RESUMO
BACKGROUND: Approximately 50% of melanomas harbor activating (V600) mutations in the serine-threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600-mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial. METHODS: We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600-mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point. RESULTS: A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients. CONCLUSIONS: Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600-mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00949702.).
Assuntos
Indóis/uso terapêutico , Melanoma/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/uso terapêutico , Adulto , Idoso , Progressão da Doença , Feminino , Humanos , Indóis/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Melanoma/genética , Melanoma/secundário , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Sulfonamidas/efeitos adversos , Resultado do Tratamento , VemurafenibRESUMO
BACKGROUND: Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors. METHODS: We performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed. RESULTS: Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L-mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)-pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L-mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or a promoter of carcinogenesis but accelerated growth of the lesions harboring HRAS mutations, and this growth was blocked by concomitant treatment with a MEK inhibitor. CONCLUSIONS: Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous-cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib. The molecular mechanism is consistent with the paradoxical activation of MAPK signaling and leads to accelerated growth of these lesions. (Funded by Hoffmann-La Roche and others; ClinicalTrials.gov numbers, NCT00405587, NCT00949702, NCT01001299, and NCT01006980.).
Assuntos
Carcinoma de Células Escamosas/genética , Genes ras , Indóis/uso terapêutico , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/genética , Sulfonamidas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Indóis/administração & dosagem , Masculino , Camundongos , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Sulfonamidas/administração & dosagem , VemurafenibRESUMO
BACKGROUND: Vemurafenib has been approved for the treatment of patients with advanced BRAF(V600E)-mutant melanoma. This report by the Vemurafenib Dermatology Working Group presents the characteristics of dermatologic adverse events (AEs) that occur in vemurafenib-treated patients, including cutaneous squamous cell carcinoma (cuSCC). METHODS: Dermatologic AEs were assessed from three ongoing trials of BRAF(V600E) mutation-positive advanced melanoma. Histologic central review and genetic characterization were completed for a subset of cuSCC lesions. RESULTS: A total of 520 patients received vemurafenib. The most commonly reported AEs were dermatologic AEs, occurring in 92%-95% of patients. Rash was the most common AE (64%-75% of patients), and the most common types were rash not otherwise specified, erythema, maculopapular rash, and folliculitis. Rash development did not appear to correlate with tumor response. Photosensitivity occurred in 35%-63% of patients, and palmar-plantar erythrodysesthesia (PPE) occurred in 8%-10% of patients. The severity of rash, photosensitivity, and PPE were mainly grade 1 or 2. In all, 19%-26% of patients developed cuSCC, mostly keratoacanthomas (KAs). The majority of patients with cuSCC continued therapy without dose reduction after resection. Genetic analysis of 29 cuSCC/KA samples demonstrated HRAS mutations in 41%. CONCLUSIONS: Dermatologic AEs associated with vemurafenib treatment in patients with melanoma were generally manageable with supportive care measures. Dose interruptions and/or reductions were required in <10% of patients.
Assuntos
Indóis/efeitos adversos , Indóis/uso terapêutico , Melanoma/tratamento farmacológico , Segunda Neoplasia Primária/induzido quimicamente , Dermatopatias/induzido quimicamente , Neoplasias Cutâneas/tratamento farmacológico , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Segunda Neoplasia Primária/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Vemurafenib , Adulto JovemRESUMO
Dyskeratosis congenita (DC) is an inherited disorder that is characterized by the triad of skin pigmentation, nail dystrophy, and mucosal leukoplakia. Individuals with DC suffer from premature mortality because of bone marrow failure, pulmonary disease, or malignant transformation within the areas of mucosal leukoplakia, caused by telomerase dysfunction. We present a case of a 31-year-old Japanese man with DC who developed laryngeal cancer (supraglottic T4aN0M0). To avoid the serious risks of accelerating the DC-associated complications by DNA-damaging therapies, he was treated with a total laryngectomy plus right modified neck dissection (levels IB, IIA, III, and IV). A contralateral nodal metastasis appeared 4 months after initial surgery and was salvaged by a left radical neck dissection. Our strategy to spare DNA-damaging therapies has proven effective so far. This is the first reported case of laryngeal cancer in a patient with DC in the English-language medical literature.
Assuntos
Carcinoma/etiologia , Disceratose Congênita/complicações , Neoplasias Laríngeas/etiologia , Adulto , Carcinoma/secundário , Carcinoma/cirurgia , Disceratose Congênita/genética , Endoscopia , Humanos , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/cirurgia , Laringectomia , Metástase Linfática , Masculino , Esvaziamento Cervical , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Reoperação , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an antiâprogrammed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer. PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review. RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events. CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Reparo de Erro de Pareamento de DNA , Instabilidade de Microssatélites , Neoplasias/tratamento farmacológico , Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Adulto JovemRESUMO
The anti-cancer properties of the green tea-derived mixture Polyphenon E (Poly E) have been demonstrated in a variety of cell culture and animal models. We recently discovered that the H460 lung cancer cell line is markedly resistant to the growth inhibitory effects of Poly E compared with SW480 colon and Flo-1 esophageal cancer cells. We investigated the mechanism of H460 resistance by comparing gene expression profiles of Poly E-sensitive and -resistant cells. Unsupervised hierarchical clustering revealed that Poly E-sensitive cells clustered separately from Poly E-resistant cells, and 6,242 genes were differentially expressed between the two groups at the 0.01 level of significance. We discovered that BCL2 gene and protein expression were significantly higher in H460 cells compared with SW480 and Flo-1 cells (10.60-fold higher gene expression; P < 0.0001). Inhibition of BCL2 expression and activity, using siRNA and the small molecule inhibitor HA14-1 respectively, restored sensitivity to Poly E and induced BCL2-related apoptosis by decreasing mitochondrial membrane potential and inducing PARP cleavage. Our results suggest that increased BCL2 expression may contribute to H460 resistance to the growth inhibitory effects of Poly E. If validated in additional laboratory and clinical models, BCL2 could ultimately be used as a marker of Poly E resistance.
Assuntos
Catequina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes bcl-2/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Apoptose/efeitos dos fármacos , Western Blotting , Catequina/farmacologia , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Potenciais da Membrana/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , RNA Interferente Pequeno , Chá/químicaRESUMO
PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors. METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points. RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports. CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/genética , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Mutação , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Tomada de Decisão Clínica , Feminino , Predisposição Genética para Doença , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/mortalidade , Ensaios Clínicos Controlados não Aleatórios como Assunto , Seleção de Pacientes , Fenótipo , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Fatores de Risco , Linfócitos T/imunologia , Fatores de Tempo , Transcriptoma , Adulto JovemRESUMO
We recently found that the inhibitory effect of (-)-epigallocatechin gallate (EGCG) on epidermal growth factor (EGF) binding to the epidermal growth factor receptor (EGFR) is associated with alterations in lipid organization in the plasma membrane of colon cancer cells. Since changes in lipid organizations are thought to play a role in the trafficking of several membrane proteins, in this study we examined the effects of EGCG on cellular localization of the EGFR in SW480 cells. Treatment of the cells for 30 min with as little as 1 microg/ml of EGCG caused a decrease in cell surface-associated EGFRs and this was associated with internalization of EGFRs into endosomal vesicles. Similar effects were seen with a green fluorescent protein (GFP)-EGFR fusion protein. As expected, the EGFR protein was phosphorylated at tyrosine residues, ubiquitinated and partially degraded when the cells were treated with EGF, but treatment with EGCG caused none of these effects. The loss of EGFRs from the cell surface induced by treating the cells with EGF for 30 min persisted for at least 2 h. However, the loss of EGFRs from the cell surface induced by temporary exposure to EGCG was partially restored within 1-2 h. These studies provide the first evidence that EGCG can induce internalization of EGFRs into endosomes, which can recycle back to the cell surface. This sequestrating of inactivated EGFRs into endosomes may explain, at least in part, the ability of EGCG to inhibit activation of the EGFR and thereby exert anticancer effects.
Assuntos
Anticarcinógenos/farmacologia , Catequina/análogos & derivados , Neoplasias do Colo/prevenção & controle , Receptores ErbB/efeitos dos fármacos , Catequina/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Endossomos/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/análise , Receptores ErbB/metabolismo , Humanos , Fosforilação , Ubiquitina/metabolismoRESUMO
Genetic association studies can be used to identify factors that may contribute to disparities in disease evident across different racial and ethnic populations. However, such studies may not account for potential confounding if study populations are genetically heterogeneous. Racial and ethnic classifications have been used as proxies for genetic relatedness. We investigated genetic admixture and developed a questionnaire to explore variables used in constructing racial identity in two cohorts: 50 African Americans and 40 Nigerians. Genetic ancestry was determined by genotyping 107 ancestry informative markers. Ancestry estimates calculated with maximum likelihood estimation were compared with population stratification detected with principal components analysis. Ancestry was approximately 95% west African, 4% European, and 1% Native American in the Nigerian cohort and 83% west African, 15% European, and 2% Native American in the African American cohort. Therefore, self-identification as African American agreed well with inferred west African ancestry. However, the cohorts differed significantly in mean percentage west African and European ancestries (P < 0.0001) and in the variance for individual ancestry (P < or = 0.01). Among African Americans, no set of questionnaire items effectively estimated degree of west African ancestry, and self-report of a high degree of African ancestry in a three-generation family tree did not accurately predict degree of African ancestry. Our findings suggest that self-reported race and ancestry can predict ancestral clusters but do not reveal the extent of admixture. Genetic classifications of ancestry may provide a more objective and accurate method of defining homogenous populations for the investigation of specific population-disease associations.
Assuntos
Negro ou Afro-Americano/genética , Adulto , África , Distribuição de Qui-Quadrado , Feminino , Marcadores Genéticos , Genótipo , Humanos , Modelos Logísticos , Masculino , Inquéritos e Questionários , Estados UnidosRESUMO
We report an extremely rare case (sixth reported case) of primary Hodgkin's lymphoma (HL) (mixed cellularity type) of the parotid gland. A 14-year-old man was referred to our hospital for evaluation of a parotid mass. Although the initial aspiration cytology was highly suggestive of HL, the confirmatory diagnosis obtained by open biopsy was non-specific lymphadenitis. Consequently, the patient was observed without any additional treatment. Because the mass continued to increase in size, we performed a total parotidectomy which led to the diagnosis of mixed cellularity HL. This case suggests that the specimen taken during open biopsy may have been too small (about 1 cm3) to detect the presence of Reed-Sternberg giant cells, which is essential for the diagnosis of HL. Therefore, although primary HL of the parotid gland is extremely rare, adequate tissue sampling of a clinically suspicious parotid mass will be required for the diagnosis of HL.
Assuntos
Doença de Hodgkin/diagnóstico , Neoplasias Parotídeas/diagnóstico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia por Agulha Fina , Quimioterapia Adjuvante , Diagnóstico Diferencial , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Doença de Hodgkin/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Estadiamento de Neoplasias , Glândula Parótida/patologia , Glândula Parótida/cirurgia , Neoplasias Parotídeas/tratamento farmacológico , Neoplasias Parotídeas/patologia , Neoplasias Parotídeas/cirurgia , Radioterapia Adjuvante , Tomografia Computadorizada por Raios XRESUMO
In previous studies, we found that sulindac sulfide and exisulind (sulindac sulfone, Aptosyn) cause growth inhibition, arrest cells in the G1 phase of the cell cycle, and induce apoptosis in human breast cancer cell lines. These effects were associated with decreased expression of cyclin D1. The present study focuses on the effects of sulindac sulfide and exisulind on hormone signaling components in breast cancer cells. We found that estrogen receptor (ER)-positive and progesterone receptor (PR)-positive T47D breast cancer cells were somewhat more sensitive to growth inhibition by sulindac sulfide or exisulind than ER-negative PR-negative MB-MDA-468 breast cancer cells. Further studies indicated that sulindac sulfide and exisulind caused marked down-regulation of expression of the ER and PR-A and PR-B in T47D cells. However, neither compound caused a major change in expression of the retinoic acid receptor alpha (RARalpha), RARbeta, or RARalpha in T47D cells. Sulindac sulfide and exisulind also caused a decrease in expression of the ER in estrogen-responsive MCF-7 breast cancer cells. Both compounds also markedly inhibited estrogen-stimulated activation of an estrogen-responsive promoter in transient transfection reporter assays. Treatment of T47D cells with specific protein kinase G (PKG) activators did not cause a decrease in ER or PR expression. Therefore, although sulindac sulfide and exisulind can cause activation of PKG, the inhibitory effects of these two compounds on ER and PR expression does not seem to be mediated by PKG. Our findings suggest that the growth inhibition by sulindac sulfide and exisulind in ER-positive and PR-positive human breast cancer cells may be mediated, in part, by inhibition of ER and PR signaling. Thus, these and related compounds may provide a novel approach to the prevention and treatment of human breast cancers, especially those that are ER positive.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Receptores de Estrogênio/antagonistas & inibidores , Receptores de Progesterona/antagonistas & inibidores , Sulindaco/análogos & derivados , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Genes Reporter , Humanos , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , RNA Mensageiro/metabolismo , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Receptores X de Retinoides/genética , Receptores X de Retinoides/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Relação Estrutura-Atividade , Sulindaco/farmacologia , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/genética , TransfecçãoRESUMO
BACKGROUND: African-American women develop more aggressive breast cancers and at an earlier age compared with Caucasian women. MATERIALS AND METHODS: We compared gene expression profiles of breast cancer cell lines that were developed from African-American and Caucasian patients to identify biological differences in breast cancers that develop in these groups. Real-time PCR was used to evaluate mRNA expression in cell lines and in a series of breast cancer cases. Gene microarray signal intensities were also analyzed in the International Genomics Consortium Expression Project for Oncology (expO) dataset. RESULTS: 17,-Hydroxysteroid dehydrogenase type 2 (17HSD 2) gene and mRNA expression were significantly higher in the African-American cell lines (p<0.05). However, 17HSD 2 expression did not differ significantly between the two cohorts in either our clinical series or the expO dataset. 17HSD 2 expression was found to be predictive of younger age at diagnosis and estrogen receptor status. CONCLUSION: Overexpression of 17HSD 2 in African-American breast cancer may contribute to the increased proportion of estrogen receptor-negative breast cancers and worse clinical outcome among African-American patients.
Assuntos
17-Hidroxiesteroide Desidrogenases/metabolismo , Negro ou Afro-Americano , Neoplasias da Mama/enzimologia , Receptores de Estrogênio/metabolismo , 17-Hidroxiesteroide Desidrogenases/biossíntese , 17-Hidroxiesteroide Desidrogenases/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Estradiol Desidrogenases , Feminino , Humanos , Invasividade Neoplásica , FenótipoRESUMO
Increased expression of COX-2 appears to play an important role in the development of colorectal cancer. The level of COX-2 expression is regulated by various factors including activation of members of the EGFR family of RTKs. We previously reported that in HT29 human colon cancer cells EGCG, the major biologically active component of green tea, inhibits activation of two members of this family, EGFR and HER2, and multiple downstream signaling pathways. In this study we examined the effects of EGCG on the HER3 RTK and on COX-2 expression in the SW837 human colon cancer cell line that expresses a high level and constitutive activation of HER3 and also expresses a high level of COX-2. Treatment of these cells with 20 microg/ml of EGCG (the IC50 concentration for growth inhibition) caused, within 6 hours, a decrease in the phosphorylated (i.e. activated) forms of not only EGFR and HER2, but also HER3. At 6 to 12 hours there was a decrease in the phosphorylated forms of the downstream signaling proteins ERK and Akt. Within 6 to 12 hours there was a decrease in cellular levels of both COX-2 protein and mRNA, and within 48 hours the cells displayed apoptosis. Reporter assays indicated that EGCG inhibited the transcriptional activities of the COX-2, AP-1, and NF-kappaB promoters. EGCG also caused a decrease in production of PGE2, a major product of COX-2. With a longer incubation time, 96 hours, a very low dose (1.0 microg/ml) of EGCG also caused inhibition of cell growth, inhibition of activation of EGFR, HER2, and HER3, a decrease in the levels of COX-2 and Bcl-xL proteins, and apoptosis. These results provide the first evidence that a low concentration of EGCG can inhibit activation of, at least, three members of the EGFR family of RTKs, and also inhibit COX-2 expression in colon cancer cells. These findings extend our previous evidence that EGCG may be useful in the chemoprevention and/or treatment of colorectal cancer.
Assuntos
Catequina/análogos & derivados , Neoplasias do Colo/enzimologia , Ciclo-Oxigenase 2/biossíntese , Genes erbB-2/genética , Biotransformação/efeitos dos fármacos , Western Blotting , Catequina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/genética , Ciclo-Oxigenase 2/genética , Fragmentação do DNA/efeitos dos fármacos , Dinoprostona/biossíntese , Indução Enzimática/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Genes Reporter/efeitos dos fármacos , Humanos , Imunoprecipitação , NF-kappa B/metabolismo , RNA Neoplásico/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição AP-1/metabolismo , Proteína bcl-X/biossíntese , Proteína bcl-X/genéticaRESUMO
BACKGROUND: African-American (AA) breast cancer patients consistently show a shortened survival when compared with Caucasian patients. This worse prognosis is most likely due to a combination of socioeconomic factors and differences in tumor biology. Previous studies have demonstrated that cyclin D1 overexpression is strongly associated with estrogen receptor (ER) expression in breast cancer, but these series either included primarily Caucasian patients or did not specify race. MATERIALS AND METHODS. We analyzed 200 breast cancer cases obtained from AA and Caucasian patients who were matched on age, stage, ER status, and year of diagnosis. We examined expression levels of cyclin D1, p53, p27Kip1 (p27), and p21Cip1 (p21), and correlated their expression with ER status. RESULTS: Cyclin D1, p53, p27, and p21 expression rates were similar in matched cases of AA and Caucasian breast cancer (p values>0.05). However, cyclin D1 overexpression was significantly associated with ER status in only the Caucasian (p=0.0005), and not the AA cases (p=0.07). CONCLUSION: This finding suggests a novel biological difference, which may contribute to the more aggressive phenotype of AA breast cancer.
Assuntos
População Negra , Neoplasias da Mama/etnologia , Neoplasias da Mama/metabolismo , Ciclina D1/biossíntese , Receptores de Estrogênio/biossíntese , População Branca , Adulto , Negro ou Afro-Americano , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular/metabolismo , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Análise MultivariadaRESUMO
PURPOSE: We examined the effects of the phytochemical resveratrol in six human cancer cell lines (MCF7, SW480, HCE7, Seg-1, Bic-1, and HL60). EXPERIMENTAL DESIGN AND RESULTS: Resveratrol induced marked growth inhibition in five of these cell lines, with IC(50) values of approximately 70-150 microM. However, only partial growth inhibition was seen in Bic-1 cells. After treatment with 300 microM resveratrol for 24 h, most of the cell lines were arrested in the S phase of the cell cycle. In addition, induction of apoptosis was demonstrated by the appearance of a sub-G(1) peak and confirmed using an annexin V-based assay. Cyclin B1 expression levels were decreased in all cell lines after 48 h of treatment. In SW480 cells, cyclin A, cyclin B1, and beta-catenin expression levels were decreased within 24 h. There was a decrease in cyclin D1 expression after only 2 h of treatment, and this persisted for up to 48 h. This decrease was partially blocked by concurrent treatment with the proteasome inhibitor calpain inhibitor I. Using a luciferase-based reporter assay, resveratrol did not inhibit cyclin D1 promoter activity in SW480 cells. Furthermore, using a reverse transcription-PCR-based assay, only a higher dose of resveratrol (300 microM) appeared to decrease cyclin D1 mRNA. Seg-1 cells expressed basal levels of cyclooxygenase-2 (cox-2), which was further induced by resveratrol. Neither basal levels nor induction of cox-2 was detectable in the remaining cell lines. Thus, cox-2 does not appear to be a critical target of this compound. CONCLUSIONS: These studies provide support for the use of resveratrol in chemoprevention and cancer therapy trials. Cyclin D1, cyclin B1, beta-catenin, and apoptotic index could be useful biomarkers to evaluate treatment efficacy.
Assuntos
Anticarcinógenos/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Ciclina D1/metabolismo , Fase S/efeitos dos fármacos , Estilbenos/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos , Ciclina D1/genética , Ciclinas/metabolismo , Primers do DNA/química , Relação Dose-Resposta a Droga , Citometria de Fluxo , Humanos , Immunoblotting , Luciferases/metabolismo , RNA Mensageiro/metabolismo , RNA Neoplásico/metabolismo , Resveratrol , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ribonucleotídeo Redutases/antagonistas & inibidores , Células Tumorais Cultivadas/metabolismoRESUMO
Vemurafenib, a selective inhibitor of oncogenic BRAF kinase carrying the V600 mutation, is approved for treatment of advanced BRAF mutation-positive melanoma. This study characterized mass balance, metabolism, rates/routes of elimination, and disposition of (14)C-labeled vemurafenib in patients with metastatic melanoma. Seven patients with metastatic BRAF-mutated melanoma received unlabeled vemurafenib 960 mg twice daily for 14 days. On the morning of day 15, patients received (14)C-labeled vemurafenib 960 mg (maximum 2.56 MBq [69.2 µCi]). Thereafter, patients resumed unlabeled vemurafenib (960 mg twice daily). Blood, urine, and feces were collected for metabolism, pharmacokinetic, and dose recovery analysis. Within 18 days after dose, â½95% of (14)C-vemurafenib-related material was recovered from feces (94.1%) and urine (<1%). The parent compound was the predominant component (95%) in plasma. The mean plasma elimination half-life of (14)C-vemurafenib-related material was 71.1 h. Each metabolite accounted for <0.5% and ≤6% of the total administered dose in urine and feces, respectively (0-96 h postdose). No new metabolites were detected. Vemurafenib was well-tolerated. Excretion of vemurafenib via bile into feces is considered the predominant elimination route from plasma with minor renal elimination (<1%). e00113.
RESUMO
This study was conducted to determine the safety and efficacy of the green tea-derived Polyphenon E (Poly E) in patients with Barrett's Esophagus (BE). Subjects were randomized to a 6-month, twice daily (BID) oral treatment of placebo or Poly E (200, 400, or 600 mg). Endoscopic evaluation, including biopsies, was performed before and after treatment. The primary objective was to demonstrate safety; secondary objectives investigated catechin accumulation and effects in clinical specimens. Of the 44 enrolled subjects, 11 received placebo, and 33 received Poly E. No dose-limiting toxicities were encountered, and a maximum tolerated dose (MTD) was not reached. The recommended phase II dose was 600 mg twice daily. The most common treatment-related adverse events (AE) in Poly E-treated subjects were grade I and II nausea, grade I belching, and grade I lactate dehydrogenase (LDH) elevation. No treatment-related AEs were reported in placebo-treated subjects, aside from grade I laboratory abnormalities. Pill counts and subject diaries were not consistently collected, and compliance was difficult to determine. However, on the basis of an intention-to-treat analysis, there was a significant relationship between Poly E dose and esophageal EGCG level--mean changes (pmol/g) of 0.79 (placebo), 6.06 (200 mg), 35.67 (400 mg), and 34.95 (600 mg); P = 0.005. There was a possible relationship between Poly E dose and urine PGE-M concentration. In conclusion, Poly E was well-tolerated, and treatment with Poly E (400 and 600 mg) but not Poly E (200 mg) or placebo resulted in clinically relevant and detectable EGCG accumulation in the target organ, esophageal mucosa.
Assuntos
Esôfago de Barrett/tratamento farmacológico , Catequina/análogos & derivados , Fitoterapia/métodos , Idoso , Idoso de 80 Anos ou mais , Biópsia , Catequina/administração & dosagem , Catequina/efeitos adversos , Catequina/análise , Catequina/metabolismo , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esofagoscopia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
We examined the effects of exisulind (sulindac sulfone) and a potent derivative CP248 on the Barrett's esophagus (BE)-related adenocarcinoma cell lines Seg-1 and Bic-1, and on HCE7 esophageal squamous carcinoma cells. Marked growth inhibition and apoptosis occurred in all cell lines with IC50 values of 100-300 microM for exisulind and 100 nM for CP248. Bic-1 and HCE7 cells were more sensitive to the growth inhibitory properties of exisulind. Treatment of all cell lines with CP248 for 24 h increased the proportion of cells in mitosis. Exisulind had no effect on cell-cycle progression. Treatment with either compound induced rapid activation of the c-Jun NH2-terminal kinase 1 (JNK1), suggesting that JNK1 activation plays a role in the induction of apoptosis by these compounds. Only Seg-1 cells expressed a detectable basal level of cyclooxygenase-2 (cox-2), providing further evidence that cox-2 is not the critical target for the growth inhibitory and apoptotic effects of these compounds. Cellular levels of reduced glutathione (GSH) increased approximately five-fold in all cell lines after 24 h of treatment with either compound. These studies provide support for the use of exisulind in BE chemoprevention trials, and of exisulind or CP248 in the therapy of patients with esophageal carcinoma.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Apoptose , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Sulindaco/uso terapêutico , Animais , Biomarcadores , Western Blotting , Ciclo Celular , Divisão Celular/efeitos dos fármacos , Ciclo-Oxigenase 2 , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Humanos , Concentração Inibidora 50 , Isoenzimas/biossíntese , Isoenzimas/metabolismo , Proteínas de Membrana , Proteína Quinase 8 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mitose , Prostaglandina-Endoperóxido Sintases/biossíntese , Prostaglandina-Endoperóxido Sintases/metabolismo , Sulindaco/análogos & derivados , Fatores de Tempo , Células Tumorais CultivadasRESUMO
Vemurafenib is an orally bioavailable BRAF inhibitor approved for the treatment of BRAF(V600) -mutant metastatic melanoma. It is important to understand the effects of a high-fat meal on the pharmacokinetics (PK) of vemurafenib in humans because it is a Biopharmaceutics Classification System Class IV drug and its PK can be altered by food. An open-label, multicenter, randomized, 2-period crossover study was performed to evaluate the effect of food (high-fat meal) on the PK of a single oral dose of vemurafenib. Secondary objectives were safety and tolerability, efficacy with best overall response rate, and overall survival during the treatment period. The concomitant intake of food (high-fat meal) increased mean Cmax 3.5 to 7.5 µg/mL and mean AUC0-∞ 119 to 360 µg·h/mL after a single 960 mg dose of vemurafenib (N = 13-15 patients). An effect of food on single-dose exposure is suggested by point estimates and 90% CI of geometric mean ratios for vemurafenib plasma AUC0-∞ (4.7) and Cmax (2.5). Toxicity and response rate of vemurafenib in this study were consistent with prior experience in patients with BRAF(V600) -mutant metastatic melanoma. A high-fat meal increased the exposure to vemurafenib without altering the mean terminal half-life.
Assuntos
Antineoplásicos/farmacocinética , Gorduras na Dieta/farmacocinética , Interações Alimento-Droga , Indóis/farmacocinética , Melanoma/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Sulfonamidas/farmacocinética , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Área Sob a Curva , Estudos Cross-Over , Feminino , Humanos , Indóis/efeitos adversos , Indóis/sangue , Masculino , Melanoma/tratamento farmacológico , Melanoma/genética , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/efeitos adversos , Sulfonamidas/sangue , VemurafenibRESUMO
Despite recent advancements in multidisciplinary treatments, the overall survival and quality of life of patients with advanced head and neck squamous cell carcinoma (HNSCC) have not improved significantly over the past decade. Molecular targeted therapies, which have been addressed and advanced by the concept of "oncogene addiction", have demonstrated only limited successes so far. To explore a novel clue for clinically effective targeted therapies, we analyzed the molecular circuitry of HNSCC through the lens that HNSCC is an evolving system. In the trajectory of this somatic evolution, HNSCC acquires biological robustness under a variety of selective pressures including genetic, epigenetic, micro-environmental and metabolic stressors, which well explains the major mechanism of "escaping from oncogene addiction". On the other hand, this systemic view appears to instruct us approaches to target latent vulnerability of HNSCC that is masked behind the plasticity and evolvability of this complex adaptive system.