RESUMO
We carried out a phase II study to investigate the activity of docetaxel plus lycopene in advanced castrate resistant adenocarcinoma of the prostate. Patients were chemotherapy and biological therapy naive. Docetaxel 75 mg/m2 was given every 21 days with daily oral lycopene 30 mg. The primary endpoint was a ≥50% reduction in PSA. Secondary endpoints were median time to PSA progression, duration of response and overall survival. Thirteen patients were initiated on protocol therapy. Median age was 77 (range 55-90). Twelve patients (92%) had bone metastases. Four patients (30%) had both bone and visceral metastases. PSA response was seen in 10 patients (76.9% [95% confidence interval (CI), 46.2-94.9%]). Two patients had stable disease (SD), yielding a disease control rate of 92%. Median time to PSA progression was 8 months [95% CI, 3.5-8.7]. Median duration of response (DOR) was 7.3 months [95% CI, 4.8-13.2]. Median overall survival at 5 years was 35.1 months [95% CI 25.7-57.7]. No new safety signals were noted. No patients experienced grade 3 or above anemia. One patient (7%) experienced febrile neutropenia. A PSA response rate of 76.9% and median survival of 35.1 months compares favorably to the 45% PSA response rate and 17.4 months median survival reported for the TAX 237 trialists. While our study was limited due to small sample size, our results suggest that the combination of docetaxel and lycopene merits further study.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Docetaxel/uso terapêutico , Licopeno/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Adenocarcinoma/sangue , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , California , Progressão da Doença , Docetaxel/efeitos adversos , Humanos , Calicreínas/sangue , Licopeno/efeitos adversos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Fatores de TempoRESUMO
Ovarian cancer growth under hypoxic conditions results in hypoxia-inducible factor-1α (HIF1α) stabilization. HIF1α is an adverse prognostic factor that may contribute to worse outcomes via its capacity to bind to p53, potentially blocking p53-mediated apoptosis. We determined whether HIF1α-p53 binding occurred in hypoxic ovarian cancer cell lines, and if this blocked p53 transcriptional activity. Topotecan (TPT), used in the treatment of ovarian cancer, inhibits HIF1α translation via a topoisomerase-1 (TOPO1)-dependent mechanism. We examined if TPT knockdown of HIF1α restored p53 transcriptional function. TPT effects on HIF1α and p53-related transcriptional targets were assessed by PCR. Associations between TPT effects and TOPO1 expression levels were examined by Western blots and knockdown by siRNA. RNA-binding protein immunoprecipitation was used to assess if TOPO1 was resident on HIF1α mRNA. We determined if sublethal doses of TPT, used to knockdown HIF1α, reversed hypoxia-related cisplatin and paclitaxel resistance (XTT assay). Flow cytometry was used to assess HIF1α-mediated upregulation of ABCB1 and ABCB5 efflux pump expression. We found that HIF1α binding to, and inhibition of, p53 transcriptional activity in hypoxic ovarian cancer cells was associated with drug resistance. TPT-mediated downregulation of HIF1α in hypoxic cells required TOPO1 resident on HIF1α mRNA, restored p53 transcriptional activity, downregulated ABCB1/ABCB5 cell surface expression, and reversed hypoxia-related cisplatin and paclitaxel resistance. IMPLICATIONS: TPT-mediated reduction of HIF1α accumulation in hypoxic ovarian cancer cell lines restores p53 tumor-suppressor function, offering a novel approach to reverse chemoresistance. Further clinical investigation is warranted.
Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/farmacologia , Topotecan/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose , DNA Topoisomerases Tipo I/química , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , RNA Interferente Pequeno , Inibidores da Topoisomerase I/farmacologia , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genéticaRESUMO
PURPOSE: This phase II study evaluated the safety and clinical activity of pazopanib, a potent and mutlitargeted tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs)-1, -2 and -3, platelet-derived growth factor receptor (PDGFR)-α and ß, and cKit, in combination with metronomic paclitaxel in patients with metastatic melanoma. EXPERIMENTAL DESIGN: Sixty chemotherapy-naive patients received pazopanib at a starting dose of 800 mg daily in combination with metronomic dosing of paclitaxel 80 mg/m2 weekly thrice every 4 weeks. The primary endpoint was 6-month progression-free survival (PFS) rate, while secondary endpoints included 1-year overall survival rate, RECIST response rates, progression-free survival rates and median overall survival. Prior BRAF-targeted therapy or checkpoint inhibitors were permitted. RESULTS: The 6-month PFS rate was 68%, with a 1-year OS rate of 48%. Objective response rate was 37% comprising one complete and 20 partial responses. Stable disease at 8 weeks was noted in 32 patients (55%) with an overall clinical benefit rate of 93%. Six-month median progression-free survival was 8 months and median OS was 12.7 months. The most frequently (> 15%) reported non-hematologic, treatment-related adverse events were fatigue, diarrhea, hypertension, transaminitis and peripheral neuropathy. Treatment-related non-fatal bowel perforation, a known class effect, occurred in one patient. No significant association was noted between plasma levels of pazopanib and response. CONCLUSIONS: The combination of pazopanib and metronomic paclitaxel was well-tolerated, demonstrating significant activity in metastatic melanoma. Further evaluation of this combination is warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Melanoma/tratamento farmacológico , Administração Metronômica , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Humanos , Indazóis , Estimativa de Kaplan-Meier , Masculino , Melanoma/sangue , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Intervalo Livre de Progressão , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/sangue , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/sangueRESUMO
PURPOSE: Axitinib, a potent and selective inhibitor of vascular endothelial growth factor receptors, showed antitumor activity as a single agent against several solid tumor types in Phase II and III trials. This study was conducted to evaluate axitinib pharmacokinetics across a variety of solid tumors. METHODS: The current study analyzed the pharmacokinetics of axitinib in 110 patients with non-small cell lung cancer (NSCLC), thyroid cancer, or melanoma from three Phase II trials plus 127 healthy volunteers, using nonlinear mixed-effects modeling. Boxplots of maximum observed plasma concentration (C max) and area under the plasma concentration-time curve (AUC) of data from these tumor populations was compared to C max and AUC from the final population pharmacokinetic model developed for metastatic renal cell carcinoma (mRCC) to compare axitinib pharmacokinetics across different tumor types. RESULTS: Axitinib disposition based on data from 237 subjects was best described using a two-compartment model with first-order absorption and lag time. Population estimates for systemic clearance, central volume of distribution, absorption rate constant, absolute bioavailability, and lag time were 20.1 L/h, 56.2 L, 1.26/h(-1), 0.663, and 0.448 h, respectively. Statistically significant covariates included gender on clearance, and body weight on central volume of distribution. However, predicted changes due to gender and body weight were found not clinically meaningful. The final analysis indicated that the pharmacokinetic model for mRCC was able to successfully describe axitinib pharmacokinetics in patients with NSCLC, thyroid cancer, and melanoma. CONCLUSION: The pharmacokinetics of axitinib appears to be similar across a variety of tumor types.
Assuntos
Imidazóis/farmacocinética , Indazóis/farmacocinética , Modelos Biológicos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacocinética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Axitinibe , Disponibilidade Biológica , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Dinâmica não Linear , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fatores Sexuais , Distribuição Tecidual , Adulto JovemRESUMO
Cisplatin-based chemotherapy is recommended for use as first-line treatment for patients with advanced transitional cell carcinoma of the bladder. Unfortunately, 30-50 % of patients are ineligible for cisplatin due to renal insufficiency. Oxaliplatin is a less nephrotoxic platin which can be used for patients with impaired renal function. We carried out a phase II study of gemcitabine (1,200 mg/m²) in combination with oxaliplatin (100 mg/m²) given on days 1 and 14 every 28 days (GEMOX) in predominantly cisplatin-'unfit' stage IV transitional cell bladder cancer patients to determine whether this combination exhibited a clinical activity profile similar to cisplatin plus gemcitabine. Eighteen patients with a median GFR of 49 ml/min were enrolled. GEMOX treatment led to a 36 % response rate in assessable patients. Median progression-free survival was 4.9 months, with a median overall survival (OS) of 10.4 months and a one-year survival rate of 44.4 %. GEMOX in bladder cancer patients exhibited a tolerable side effects profile, with thrombocytopenia as the most frequent grade 3/4 toxicity. These findings suggest that GEMOX is an active combination in advanced bladder cancer patients with reduced renal function.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células de Transição/complicações , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/fisiopatologia , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Monitoramento de Medicamentos , Feminino , Taxa de Filtração Glomerular , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/uso terapêutico , Insuficiência Renal/complicações , Insuficiência Renal/fisiopatologia , Índice de Gravidade de Doença , Análise de Sobrevida , Trombocitopenia/induzido quimicamente , Trombocitopenia/fisiopatologia , Neoplasias da Bexiga Urinária/complicações , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/fisiopatologiaRESUMO
BACKGROUND: Reversibility of aberrant methylation via pharmacological means is an attractive target for therapies through epigenetic reprogramming. To establish that pharmacologic reversal of methylation could result in functional inhibition of angiogenesis, we undertook in vitro and in vivo studies of thrombospondin-1 (TSP1), a known inhibitor of angiogenesis. TSP1 is methylated in several malignancies, and can inhibit angiogenesis in melanoma xenografts. We analyzed effects of 5-Aza-deoxycytidine (5-Aza-dC) on melanoma cells in vitro to confirm reversal of promoter hypermethylation and restoration of TSP1 expression. We then investigated the effects of TSP1 expression on new blood vessel formation and tumor growth in vivo. Finally, to determine potential for clinical translation, the methylation status of TSP1 promoter regions of nevi and melanoma tissues was investigated. RESULTS: 5-Aza-dC reduced DNA (cytosine-5)-methyltransferase 1 (DNMT1) protein, reversed promoter hypermethylation, and restored TSP1 expression in five melanoma cell lines, while having no effect on TSP1 protein levels in normal human melanocytes. In in vivo neovascularization studies, mice were implanted with melanoma cells (A375) either untreated or treated with 5Aza-dC. Vessels at tumor sites were counted by an observer blinded to treatments and the number of tumor vessels was significantly decreased at pretreated tumor sites. This difference occurred before a significant difference in tumor volumes was seen, yet in further studies the average tumor volume in mice treated in vivo with 5-Aza-dC was decreased by 55% compared to untreated controls. Knockdown of TSP1 expression with shRNA enhanced tumor-induced angiogenesis by 68%. Analyses of promoter methylation status of TSP1 in tumors derived from untreated and treated mice identified 67% of tumors from untreated and 17% of tumors from treated mice with partial methylation consistent with the methylation specific PCR analysis of A375 cells. Examination of methylation patterns in the promoter of TSP1 and comparison of aberrantly methylated TSP1 in melanoma with non-malignant nevi identified a significantly higher frequency of promoter methylation in tumor samples from melanoma patients. CONCLUSIONS: Pharmacological reversal of methylation silenced TSP1 had functional biological consequences in enhancing angiogenesis inhibition and inducing antitumor effects to decrease murine melanoma growth. Angiogenesis inhibition is an additional mechanism by which epigenetic modulators can have antitumor effects.
Assuntos
Azacitidina/análogos & derivados , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Epigênese Genética/genética , Melanoma/genética , Neovascularização Patológica/genética , Animais , Azacitidina/administração & dosagem , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/antagonistas & inibidores , Decitabina , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Melanoma/metabolismo , Melanoma/terapia , Metilação/efeitos dos fármacos , Camundongos , Neovascularização Patológica/tratamento farmacológico , Regiões Promotoras Genéticas/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To explore feasibility of measuring tumor blood flow as marker for antiangiogenic activity using DCE-MRI (Dynamic Contrast-Enhanced Magnetic Resonance Imaging) in women with recurrent EOC/PPC treated with bevacizumab. METHODS: In a phase II study, 62 patients with recurrent/persistent EOC/PPC were treated with bevacizumab (15 mg/kg IV q21 days) until disease progression. DCE-MRI was performed pre-cycle 1 and 4 of bevacizumab. Images were analyzed retrospectively by a single experienced blinded radiologist. Tumor and muscle contrast enhancement was measured by region of interest signal intensity within the same DCE-MRI images. Flow rates were obtained with concentration of dye as a function of time. Relative blood flow (RBF) was calculated as a ratio of average blood flow into tumor to muscle tissue. Associations between RBF and characteristics/outcomes were explored. RESULTS: Sixty-two patients were eligible for study. Unfortunately, only 14 (23%) patients had imaging data available for analysis at baseline and 13 of those same patients (21%) had imaging data available for analysis pre-cycle 4. The RBF distribution was similar from pre-cycle 1 to 4. RBF remained stable for the majority of the cases (median change -0.21). Baseline RBF was not significantly associated with being progression-free at 6 months, microvessel density, 17 month overall survival, tumor response, or platinum sensitivity. However, increases in blood flow rates were associated with likelihood to be progression-free at 6 months. CONCLUSION: Functional imaging of tumor blood flow is a potential research endpoint that may be explored further. Consideration should be given to timing of endpoint and standardizing the technique.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Imageamento por Ressonância Magnética , Neoplasias Epiteliais e Glandulares/irrigação sanguínea , Neoplasias Ovarianas/irrigação sanguínea , Neoplasias Peritoneais/irrigação sanguínea , Idoso , Inibidores da Angiogênese/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Bevacizumab , Vasos Sanguíneos/patologia , Carcinoma Epitelial do Ovário , Meios de Contraste , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neovascularização Patológica/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Valor Preditivo dos Testes , Fluxo Sanguíneo Regional/efeitos dos fármacos , Método Simples-CegoRESUMO
PURPOSE: Metastatic melanoma, a highly vascularized tumor with strong expression of vascular endothelial growth factor, has an overall poor prognosis. We conducted a placebo-controlled, double-blind phase II study of carboplatin plus paclitaxel with or without bevacizumab in patients with previously untreated metastatic melanoma. PATIENTS AND METHODS: Patients were randomly assigned in a two-to-one ratio to carboplatin (area under the curve, 5) plus paclitaxel (175 mg/m(2)) and bevacizumab (15 mg/kg; CPB) or placebo (CP) administered intravenously once every 3 weeks. Progression-free survival (PFS) was the primary end point. Secondary end points included overall survival (OS) and safety. RESULTS: Two hundred fourteen patients (73% with M1c disease) were randomly assigned. With a median follow-up of 13 months, median PFS was 4.2 months for the CP arm (n = 71) and 5.6 months for the CPB arm (n = 143; hazard ratio [HR], 0.78; P = .1414). Overall response rates were 16.4% and 25.5%, respectively (P = .1577). With 13-month follow-up, median OS was 8.6 months in the CP arm versus 12.3 months in the CPB arm (HR, 0.67; P = .0366), whereas in an evaluation 4 months later, it was 9.2 versus 12.3 months, respectively (HR, 0.79; P = .1916). In patients with elevated serum lactate dehydrogenase (n = 84), median PFS and OS were longer in the CPB arm (PFS: 4.4 v 2.7 months; HR, 0.62; OS: 8.5 v 7.5 months; HR, 0.52). No new safety signals were observed. CONCLUSION: The study did not meet the primary objective of statistically significant improvement in PFS with the addition of bevacizumab to carboplatin plus paclitaxel. A larger phase III study will be necessary to determine whether there is benefit to the addition of bevacizumab to carboplatin plus paclitaxel in this disease setting.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Carboplatina/administração & dosagem , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Estimativa de Kaplan-Meier , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
PURPOSE: Metastatic melanoma patients have a poor prognosis. No chemotherapy regimen has improved overall survival. More effective treatments are needed. Docetaxel has clinical activity in melanoma and may be more active when combined with vinorelbine. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown activity as an adjuvant melanoma therapy. We carried out a phase II study of these agents in patients with stage IV melanoma. METHODS: Patients had documented stage IV melanoma and may have had prior immuno or chemotherapy. Previously treated brain metastases were allowed. Docetaxel (40 mg/m(2) IV) and vinorelbine (30 mg/m(2) IV) were administered every 14 days, followed by GM-CSF (250 mg/m2 SC on days 2 to 12). The primary endpoint of the study was 1-year overall survival (OS). Secondary objectives were median overall survival, response rate (per RECIST criteria), and the toxicity profiles. RESULTS: Fifty-two patients were enrolled; 80% had stage M1c disease. Brain metastases were present in 21%. Fifty-two percent of patients had received prior chemotherapy, including 35% who received prior biochemotherapy. Toxicity was manageable. Grade III/IV toxicities included neutropenia (31%), anemia (14%), febrile neutropenia (11.5%), and thrombocytopenia (9%). DVS chemotherapy demonstrated clinical activity, with a partial response in 15%, and disease stabilization in 37%. Six-month PFS was 37%. Median OS was 11.4 months and 1-year OS rate was 48.1%. CONCLUSIONS: The DVS regimen was active in patients with advanced, previously treated melanoma, with manageable toxicity. The favorable 1-year overall survival and median survival rates suggest that further evaluation of the DVS regimen is warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Melanoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/secundário , Docetaxel , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Sobrevida , Taxoides/administração & dosagem , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , Vinorelbina , Adulto JovemRESUMO
PURPOSE: To evaluate if diastolic blood pressure (dBP) ≥90 mm Hg during axitinib treatment is a marker of efficacy. EXPERIMENTAL DESIGN: The relationship between dBP ≥90 mm Hg and efficacy was retrospectively explored across 5 phase II studies of single-agent axitinib for the treatment of 4 different tumor types. All patients had baseline BP ≤140/90 mm Hg and were stratified into 2 groups based on in-clinic BP measurements after initiating therapy: those with dBP <90 mm Hg throughout therapy and those with at least 1 dBP ≥90 mm Hg. Median overall survival (mOS), median progression-free survival (mPFS), objective response rate (ORR), and adverse events were evaluated by dBP group in individual and pooled analyses. RESULTS: Two-hundred thirty patients were evaluated. Patients with dBP ≥90 mm Hg had a significantly lower relative risk of death than those with dBP <90 mm Hg [adjusted HR (95% CI) = 0.55 (0.39, 0.77); P < 0.001]. The relative risk of progression was also lower in patients with dBP ≥90 mm Hg [HR (95% CI) = 0.76 (0.54, 1.06), P = 0.107], and ORR was significantly higher (43.9% vs. 12.0%; P < 0.001). In an 8-week landmark analysis, mOS (25.8 vs. 14.9 months) and mPFS (10.2 vs. 7.1 months) were greater for patients in the ≥90 mm Hg group. Adverse events were similar between groups. CONCLUSIONS: Axitinib efficacy correlated with dBP ≥90 mm Hg. Further investigation of dBP as a predictive biomarker of efficacy in patients receiving axitinib is warranted.
Assuntos
Antineoplásicos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Axitinibe , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Resveratrol, a naturally occurring polyphenol, has been reported to be an anti-tumor and chemopreventive agent. Recent data show that it may also exert anti-angiogenic effects. We hypothesized that the anti-angiogenic activity of resveratrol may be caused by modulation of tumor cell release of thrombospondin-1 (TSP1) and vascular endothelial growth factor (VEGF) into the extracellular matrix, leading to vascular endothelial cell (VEC) apoptosis. We therefore evaluated the effects of resveratrol on melanoma cell lines co-cultured with vascular endothelial cells in monolayer and in three dimensional spheroids. We found that resveratrol stimulated isolated VEC proliferation, while it caused growth inhibition of VECs grown with melanoma cells in three-dimensional co-culture. This effect was associated with increased melanoma cell expression of tumor suppressor protein 53 and matrix protein TSP1, as well as decreased hypoxia-driven expression of hypoxia inducible factor-1α and inhibition of VEGF production.
Assuntos
Células Endoteliais/patologia , Melanoma/patologia , Estilbenos/farmacologia , Trombospondina 1/genética , Fator A de Crescimento do Endotélio Vascular/genética , Inibidores da Angiogênese/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Avaliação Pré-Clínica de Medicamentos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes p53/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Melanoma/genética , Melanoma/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/prevenção & controle , Estabilidade Proteica/efeitos dos fármacos , Resveratrol , Trombospondina 1/antagonistas & inibidores , Trombospondina 1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVES: To investigate the feasibility of performing a fresh-tissue, in vitro radiation resistance assay (IVRRA) in a cooperative group setting and to assess the association of IVRRA results with clinical outcomes. METHODS: Women with Stages IIB-IVA carcinoma of the uterine cervix without obvious para-aortic lymphadenopathy on imaging were eligible. Primary tumor biopsies were shipped to a central testing facility where agar-based cell suspensions were exposed to 300 cGy of RT ± cisplatin and cultured for 5 days. ³H-thymidine incorporation was used to determine percent cell inhibition (PCI) of test specimen compared to that of the untreated control. Tumors were considered to exhibit extreme radiation resistance (ERR), intermediate radiation resistance (IRR) or low radiation resistance (LRR) based on a standard data set from 39 previously studied specimens. Standardized doses of external beam radiation and intracavitary brachytherapy, when feasible, in addition to platinum-based chemotherapy were mandated. Progression-free survival (PFS) was the primary endpoint. Clinical response and overall survival (OS) were secondary endpoints. Clinical investigators were blinded to assay data and vice versa. RESULTS: Thirty-six patients were enrolled, but analysis was limited to 17 patients whose specimens were adequate for IVRRA. The median follow-up time among patients still alive at last contact was 40 months (range: 0-56 months). There was no association between IVRRA and response. In the Cox model, IRR/ERR tumors showed worse PFS [HR = 11.2 (95% CI 1.3-96, p = 0.03)] and worse OS [HR=11.7 (95% CI 1.4-99.6, p = 0.03)] compared to LRR tumors when IVRRA was performed with RT alone, but there were no associations between IVRRA and PFS or OS when cisplatin was added to the IVRRA. CONCLUSIONS: IVRRA (RT alone) results correlated with PFS and OS in this prospective trial, but follow-up trials are indicated to address feasibility and to confirm results in an expanded cohort. If confirmed, IVRRA could potentially direct molecular identification of novel targeted therapeutic approaches which might counteract radiation resistance.
Assuntos
Neoplasias do Colo do Útero/radioterapia , Biópsia , Cisplatino/uso terapêutico , Terapia Combinada , Intervalo Livre de Doença , Estudos de Viabilidade , Feminino , Humanos , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Estudos Prospectivos , Tolerância a Radiação , Resultado do Tratamento , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/efeitos da radiação , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologiaRESUMO
OBJECTIVE: Potential predictive/prognostic angiogenic markers were prospectively examined in a phase II trial of bevacizumab in epithelial ovarian cancer (EOC)/primary peritoneal cancer (PPC). METHODS: Recurrent/persistent EOC/PPC patients were treated with bevacizumab (15 mg/kg IV q21days) until disease progression. Validated-immunohistochemistry (IHC) assays were performed on pre-cycle 1/4 tumor biopsies for CD31-microvessel density (MVD), VEGF-histoscore (HS), p53-HS, and TSP1 image analysis score (IA). Pre-cycle 1/4 serum and plasma VEGF were quantified using a validated-ELISA. RESULTS: CD31-MVD and serum VEGF, evaluated pre-cycle 1 in 41/61 and 51/61 eligible patients, respectively, did not appear to be correlated. High CD31-MVD, categorized at the median, appeared to be associated with tumor response, a 13-month shorter median survival, and an increased risk of death (unadjusted hazard ratio [HR] = 2.2, 95% confidence interval [CI] = 1.067-4.467). In addition, each standard deviation (SD) increase in CD31-MVD appeared to be associated with worse survival in unadjusted and adjusted analyses. IHC and plasma biomarkers did not change with bevacizumab treatment except for serum VEGF, which appeared to decrease during bevacizumab treatment. This decrease was not associated with response. High pre-cycle 1 serum VEGF, categorized at the median, was associated with 22-month shorter median survival and an increased risk of death (unadjusted HR = 2.7, 95% CI = 1.369-5.191). Categorized p53 appeared to be associated with unadjusted survival and each SD increase in TSP1-IA appeared to be associated with a decreased risk of progression in unadjusted and adjusted analyses. CONCLUSIONS: Despite the limitations in sample size and exploratory nature of the study, angiogenic markers in tumor and serum may provide prognostic value in recurrent/persistent EOC/PPC, and are being prospectively evaluated in the GOG phase III trial of carboplatin, paclitaxel and bevacizumab/placebo in previously untreated EOC/PPC.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Molécula-1 de Adesão Celular Endotelial a Plaquetas/biossíntese , Trombospondina 1/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Idoso , Anticorpos Monoclonais Humanizados , Bevacizumab , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Microvasos/metabolismo , Microvasos/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/irrigação sanguínea , Recidiva Local de Neoplasia/tratamento farmacológico , Neovascularização Patológica/sangue , Neovascularização Patológica/patologia , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/irrigação sanguínea , Neoplasias Peritoneais/sangue , Neoplasias Peritoneais/irrigação sanguínea , Prognóstico , Estudos Prospectivos , Proteína Supressora de Tumor p53/metabolismoRESUMO
Ovarian cancer is the most common cause of mortality of tumors from gynecologic origin and is often diagnosed after patients have already progressed to advanced disease stage. The current standard of care for treatment of ovarian cancer includes cytoreductive surgery followed by adjuvant chemotherapy. Unfortunately, many patients will recur and ultimately die from their disease. Targeted therapies have been evaluated in ovarian cancer as a method to overcome resistant disease. Angiogenesis inhibitors have shown success in many tumor types and have also demonstrated promise in trials involving patients with ovarian cancer. PARP inhibitors may be potentially active agents in patients with BRCA-associated ovarian cancer. Trials that have evaluated combinations of targeted agents have often revealed untoward toxicities, thus tempering enthusiasm for this approach.
RESUMO
OBJECTIVES: This study aimed to determine whether carbonic anhydrase-IX (CA-IX) was associated with progression-free survival (PFS) and overall survival (OS) in women with high-risk, early-stage cervical cancer treated with adjuvant pelvic radiotherapy with or without radiosensitizing chemotherapy. METHODS: CA-IX expression was detected using an immunohistochemistry assay and categorized as low when
Assuntos
Antígenos de Neoplasias/biossíntese , Anidrases Carbônicas/biossíntese , Neoplasias do Colo do Útero/enzimologia , Neoplasias do Colo do Útero/terapia , Adulto , Idoso , Anidrase Carbônica IX , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Fatores de Risco , Taxa de Sobrevida , Neoplasias do Colo do Útero/patologiaRESUMO
Nearly 30% of women with early-stage breast cancer develop recurrent disease attributed to resistance to systemic therapy. Prevailing models of chemotherapy failure describe three resistant phenotypes: cells with alterations in transmembrane drug transport, increased detoxification and repair pathways, and alterations leading to failure of apoptosis. Proliferative activity correlates with tumor sensitivity. Cell-cycle status, controlling proliferation, depends on local concentration of oxygen and nutrients. Although physiologic resistance due to diffusion gradients of these substances and drugs is a recognized phenomenon, it has been difficult to quantify its role with any accuracy that can be exploited clinically. We implement a mathematical model of tumor drug response that hypothesizes specific functional relationships linking tumor growth and regression to the underlying phenotype. The model incorporates the effects of local drug, oxygen, and nutrient concentrations within the three-dimensional tumor volume, and includes the experimentally observed resistant phenotypes of individual cells. We conclude that this integrative method, tightly coupling computational modeling with biological data, enhances the value of knowledge gained from current pharmacokinetic measurements, and, further, that such an approach could predict resistance based on specific tumor properties and thus improve treatment outcome.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Computadores Moleculares , Apoptose , Neoplasias da Mama/patologia , Técnicas de Cultura de Células , Morte Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Humanos , Modelos Biológicos , Modelos Teóricos , Necrose , Valor Preditivo dos TestesRESUMO
OBJECTIVES: To determine whether markers of tumor angiogenesis were associated with progression-free survival (PFS) and overall survival (OS) in women with high-risk, early-stage cervical cancer treated on a phase III trial. METHODS: One hundred seventy-three tumor specimens were analyzed by semi-quantitative immunohistochemical (IHC) staining for vascular endothelial growth factor (VEGF, pro-angiogenesis factor), thrombospondin-1 (TSP-1, anti-angiogenesis factor), CD31 (non-specific endothelial marker), and CD105 (tumor-specific endothelial marker). Tumoral histoscores (HS) were calculated for VEGF using the formula: [% cells positivex(intensity+1)]. TSP-1 specimens were categorized as negative or positive. CD31 and CD105 microvessel density (MVD) "hotspots" were counted in three 20x high-power fields. Associations between angiogenesis markers and survival were evaluated. RESULTS: TSP-1 expression was observed in 65% of cases while 66% expressed high VEGF (>or=200), 34% exhibited high CD31 (CD31>or=110) and 66% displayed high CD105 (CD105>or=28). In univariate analyses CD31 MVD, but not tumor TSP-1, was associated with improved PFS (HR=0.37; 95% CI=0.18-0.76; p=0.007) and OS (HR=0.37; 95% CI=0.17-0.79; p=0.010). After adjusting for prognostic clinical covariates, high CD31 MVD, but not TSP-1, VEGF or CD105 MVD, was an independent prognostic factor for PFS (HR=0.36; 95% CI=0.17-0.75; p=0.006) and OS (HR=0.36; 95% CI=0.17-0.79; p=0.010). CONCLUSIONS: Tumor angiogenesis measured by CD31 MVD is an independent prognostic factor for both PFS and OS in high-risk, early-stage cervical cancer. We hypothesize that this finding may be explained by improved treatment response in well-vascularized, well-oxygenated tumors.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias do Colo do Útero/irrigação sanguínea , Adulto , Idoso , Antígenos CD/metabolismo , Estudos de Coortes , Terapia Combinada , Intervalo Livre de Doença , Endoglina , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptores de Superfície Celular/metabolismo , Fatores de Risco , Trombospondina 1/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/radioterapia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Melanoma cells characteristically produce increased levels of reactive oxygen species (ROS) because of the metal-binding properties of melanin and loss of structural integrity of the melanosome. Agents that deplete gluthathione or inhibit superoxide dismutase, thereby blocking ROS scavenging mechanisms, may be selectively toxic to melanoma. To determine whether the inhibition of ROS scavenging could potentiate alkylator activity, we evaluated the activity of tetrathiomolybdate (ATN-224), a superoxide dismutase inhibitor, alone and in combination with temozolomide, on five melanoma cell lines. We also determined whether the ATN-224 would act synergistically with other agents that interfere with ROS scavenging. We found that the combination of ATN-224 and temozolomide generally exhibited additive cytotoxic effects on the cell lines tested. ATN-224 acted synergistically with buthionine sulfoximine, an agent that causes gluthathione depletion. Combinations of ATN-224 with arsenic trioxide, which may deplete glutathione, or disulfiram, an agent that interferes with recycling of glutathione, were antagonistic. These data suggest that strategically tailoring combination regimens that include ATN-224 and target ROS may be a viable approach to advance the treatment of melanoma.
Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Glutationa/metabolismo , Melanoma/tratamento farmacológico , Molibdênio/farmacologia , Superóxido Dismutase/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Trióxido de Arsênio , Arsenicais/farmacologia , Butionina Sulfoximina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Dissulfiram/farmacologia , Sinergismo Farmacológico , Humanos , Melaninas/metabolismo , Melanoma/metabolismo , Oxirredução , Óxidos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , TemozolomidaRESUMO
The successful treatment of melanoma has been hampered by the unique biology of this cancer. Fortunately, research to further our understanding of how melanoma cells differ from normal tissues has led to the discovery of potential new avenues of attack. One promising strategy relates to targeting the excess free radicals produced by melanomas. Melanocyte transformation into cancer is associated with significant structural alterations in the melanosome. In addition to pigment production, melanosomes also protect the cell by scavenging free radicals generated by sunlight and cellular metabolism. In melanoma, the disrupted and disorganized melanosome structure reverses this process. Melanosomes found in melanoma produce free radicals, such as hydrogen peroxide, furthering DNA damage. Melanosome generation of reactive oxygen species (ROS), in tandem with those generated by cancer metabolism, activate cellular signal transduction pathways that prevent cell death. ROS activation of proto-oncogene pathways in melanoma contributes to their resistance to chemotherapy. Fortunately, it may be possible to target these free radicals, just as Paris was able to successfully target Achilles' heel. The use of agents that block ROS scavenging, such as ATN-224 and disulfiram, have been explored clinically. A recent randomized Phase II trial with elesclomol, an agent that generates ROS, in combination with paclitaxel led to improved patient survival, suggesting that this may be a viable approach to advance the treatment of melanoma.
Assuntos
Melanoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Cutâneas/metabolismo , Animais , Sobrevivência Celular/fisiologia , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Radicais Livres/metabolismo , Humanos , Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/patologia , Melanoma/terapia , Proto-Oncogene Mas , Ensaios Clínicos Controlados Aleatórios como Assunto/tendências , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapiaRESUMO
BACKGROUND: Bevacizumab is FDA approved to treat colon cancer and is currently used off label for metastatic breast, kidney, and lung cancers. Bevacizumab is a monoclonal antibody that binds to, and inactivates, VEGF and is believed to be antiangiogenic. CASE DESCRIPTION: The authors report the case of a 54-year-old woman with metastatic infiltrating ductal breast carcinoma who developed left occipital and right parietal intraaxial contrast-enhancing masses on surveillance magnetic resonance imaging (MRI). After surgical resection, she was placed on bevacizumab for control of systemic disease. Six months later, a nonenhancing right occipital lesion was detected on MRI. After stopping bevacizumab therapy, the patient underwent microsurgical resection of the lesion. Histopathologic examination was consistent with metastatic breast cancer indistinguishable from her previously resected enhancing brain metastasis. Six weeks after stopping bevacizumab therapy and 3 weeks after microsurgical resection, a new contrast-enhancing mass was noted on magnetic resonance in the right temporal lobe. CONCLUSION: This case is unique in that we have neuroimaging on prebevacizumab, concurrent bevacizumab, and postbevacizumab brain metastases in the same patient with a single cancer primary, thus, assuring that alterations in neuroimaging characteristics are consistent with bevacizumab effect. As an internal control, it provides strong support for the premise that bevacizumab therapy can confound the diagnosis of brain metastases because of its effect on tumor enhancement.