group. No serious adverse events occurred. CONCLUSION(S): IKH-01 could be used as a single agent or in combination with analgesics for treatment of primary dysmenorrhea.
Assuntos
Anticoncepcionais Orais/administração & dosagem , Dismenorreia/tratamento farmacológico , Etinilestradiol/administração & dosagem , Noretindrona/administração & dosagem , Adulto , Algoritmos , Anticoncepcionais Orais/efeitos adversos , Anticoncepcionais Orais Combinados/administração & dosagem , Anticoncepcionais Orais Combinados/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Etinilestradiol/efeitos adversos , Feminino , Humanos , Japão , Noretindrona/efeitos adversos , Placebos , Comprimidos , Resultado do Tratamento , Adulto JovemRESUMO
Apoptosis is a distinctive form of programmed cell death resulting in the efficient elimination of cells without eliciting an inflammatory response. Endometriosis is characterized by the presence of endometrial cells with capacity to avoid apoptosis outside the uterus. Apoptosis plays a fundamental role for the pathogenesis of endometriosis. Eutopic endometrium from women with endometriosis has increased expression of anti-apoptotic factor and decreased expression of pro-apoptotic factors compared with endometrium from healthy women. These differences could contribute to the survival of regurgitating endometrial cells into the peritoneal cavity and development of endometriosis. Increased apoptosis of Fas-bearing immune cells in the peritoneal cavity may leads to their decreased scavenger activity that eventually results in prolonged survival of ectopic endometrial cells in women with endometriosis. This study is a current review of the literatures focused on the physiological role of apoptosis in normal endometrium and alterations in regulation of apoptosis in eutopic and ectopic endometrium from women with endometriosis. The role of apoptosis in the treatment of endometriosis is also reviewed.
Assuntos
Apoptose/fisiologia , Endometriose/fisiopatologia , Endométrio/metabolismo , Proteína Ligante Fas/metabolismo , Macrófagos Peritoneais/metabolismo , Mitocôndrias/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Endometriose/tratamento farmacológico , Endometriose/metabolismo , Endométrio/citologia , Endométrio/fisiologia , Feminino , Humanos , Mitocôndrias/metabolismoRESUMO
Apigenin suppressed tumor necrosis factor α-induced cell proliferation and prostaglandin E2 expression via the attenuation of nuclear factor κB pathway in endometriotic stromal cells in vitro. Apigenin reduced the mitogenic activity and inflammatory reaction in endometriotic stromal cells.
Assuntos
Apigenina/farmacologia , Dinoprostona/antagonistas & inibidores , Endométrio/citologia , Endométrio/efeitos dos fármacos , Inibidores do Crescimento/fisiologia , NF-kappa B/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Dinoprostona/biossíntese , Endométrio/metabolismo , Feminino , Humanos , NF-kappa B/fisiologia , Células Estromais/citologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVE: To search for the demethylated cytosine-phosphate-guanine (CpG) islands within the aromatase gene in stromal cells derived from endometriotic chocolate cysts. DESIGN: Prospective study. SETTING: Department of Obstetrics and Gynecology and Department of Biosignaling, Tottori University, Yonago, Japan. PATIENT(S): Twenty-eight women who underwent laparoscopy (n=14) and laparotomy (n=14). INTERVENTION(S): Endometrial and endometriotic stromal cells were obtained from the uterus and chocolate cyst lining of the ovary. MAIN OUTCOME MEASURE(S): We searched for the CpG island and examined methylation profile and the association of methyl-binding proteins with the CpG island. RESULT(S): Up-regulation of aromatase messenger RNA (mRNA) expression was demonstrated in endometriotic cells. Three proximal promoters drove the mRNA expression. In endometrial cells, a marginal level of aromatase mRNA expression was observed. Treating endometrial cells with the demethylating agent 5-aza-2'-deoxycytidine markedly enhanced aromatase mRNA expression. The same promoters as in the endometriotic cells were used. To identify the unmethylated CpGs in endometriotic cells, we searched for CpG islands within the aromatase gene and subsequently examined the methylation profiles. Sequence analysis of bisulfite-treated genomic DNA demonstrated a stretch of CpG demethylation within a nonpromoter CpG island of the aromatase gene in endometriotic cells. In endometrial cells, the CpG sequences were heavily methylated and associated with methyl-CpG-binding proteins. CONCLUSION(S): The up-regulation of the aromatase gene in endometriosis may be ascribed to the epigenetic disorder associated with aberrant DNA demethylation in a nonpromoter CpG island.
Assuntos
Aromatase/genética , Ilhas de CpG/fisiologia , Metilação de DNA/fisiologia , Endometriose/genética , Regulação Enzimológica da Expressão Gênica/fisiologia , Aromatase/metabolismo , Endometriose/metabolismo , Endometriose/patologia , Epigênese Genética/fisiologia , Feminino , Humanos , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Células Estromais/enzimologia , Células Estromais/patologia , Regulação para Cima/fisiologia , Útero/enzimologia , Útero/patologiaRESUMO
Lipopolysaccharide-enhanced cyclooxygenase 2 (COX-2) expression and prostaglandin E2 (PGE2) production were compared in endometriotic stromal cells (ESCs) and eutopic endometrial stromal cells. Lipopolysaccharide promotes the proliferation and invasion of ESCs via up-regulation of COX-2 and PGE2 expression, suggesting that pelvic inflammation may promote the progression of endometriosis.
Assuntos
Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/biossíntese , Endometriose/enzimologia , Endométrio/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Doenças Ovarianas/enzimologia , Células Estromais/efeitos dos fármacos , Estudos de Casos e Controles , Células Cultivadas , Ciclo-Oxigenase 2/genética , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Endometriose/patologia , Endométrio/enzimologia , Endométrio/patologia , Indução Enzimática , Feminino , Humanos , Nitrobenzenos/farmacologia , Doenças Ovarianas/patologia , Interferência de RNA , RNA Mensageiro/metabolismo , Células Estromais/enzimologia , Células Estromais/patologia , Sulfonamidas/farmacologia , Fatores de TempoRESUMO
The efficacy and toxicity of combination chemotherapy with docetaxel + carboplatin were evaluated in patients with locally advanced or recurrent cervical cancer. A total of 71 patients with cervical cancer were enrolled into this trial, and 66 patients were considered eligible. The patients were administered docetaxel at 60 mg/m2 followed by carboplatin based on area under the curve of 6, both by intravenous infusion, every 3 weeks, with the treatment repeated for 1 to 6 cycles depending on the goal of the therapy. The response was evaluated based on the Response Evaluation Criteria in Solid Tumors criteria. Toxicity to chemotherapy was evaluated according to the National Cancer Institute Common Toxicity Criteria. Of the 66 eligible patients, 62 had locally advanced cervical cancer with no history of previous treatment, whereas 4 patients had recurrent cervical cancer. A total 149 cycles of chemotherapy were administered, with a median of 2.3 cycles (range, 1-6) per patient. The overall clinical response rate was 63.7% (44/66, 95% confidence interval, 52.1-75.3). In the neoadjuvant chemotherapy setting, the overall clinical response rate was 69.3% (43/62; 43/62, 95% confidence interval, 57.8-80.8), and the response rates in patients with squamous cell carcinoma and nonsquamous cell carcinoma were 69.7% (23/33, 95% confidence interval, 54.0-85.4) and 68.9% (20/29, 95% confidence interval, 52.1-85.7), respectively. On the other hand, in patients with recurrent cervical cancer, the overall response rate was 25.0% (1/4, 95% confidence interval, -17.4 to 67.4). Nonhematological toxicities were mainly grade 1 or 2. Hematological toxicity was encountered mostly in the form of neutropenia and thrombocytopenia. Combination chemotherapy with docetaxel + carboplatin is a safe and well-tolerated treatment for patients with advanced cervical cancer and is effective against not only squamous cell carcinoma, but also adenocarcinoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Taxoides/administração & dosagem , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Carcinoma/patologia , Progressão da Doença , Docetaxel , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Taxoides/efeitos adversos , Resultado do Tratamento , Neoplasias do Colo do Útero/patologiaRESUMO
AIM: To investigate the safety and efficacy of 52 weeks of dienogest treatment in patients with endometriosis. METHODS: One hundred and thirty-five patients with endometriosis received 2 mg of dienogest orally each day for 52 weeks. Adverse drug reactions and bone density were evaluated. Global improvement was assessed based on the changes in severity categories of five subjective symptoms during non-menstruation (lower abdominal pain, lumbago, dyschezia, dyspareunia, and pain on vaginal examination) and two objective findings (induration involving the pouch of Douglas and limited uterine mobility). RESULTS: The most common adverse drug reactions included metrorrhagia (71.9%), headaches (18.5%), and constipation (10.4%). No clinically significant changes were noted in the incidence or severity of reactions associated with the course of the treatment period (52 weeks). Changes from the baseline bone mineral density of the lumbar spine measured by dual-energy X-ray absorptiometry were -1.6 +/- 2.4% and -1.7 +/- 2.2% (mean +/- standard deviation) at 24 and 52 weeks, respectively, which were statistically significant decreases; however, there was no cumulative decrease. The proportions of patients assessed as marked or moderate improvement in terms of global improvement were 72.5% (95/131 cases) at 24 weeks and 90.6% (106/117 cases) at 52 weeks. CONCLUSION: The long-term effect of dienogest on bone mineral density was slight, whereas the efficacy increased cumulatively.
Assuntos
Endometriose/tratamento farmacológico , Antagonistas de Hormônios/administração & dosagem , Nandrolona/análogos & derivados , Adulto , Densidade Óssea/efeitos dos fármacos , Endometriose/patologia , Feminino , Antagonistas de Hormônios/efeitos adversos , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Nandrolona/administração & dosagem , Nandrolona/efeitos adversos , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: Decreased susceptibility of endometrial tissue to apoptosis may contribute to the pathogenesis of endometriosis. We investigate the role of survivin in the pathophysiology of endometriosis through the ability of ectopic and eutopic endometrial stromal cells (ESCs) to resist apoptosis. METHODS: Ectopic ESCs were obtained from ovarian chocolate cysts in patients undergoing laparoscopic surgery (n = 22). Eutopic ESCs were isolated from endometrial tissue of cyclic premenopausal women undergoing hysterectomy for fibroids (n = 22). Purified stromal cells were studied in vitro. The number of surviving cells and activation of caspases were assessed by WST-8 assay and immunoblotting. Expression of inhibitor of apoptosis proteins (IAP) family members: cIAP1 (birc2), cIAP2 (birc3), XIAP (birc4), survivin (birc5) were examined using cDNA array and real-time RT-PCR. Effects of gene silencing by small inhibitor RNAs (siRNA) were examined by WST-8-assay, Annexin-V staining and immunoblotting. RESULTS: After staurosporine (SS) treatment, 55% of eutopic ESCs survived versus 70% of ectopic ESCs. Procaspase-3 or -7 was more intensely activated by SS treatment in eutopic than in ectopic ESCs (P < 0.01). mRNAs for IAP-family genes, such as cIAP-1, XIAP and survivin, were highly expressed in ectopic ESCs before SS treatment. The fold induction of survivin expression after SS treatment was higher in ectopic than eutopic ESCs (2.8 +/- 0.27 versus 0.69 +/- 0.07, respectively). Survivin gene silencing in SS-treated ectopic ESCs led to an increase of apoptotic cells (P < 0.05, versus control siRNA). CONCLUSIONS: We demonstrated that survivin plays a critical role in susceptibility of ESCs to apoptosis. Our results indicate that a survivin inhibitor may be effective as a novel treatment for endometriosis.