RESUMO
Epithelial Ovarian Cancer (EOC) cells expression of a novel carbohydrate antigen was defined using a human VH4-34 encoded IgM monoclonal antibody (mAb216). MAb216 binds to a poly N-acetyllactosamine epitope expressed on B cells and kills normal and malignant B cells in vitro and in vivo. EOC patient ascites and EOC cell lines were used to study the anti tumor effect of mAb216. Various assays were used to characterize the epitope and demonstrate antibody-mediated binding and cytotoxicity in EOC. Drug and antibody combination effects were determined by calculating the combination index values using the Chou and Talalay method. MAb216 displays direct antibody mediated cytotoxicity on a population of human EOC tumor and ascites samples and EOC cell lines, which express high amounts of poly N-acetyllactosamine epitope, carried by CD147/CD98. Eighty four percent of patient samples, including platin resistant, had a tumor population that bound the monoclonal antibody. The binding pattern of mAb216 and mechanism of cytotoxicity was similar to that seen on normal and malignant B cells with unique general membrane disruption and "pore" formation. In vitro incubation with mAb216 and cisplatin enhanced killing of OVCAR3 cell line. In EOC cell lines percent cytotoxicity correlated with percent expression of epitope. Although in vitro data shows specific EOC cytotoxicity, for possible treatment of EOC MAb216 would need to be evaluated in a clinical trial with or without chemotherapy.
Assuntos
Anticorpos Monoclonais/imunologia , Antígenos de Neoplasias/imunologia , Imunoglobulina M/imunologia , Neoplasias Epiteliais e Glandulares/imunologia , Neoplasias Ovarianas/imunologia , Amino Açúcares/imunologia , Ascite/imunologia , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Feminino , Humanos , Microscopia Eletrônica de VarreduraRESUMO
OBJECTIVE: Aberrantly activated FOXM1 (forkhead box protein M1) leading to uncontrolled cell proliferation and dysregulation of FOXM1 transcription network occurs in 84% of ovarian cancer cases. It was demonstrated that thiostrepton, a thiazole antibiotic, decreases FOXM1 expression. We aimed to determine if targeting the FOXM1 pathway with thiostrepton could improve the efficacy of paclitaxel and cisplatin in human ovarian cancer ascites cells ex vivo. METHODS: Human ovarian cancer cell lines and patients' ascites cells were treated with paclitaxel, cisplatin, and thiostrepton or a combination for 48 hours, and cytotoxicity was assessed. Drug combination effects were determined by calculating the combination index values using the Chou and Talalay method. Quantitative reverse transcriptase-polymerase chain reaction was performed to determine changes in FOXM1 expression and its downstream targets. RESULTS: Ovarian cancer cell lines and the patients' ascites cancer cells had an overexpression of FOXM1 expression levels. Targeting FOXM1 with thiostrepton decreased FOXM1 mRNA expression and its downstream targets such as CCNB1 and CDC25B, leading to cell death in both cell lines and patients' ascites cancer cells. Furthermore, addition of thiostrepton to paclitaxel and cisplatin showed synergistic effects in chemoresistant ovarian cancer patients' ascites cells ex vivo. CONCLUSION: Targeting FOXM1 may lead to novel therapeutics for chemoresistant epithelial ovarian cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Proteína Forkhead Box M1/antagonistas & inibidores , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/farmacologia , Tioestreptona/farmacologia , Ascite/tratamento farmacológico , Ascite/patologia , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Proteína Forkhead Box M1/metabolismo , Humanos , Terapia de Alvo Molecular , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Tioestreptona/administração & dosagemRESUMO
High-grade epithelial ovarian carcinomas containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and PARP inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pretreatment and postprogression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase II study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed ovarian carcinoma. In 6 of 12 pretreatment biopsies, a truncation mutation in BRCA1, RAD51C, or RAD51D was identified. In five of six paired postprogression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51CIn vitro complementation assays and a patient-derived xenograft, as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations.Significance: Analyses of primary and secondary mutations in RAD51C and RAD51D provide evidence for these primary mutations in conferring PARPi sensitivity and secondary mutations as a mechanism of acquired PARPi resistance. PARPi resistance due to secondary mutations underpins the need for early delivery of PARPi therapy and for combination strategies. Cancer Discov; 7(9); 984-98. ©2017 AACR.See related commentary by Domchek, p. 937See related article by Quigley et al., p. 999See related article by Goodall et al., p. 1006This article is highlighted in the In This Issue feature, p. 920.
Assuntos
Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Indóis/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Animais , Células CHO , Linhagem Celular Tumoral , Cricetulus , Feminino , Células HEK293 , Humanos , Mutação , Neoplasias Ovarianas/genéticaRESUMO
OBJECTIVE: Aberrantly activated FOXM1 (forkhead box protein M1) leading to uncontrolled cell proliferation and dysregulation of FOXM1 transcription network occurs in 84% of ovarian cancer cases. It was demonstrated that thiostrepton, a thiazole antibiotic, decreases FOXM1 expression. We aimed to determine if targeting the FOXM1 pathway with thiostrepton could improve the efficacy of paclitaxel and cisplatin in human ovarian cancer ascites cells ex vivo. METHODS: Human ovarian cancer cell lines and patients' ascites cells were treated with paclitaxel, cisplatin, and thiostrepton or a combination for 48 hours, and cytotoxicity was assessed. Drug combination effects were determined by calculating the combination index values using the Chou and Talalay method. Quantitative real-time polymerase chain reaction was performed to determine changes in FOXM1 expression and its downstream targets. RESULTS: Ovarian cancer cell lines and the patients' ascites cancer cells had an overexpression of FOXM1 expression levels. Targeting FOXM1 with thiostrepton decreased FOXM1 mRNA expression and its downstream targets such as CCNB1, CDC25B, leading to cell death in both cell lines and patients' ascites cancer cells. Furthermore, addition of thiostrepton to paclitaxel and cisplatin showed synergistic effects in chemoresistant ovarian cancer patients' ascites cells ex vivo. CONCLUSION: Targeting FOXM1 may lead to novel therapeutics for chemoresistant epithelial ovarian cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteína Forkhead Box M1/antagonistas & inibidores , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Ascite/tratamento farmacológico , Ascite/metabolismo , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Proteína Forkhead Box M1/biossíntese , Proteína Forkhead Box M1/genética , Humanos , Terapia de Alvo Molecular , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/metabolismo , Platina/administração & dosagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tioestreptona/administração & dosagemRESUMO
B cell binding and cytotoxicity by human VH4-34-encoded Abs of the IgM isotype has been well documented. A VH4-34-IgM has recently shown a favorable early response in a phase 1 trial for treatment of B cell acute lymphoblastic leukemia. Although its B cell ligand has been identified as straight chain poly-N-acetyl-lactosamine (SC-PNAL), the carrier of the sugar moiety has not been identified. Using nanoelectrospray ionization mass spectrometry, we identify the metabolic activation related protein complex of CD147-CD98 as a major carrier of poly-N-acetyl-lactosamine (SC-PNAL) on human pre-B cell line Nalm-6. Previous studies have suggested CD45 as the SC-PNAL carrier for VH4-34-encoded IgG Abs. Because Nalm-6 is CD45 negative, human peripheral blood B lymphocytes and human B cell line, Reh, with high CD45 expression, were examined for SC-PNAL carrier proteins. Western blot analysis shows that the CD147-98 complex is indeed immunoprecipitated by VH4-34-encoded IgMs from human peripheral blood B lymphocytes and human B cell lines, Reh, OCI-Ly8, and Nalm-6. However, CD45 is immunoprecipitated only from peripheral B lymphocytes, but not from Reh despite the high expression of CD45. These results suggest that human B cells retain SC-PNAL on the CD147-98 complex, but modulate the sugar moiety on CD45. Because the carbohydrate moiety may act as a selecting Ag for VH4-34 autoantibody repertoire, its differential expression on proteins may provide a clue to the intricate atypical regulation of the VH4-34 gene.
Assuntos
Linfócitos B/imunologia , Basigina/imunologia , Proteína-1 Reguladora de Fusão/imunologia , Imunoglobulina M/imunologia , Polissacarídeos/imunologia , Anticorpos Monoclonais/imunologia , Autoanticorpos/imunologia , Linhagem Celular , Regulação da Expressão Gênica/imunologia , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Imunoprecipitação , Antígenos Comuns de Leucócito/metabolismo , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
OBJECTIVE: The objective of this study was to build a model to differentiate between borderline and invasive ovarian tumors. MATERIALS AND METHODS: We performed a retrospective study involving 148 patients with borderline or invasive ovarian tumors in our institute between 1997 and 2012. Clinical and pathologic data were collected. Logistic regression was used to build the model. RESULTS: The model was created based on the following variables (p < 0.05): menopausal status; preoperative serum level of cancer antigen 125; the greatest diameter of the tumor; and the presence of solid parts on ultrasound imaging. The sensitivity and specificity of the model were 94.6% [95% confidence interval (CI), 0.887-1] and 78.3% (95% CI, 0.614-0.952) for patients aged ≥ 50 years, and 76.0% (95% CI, 0.622-0.903) and 60.0% (95% CI, 0.438-0.762) for those aged < 50 years, respectively. The performance of the model was tested using cross-validation. CONCLUSION: Differentiation between borderline and invasive ovarian tumors can be achieved using a model based on the following criteria: menopausal status; cancer antigen 125 level; and ultrasound parameters. The model is helpful to oncologists and patients in the initial evaluation phase of ovarian tumors.
Assuntos
Biomarcadores Tumorais/sangue , Antígeno Ca-125/sangue , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/patologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Diagnóstico Diferencial , Endossonografia/métodos , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/diagnóstico , Curva ROC , Estudos Retrospectivos , Medição de Risco , Sensibilidade e Especificidade , Taiwan , Carga Tumoral/fisiologia , Adulto JovemRESUMO
OBJECTIVE: Using TCGA database, we had demonstrated that aberrantly activated Forkhead box M1 (FOXM1) correlates to worse overall survival in a subgroup of platinum resistant patients. Application of thiostrepton, a natural thiazole antibiotics that inhibits FOXM1 transcription activity in the clinic is hampered by difficulties in synthesis, degradation potential, and solubility. In this study, we aim to identify potential FOXM1 small molecule inhibitors to develop a new class of therapeutic agents to address the challenges in treating chemotherapy resistant EOC. METHODS: We used in silico screening of compounds against a solved structure of FOXM1 and subsequently to derive a list of possible compounds that could inhibit FOXM1. Three compounds were tested for in vitro cytotoxicity and FOXM1 expression level was confirmed by RT-PCR and Western blot in EOC cell lines. RESULTS: The FOXM1 structure obtained from 3G73 represented the DNA binding region of FOXM1 and possessed the winged helix fold representative of the Forkhead family of enzymes with two wings in direct contact with DNA. For ease of representation, we described both wings as a dimer and a single wing as a monomer. From this structure, we hypothesized two main models of how thiostrepton binding to FOXM1 could possibly curtail its transcriptional activity. In the first model thiostrepton could bind either of the wings or both wings and prevent association to DNA. In the second model thiostrepton bind the FOXM1/DNA complex and weaken association of FOXM1 to DNA. Subsequently, small molecular inhibitors could also use either of the models to inhibit transcription. To account for both models, the NCI diversity set was screened against the FOXM1 dimer:DNA complex (39 hits), dimer (11 hits) and monomer (14 hits). Those hits were further classified by chemical structure, biological function and chemical similarities to known molecules that target FOXM1. In cellular cytotoxicity assays, N-phenylphenanthren-9-amine (related to hit #225) successfully showed cytotoxicity to all three cell lines with IC50 around 1µM, and downregulate FOXM1 and transcription of its downstream molecules such as CCNB1. CONCLUSION: By a combination of in silico screening coupled to cellular cytotoxicity studies, we have taken the first step towards identifying potential inhibitors of FOXM1 that can replace thiostrepton.
Assuntos
Fatores de Transcrição Forkhead/metabolismo , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/metabolismo , Carcinoma Epitelial do Ovário , Simulação por Computador , Feminino , Proteína Forkhead Box M1 , Fatores de Transcrição Forkhead/antagonistas & inibidores , Humanos , Ligação ProteicaRESUMO
VH4-34 gene encoded autoantibodies are elevated in systemic lupus erythematosus (SLE) and in other diseases associated with B-cell hyperproliferation/dysfunction. One of the autoantigens recognized by VH4-34-encoded antibodies are branched/linear poly N-acetyl lactosamine chains. Since the anti-carbohydrate response in humans is dominated by the IgG2 subclass, here we tested whether VH4-34 encoded IgG showed similar subclass segregation. Serum samples from SLE, infectious mononucleosis, nasopharyngeal carcinoma and hepatitis-C were analyzed. Levels of VH4-34-encoded IgM and IgA isotypes were also tested. VH4-34-IgM and IgA were elevated in all four clinical conditions. VH4-34-IgG was detected in the IgG1 and IgG3 subclass but not in the IgG2 and IgG4 subclass. Interestingly, VH4-34-IgG3 was also detected in serum samples of normal healthy adults. These observations are discussed in context of the VH4-34 gene regulation. VH4-34 repertoire development is of interest since it is the only human VH gene profoundly overrepresented in the naïve repertoire but counter-selected for antibody secretion. VH4-34 B-cell could thus become a unique tool to inspect germinal center independent/dependent pathways of subclass and isotype-specific antibody secretion.
Assuntos
Autoanticorpos/genética , Autoanticorpos/imunologia , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Autoanticorpos/sangue , Linfócitos B/imunologia , Linfócitos B/metabolismo , Epitopos/imunologia , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/genética , Imunoglobulina A/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/genética , Imunoglobulina M/imunologia , Imunofenotipagem , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Masculino , FenótipoRESUMO
OBJECTIVE: Although omentectomy is part of the staging and treatment of epithelial ovarian cancer (EOC), its performance in a patient with a grossly normal omentumacknowledging its role in debulking gross tumor depositshas never been definitively shown to improve survival. METHODS/MATERIALS: Using Surveillance, Epidemiology, and End Results data from 1998 to 2010, we identified patients with EOC and assessed their age, race, year of diagnosis, tumor grade, histologic subtype, International Federation of Gynecology and Obstetrics stage, lymph node dissection, nodal findings, and performance of omentectomy. We compared disease-specific survival (DSS) based on the presence or absence of omentectomy using log-rank univariate analysis, Cox multivariate analysis, and Kaplan-Meier survival curves. RESULTS: A total of 20,975 patients with invasive EOC underwent surgical treatment. Initial univariate analysis indicated a lower mean DSS with performance of omentectomy. However, multivariate analysis demonstrated no significant association between DSS and performance of omentectomy (hazard ratio, 0.978; P = 0.506). The DSS was improved if lymphadenectomy was performed (hazard ratio, 0.60; P < 0.001). In recent years, there was a trend toward decreased performance of omentectomy.To look specifically at patients without bulky omental disease, a subset analysis was done looking at patients with stage I-IIIA disease who had had lymphadenectomy performed. There were 5454 patients in the group who underwent an omentectomy and 2404 patients in the group who did not. No difference in DSS was seen between the groups based on performance of omentectomy (P = 0.89). However, the analysis was limited by the lack of Surveillance, Epidemiology, and End Results data on the extent of omentectomy, amount of residual disease, and adjuvant chemotherapy. CONCLUSIONS: In this analysis, performance of omentectomy in patients with EOC without bulky disease (≤stage IIIA) did not seem to confer improvement in survival. A randomized control trial would be needed to fully address this question.
Assuntos
Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma Mucinoso/mortalidade , Cistadenocarcinoma Seroso/mortalidade , Neoplasias do Endométrio/mortalidade , Omento/cirurgia , Neoplasias Ovarianas/mortalidade , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/cirurgia , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/cirurgia , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Prognóstico , Programa de SEER , Taxa de Sobrevida , Adulto JovemRESUMO
Racial, ethnic and economic disparities in cancer rates, outcomes, and clinical trials participation persist despite significant research. We examined barriers to clinical trials enrollment among Chinese patients, and developed a navigation program for Chinese gynecologic and breast cancer patients. Six bilingual navigators were trained and a navigator assigned to each patient for at least 2 months. All patients received a clinical trials booklet in Chinese and English. Data collection included pre-and post-navigation surveys, intake forms, and documentation of navigation encounters. Between July 2010 and May 31, 2011, we recruited 28 breast and gynecologic cancer patients. Patients averaged 317 min of navigation (range 63-1,852) during 8 sessions (range 3-28). They improved in 4 of 10 true-false knowledge statements about clinical trials. A patient navigation program for Chinese-speaking cancer patients is feasible. It results in high patient satisfaction rates and modest improvements in clinical trials knowledge and participation.
Assuntos
Asiático , Neoplasias da Mama/terapia , Ensaios Clínicos como Assunto , Neoplasias dos Genitais Femininos/terapia , Conhecimentos, Atitudes e Prática em Saúde , Navegação de Pacientes , Adulto , Idoso , Idoso de 80 Anos ou mais , China/etnologia , Feminino , Humanos , Pessoa de Meia-Idade , Satisfação do Paciente , Projetos Piloto , Estados UnidosRESUMO
Multidrug resistance (MDR) is a major cause of chemotherapy failure in the clinic. Drugs that were once effective against naïve disease subsequently prove ineffective against recurrent disease, which often exhibits an MDR phenotype. MDR can be attributed to many factors; often dominating among these is the ability of a cell to suppress or block drug entry through upregulation of membrane-bound drug efflux pumps. Efflux pumps exhibit polyspecificity, recognizing and exporting many different types of drugs, especially those whose lipophilic nature contributes to residence in the membrane. We have developed a general strategy to overcome efflux-based resistance. This strategy involves conjugating a known drug that succumbs to efflux-mediated resistance to a cell-penetrating molecular transporter, specifically, the cell-penetrating peptide (CPP), d-octaarginine. The resultant conjugates are discrete single entities (not particle mixtures) and highly water-soluble. They rapidly enter cells, are not substrates for efflux pumps, and release the free drug only after cellular entry at a rate controlled by linker design and favored by target cell chemistry. This general strategy can be applied to many classes of drugs and allows for an exceptionally rapid advance to clinical testing, especially of drugs that succumb to resistance. The efficacy of this strategy has been successfully demonstrated with Taxol in cellular and animal models of resistant cancer and with ex vivo samples from patients with ovarian cancer. Next generation efforts in this area will involve the extension of this strategy to other chemotherapeutics and other MDR-susceptible diseases.
Assuntos
Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Guanidina/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Animais , Transporte Biológico , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Oligopeptídeos/química , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/administração & dosagem , Peptídeos/química , Transporte Proteico , Interferência de RNA , Solubilidade , Água/químicaRESUMO
A major challenge of successful chemotherapy in ovarian cancer is overcoming intrinsic or acquired multi-drug resistance caused by active drug efflux mediated by ATP-binding cassette (ABC) transporters. Regulation of these transporters in ovarian cancer is poorly understood. We have found that abnormal expression of the hedgehog (Hh) signaling pathway transcription factor Gli1 is involved in the regulation of ABC transporters ABCB1 and ABCG2 in ovarian cancer. Hh is a known regulator of cancer cell proliferation and differentiation in several other types of invasive and metastatic malignancies. Our work has demonstrated that Gli1 is abnormally activated in a portion of ovarian cancers. Inhibition of Gli1 expression decreases ABCB1 and ABCG2 gene expression levels and enhances the response of ovarian cancer cells to certain chemotherapeutic drugs. The underlying mechanism is a direct association of Gli1 with a specific consensus sequence located in the promoter region of ABCB1 and ABCG2 genes. This study provides new understanding of ABC gene regulation by Hh signaling pathway, which may lead to the identification of new markers to detect and to anticipate ovarian cancer chemotherapy drug sensitivity.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Proteínas Hedgehog/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Apoptose/efeitos dos fármacos , Western Blotting , Carcinoma Epitelial do Ovário , Proliferação de Células/efeitos dos fármacos , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Proteínas Hedgehog/genética , Humanos , Técnicas Imunoenzimáticas , Luciferases/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
OBJECTIVE: This article reviews the literature concerning the function of the omentum and how omentectomy came to be part of the staging and treatment of epithelial ovarian cancer. METHODS: A review of the English language literature based on a MEDLINE (PubMed) database search using the key words: ovary, cancer, carcinoma, omentum, and omentectomy. An additional collection of reports was found by systematically reviewing all references from retrieved papers. RESULTS: Descriptions of the omentum can be found as far back as the time of the ancient Egyptians. An immunologic role of the omentum was confirmed in 1980s when "milky spots" were described. Omentectomy arrived as part of the ovarian cancer guidelines in the 1960s after observing that the omentum was a frequent site of metastasis and that patients with removal of all diseased tissue did better. The exact role of the omentum in immunology and cancer remains incompletely understood. CONCLUSIONS: Historically, occult omental metastases in otherwise early disease have led to the inclusion of omentectomy for the purpose of accurate staging and for a possible therapeutic benefit. Laboratory studies on the role in cancer of the omental fat and milky spots are controversial.
Assuntos
Neoplasias Epiteliais e Glandulares/cirurgia , Omento/fisiologia , Omento/cirurgia , Neoplasias Ovarianas/cirurgia , Animais , Carcinoma Epitelial do Ovário , Modelos Animais de Doenças , Feminino , Humanos , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/patologia , Omento/patologia , Neoplasias Ovarianas/patologiaRESUMO
OBJECTIVE: This article reviews the literature concerning the role of omentectomy in the staging and treatment of clinically apparent early stage epithelial ovarian cancer. METHODS: A review of the English language literature based on a MEDLINE (PubMed) database search using the keywords: ovary, cancer, carcinoma, omentum, and omentectomy. An additional collection of reports was found by systematically reviewing all references from retrieved papers. RESULTS: Historically, the realization that ovarian cancer cells have a predisposition to metastasize to the omentum has led to the inclusion of omentectomy, both for the purpose of accurate staging of ovarian cancer and for its possible therapeutic benefit. In apparently early stage epithelial ovarian cancer, microscopic disease in the omentum is found in 0-22% of the cases; however extra-ovarian disease isolated to the omentum is found in 2-7% of cases at most. There are no specific guidelines as to how much of the omentum should be removed, but pathology studies show that for the purpose of staging and detecting microscopic disease, omental biopsies are probably sufficient in a grossly normal appearing omentum. In cases where adjuvant chemotherapy is planned, the role of omentectomy appears to be primarily for staging, while its therapeutic role remains unclear in microscopic omental disease. CONCLUSIONS: In apparent early stage ovarian cancer, the presence of isolated omental metastases is relatively rare. For staging purposes in such cases, random omental biopsies rather than total omentectomy may suffice. Furthermore, chemotherapy appears to effectively treat microscopic disease and therefore if this is already planned the benefit of omentectomy is unclear.
Assuntos
Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Epiteliais e Glandulares/cirurgia , Omento/patologia , Omento/cirurgia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Animais , Biópsia , Carcinoma Epitelial do Ovário , Feminino , Humanos , Estadiamento de NeoplasiasRESUMO
OBJECTIVE: Multidrug resistance is the major cause of failure of many chemotherapeutic agents. While resistance can arise from several factors, it is often dominated by drug efflux mediated by P-glycoprotein (P-gp), a membrane-bound polysubstrate export pump expressed at high levels in resistant cells. While co-administration of pump inhibitors and a drug could suppress efflux, this two-drug strategy has not yet advanced to therapy. We recently demonstrated that the reversible attachment of a guanidinium-rich molecular transporter, polyarginine, to a drug provides a conjugate that overcomes efflux-based resistance in cells and animals. This study is to determine whether this strategy for overcoming resistance is effective against human disease. METHODS: Tumor samples from ovarian cancer patients, both malignant ascites cells and dissociated solid tumor cells, were exposed to Taxol-oligoarginine conjugates designed to release free drug only after cell entry. Cell viability was determined via propidium-iodide uptake by flow cytometry. To analyze bystander effect, toxicity of the drug conjugates was also tested on peripheral blood leucocytes. RESULTS: Human ovarian carcinoma specimens resistant to Taxol in vitro demonstrated increased sensitivity to killing by all Taxol-transporter conjugates tested. These studies also show that the drug conjugates were not significantly more toxic to normal human peripheral blood leukocytes than Taxol. CONCLUSIONS: These studies with human tumor indicate that oligoarginine conjugates of known drugs can be used to overcome the efflux-based resistance to the drug, providing a strategy that could improve the treatment outcomes of patients with efflux-based drug-resistance.
Assuntos
Arginina/análogos & derivados , Oligopeptídeos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Arginina/farmacocinética , Arginina/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Pessoa de Meia-Idade , Oligopeptídeos/farmacocinética , Neoplasias Ovarianas/metabolismo , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologiaRESUMO
CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.
Assuntos
Antígenos de Diferenciação/metabolismo , Antígeno CD47/imunologia , Neoplasias/imunologia , RNA Mensageiro/genética , Receptores Imunológicos/metabolismo , Anticorpos/imunologia , Antígeno CD47/genética , Divisão Celular/imunologia , Citometria de Fluxo , Humanos , Neoplasias/patologia , Neoplasias/terapia , Fagocitose/imunologia , Prognóstico , Análise de SobrevidaAssuntos
Condiloma Acuminado/diagnóstico , Proteínas de Homeodomínio/biossíntese , Linfangioma/diagnóstico , Glicoproteínas de Membrana/biossíntese , Proteínas Supressoras de Tumor/biossíntese , Neoplasias Vulvares/diagnóstico , Adulto , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/terapia , Diagnóstico Diferencial , Feminino , Humanos , Histerectomia , Linfangioma/complicações , Linfangioma/metabolismo , Segunda Neoplasia Primária/patologia , Papillomaviridae , Infecções por Papillomavirus/diagnóstico , Radioterapia , Neoplasias do Colo do Útero/complicações , Neoplasias do Colo do Útero/terapia , Neoplasias Vulvares/complicações , Neoplasias Vulvares/metabolismoRESUMO
The constitutive proliferation and resistance to differentiation and apoptosis of neoplastic cervical cells depend on sustained expression of human papillomavirus oncogenes. Inhibition of these oncogenes is a goal for the prevention of progression of HPV-induced neoplasias to cervical cancer. SiHa cervical cancer cells were transfected with an HPV-16 promoter reporter construct and treated with leukemia inhibitory factor (LIF), a human cytokine of the interleukin 6 superfamily. SiHa and CaSki cervical cancer cells were also assessed for proliferation by MTT precipitation, programmed cell death by flow cytometry, and HPV E6 and E7 expression by real-time PCR. LIF-treated cervical cancer cells showed significantly reduced HPV LCR activation, reduced levels of E6 and E7 mRNA, and reduced proliferation. We report the novel use of LIF to inhibit viral oncogene expression in cervical cancer cells, with concomitant reduction in proliferation suggesting re-engagement of cell-cycle regulation.
Assuntos
Papillomavirus Humano 16/genética , Fator Inibidor de Leucemia/farmacologia , Oncogenes , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/virologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Viral , Regulação para Baixo/efeitos dos fármacos , Feminino , Papillomavirus Humano 16/metabolismo , Humanos , Luciferases/genética , Luciferases/metabolismo , Fosforilação , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/metabolismo , Transcrição Gênica/efeitos dos fármacos , Transfecção , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologiaRESUMO
OBJECTIVE: Ovarian cancer has very heterogeneous histological classification, and response to therapy of the same grade and type varies. We studied genes in the Wnt and hedgehog (Hh) pathways, which are essential for embryonic development and which play critical roles in proliferation in a variety of human cancers. Variations in these pathway genes causing proliferation could play a role in the variation in tumor progression and response to therapy. METHODS/MATERIALS: Using real-time polymerase chain reaction, we studied 16 primary grade 3 International Federation of Gynecology and Obstetrics stage III serous ovarian cancer samples for expression of the Wnt pathway gene AXIN2, fibroblast growth factor 9, and Hh pathway gene expressions of glioma-associated oncogene 1, glioma-associated oncogene 2, patched homolog 1, patched homolog 2, Indian Hedgehog (HH), sonic HH, and Smoothened, a G protein-coupled receptor protein. Normal ovary epithelial cell line was used as control. RESULTS: We found wide variation of up-regulation of pathway component and target genes in the primary tumor samples and apparent cross talk between the pathways. AXIN2, a Wnt target gene, showed increased expression in all serous ovarian cancer samples. Fibroblast growth factor 9 was also overexpressed in all tumors with greater than 1000-fold increase in gene expression in 4 tumors. Expression of Hh pathway genes varied greatly. More than half of the tumor samples showed involvement of Hh signaling or pathway activation either by expression of transcription factors and Hh ligands or by overexpression of Indian HH/sonic HH and the receptor-encoding patched homolog 1/patched homolog 2. CONCLUSION: We found a wide variation in fold expression of genes involved in the Wnt and Hh pathway between patient samples.
Assuntos
Adenocarcinoma Papilar/genética , Proteínas Hedgehog/genética , Neoplasias Ovarianas/genética , Via de Sinalização Wnt/genética , Adenocarcinoma Papilar/patologia , Proteína Axina/genética , Feminino , Fator 9 de Crescimento de Fibroblastos/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/metabolismo , Humanos , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Reação em Cadeia da PolimeraseRESUMO
OBJECTIVE: Squamous cell carcinoma (SCC) is the most common type of malignant transformation in mature cystic teratoma (MCT) of the ovary. The SCC is difficult to preoperatively diagnose. We conducted a retrospective study to seek the possible risk/prognostic factors and treatments for SCC arising from MCT of the ovary. METHODS: Using an institutional database, we identified 3 women treated for SCC arising from an MCT of the ovary at the Kaohsiung Veteran General Hospital. A retrospective chart review was conducted, with information obtained from radiographs, operative reports, pathology reports, and radiation oncology records. RESULTS: A total of 1551 cases of MCT were diagnosed at Kaohsiung Veteran General Hospital from 1990 to 2009, of which, malignant teratoma SCC type was noted in 3 cases (0.19%). The median age of the subjects was 39 years. Abdominal fullness was the most common symptom (3/3 cases). The mean diameter of the ovarian tumor was 17.3 cm, ranging from 16 to 18 cm. All 3 patients received simple right salpingo-oophorectomy or debulking surgery. Two of the patients reached stage IIIC and died. CONCLUSIONS: : With our review as basis, we recommend being cautious of the following risk factors: patient age, tumor size, ultrasound characteristics, sonar tumor vessel wave form, computed tomography, and levels of SCC and CA125 tumor markers. We suggest that patients have regular ovarian ultrasound examination. Based on our literature review, stage IA patients who undergo standardized operational procedures do well without adjuvant treatment, but such patients must be confirmed accurately with complete surgical staging to be in stage IA before undergoing conservative management. The optimal approach to the management of patients with advanced stage and recurrent disease is unclear. Surgical cytoreduction with proper staging, adjuvant therapy with platinum-based or paclitaxel-based chemotherapy, and concurrent whole pelvic radiation have been recommended as possible methods of treatment.