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1.
Drug Deliv ; 26(1): 756-764, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31357893

RESUMO

Tumor microenvironment is closely related to the occurrence and development of liver cancer. Tumor-associated macrophages (TAMs) are an important part of tumor microenvironment promoting tumor deterioration and metastasis by inhibiting immune cells. Previous studies showed that PI3Kγ inhibitor could reverse the phenotype of TAMs, relieve immunosuppression and sensitize chemotherapy drugs, suggesting that the combination of PI3Kγ inhibitor and chemotherapeutics is likely to bring new breakthroughs in the treatment of liver cancer. Based on it, this paper builds HES-TG100-115-CDM-PEG micelles with tumor microenvironment responsiveness that simultaneously loaded sorafenib and TG100-115 to synergistically treat liver cancer. Pharmacokinetic study showed that the prepared micelles had longer half-life than that of the free drug solutions, which was favorable for high propensity of extravasation through tumor vascular fenestrations. Under low pH and high α-amylasereductive conditions, micelles could depolymerize quickly due to the sensitivity of bonds and enhance significantly cytotoxic activity against Hep-3B liver cancer cell. Additionally, micelles demonstrated higher levels of antitumor efficiency and better tolerance against nude mouse with Hep-3B cell than the free drug solutions. These findings reveal that HES-TG100-115-CDM-PEG micelles are a promising drug delivery system in clinical comprehensive therapy of liver cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Fenóis/administração & dosagem , Pteridinas/administração & dosagem , Sorafenibe/administração & dosagem , Microambiente Tumoral/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Derivados de Hidroxietil Amido , Camundongos Nus , Micelas , Fenóis/síntese química , Fenóis/farmacocinética , Fenóis/uso terapêutico , Polietilenoglicóis , Pteridinas/síntese química , Pteridinas/farmacocinética , Pteridinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Sorafenibe/farmacocinética , Sorafenibe/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Pediatr Blood Cancer ; 66(10): e27900, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31276318

RESUMO

BACKGROUND: Volasertib induces mitotic arrest and apoptosis by targeting Polo-like kinases. In this phase I dose-escalation study, the maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary efficacy of volasertib were determined in pediatric patients. METHODS: Patients aged 2 to <18 years with relapsed/refractory acute leukemia/advanced solid tumors (ST) without available effective treatments were enrolled-cohort C1 (aged 2 to <12 years); cohort C2 (aged 12 to <18 years). The patients received volasertib intravenously (starting dose: 200 mg/m2 body surface area on day 1, every 14 days). The primary endpoint was the pediatric MTD for further development. RESULTS: Twenty-two patients received treatment (C1: leukemia, n = 4; ST, n = 8; C2: leukemia, n = 3; ST, n = 7). No dose-limiting toxicities (DLTs) occurred up to 300 mg/m2 volasertib in C1; two patients in C2, at 250 mg/m2 volasertib, had DLTs in cycle 1, one of which led to death; therefore, the MTD of volasertib in C2 was 200 mg/m2 . The most common grade 3/4 adverse events (all patients) were febrile neutropenia, thrombocytopenia, and neutropenia (41% each). Stable disease (SD) was the best objective response (leukemia, n = 5; ST, n = 2); the duration of SD was short in all patients, except in one with an ST. PK profiles were generally comparable across dose groups and were consistent with those in adults. CONCLUSION: The pediatric MTD/dose for further development was identified. There were no unexpected safety or PK findings; limited antitumor/antileukemic activity was demonstrated.


Assuntos
Leucemia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Pteridinas/administração & dosagem , Pteridinas/farmacocinética , Adolescente , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pteridinas/efeitos adversos
3.
EBioMedicine ; 41: 244-255, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30876762

RESUMO

BACKGROUND: Targeting PLK1 has recently been proven as a viable therapeutic strategy against oesophageal squamous cell carcinom (ESCC). Therefore, this study aimed to explore whether the PLK1 inhibitor BI2536 is able to sensitize ESCC cells to cisplatin (DDP) and determine the underlying mechanisms. METHODS: Viability, clonogenicity, cell cycle distribution and apoptosis were assessed in ESCC cells treated with BI2536 or DDP alone or in combination. Checkpoint activation was examined by immunoblotting and immunohistochemistry. Xenograft model was used to assess the efficacy of the co-treatment. The expression level of GSDME in tissue samples were examined by immunohistochemistry. FINDINGS: We found that the combination of BI2536 and DDP was synergistic in ESCC cells, which induced pyroptosis in ESCC cells at low doses. Mechanistic studies revealed that BI2536 significantly induced DNA damage and impaired the DNA damage repair pathway in DDP-treated cells both in vitro and in vivo. Interestingly, we found that co-treatment with BI2536 and DDP induced pyroptosis in ESCC cells depending on the caspase-3/GSDME pathway. Importantly, our study found that GSDME was more highly expressed in tumour tissue than that in normal adjacent tissues, and could serve as a prognostic factor. INTERPRETATION: BI2536 sensitizes ESCC cells to DDP by inhibiting the DNA damage repair pathway and inducing pyroptosis, which provides new information for understanding pyroptosis. Our study also reveals that the PLK1 inhibitor BI2536 may be an attractive candidate for ESCC targeted therapy, especially when combined with DDP for treating the GSDME overexpression subtype. FUND: National 973 Program and National Natural Science Fundation of China.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Proteínas de Ciclo Celular/antagonistas & inibidores , Cisplatino/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pteridinas/uso terapêutico , Piroptose/efeitos dos fármacos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Neoplasias Esofágicas/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pteridinas/administração & dosagem , Pteridinas/farmacologia
4.
Cancer Lett ; 445: 24-33, 2019 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-30611741

RESUMO

Medulloblastoma is the most prevalent central nervous system tumor in children. Targeted treatment approaches for patients with high-risk medulloblastoma are needed as current treatment regimens are not curative in many cases and cause significant therapy-related morbidity. Medulloblastoma harboring MYC amplification have the most aggressive clinical course and worst outcome. Targeting the BET protein BRD4 has significant anti-tumor effects in preclinical models of MYC-amplified medulloblastoma, however, in most cases these are not curative. We here assessed the therapeutic efficacy of the orally bioavailable BRD4 inhibitor, MK-8628, in preclinical models of medulloblastoma. MK-8628 showed therapeutic efficacy against in vitro and in vivo models of MYC-amplified medulloblastoma by inducing apoptotic cell death and cell cycle arrest. Gene expression analysis of cells treated with MK-8628 showed that anti-tumor effects were accompanied by significant repression of MYC transcription as well as disruption of MYC-regulated transcriptional programs. Additionally, we found that targeting of MYC protein stability through pharmacological PLK1 inhibition showed synergistic anti-medulloblastoma effects when combined with MK-8628 treatment. Thus, MK-8628 is effective against preclinical high-risk medulloblastoma models and its effects can be enhanced through simultaneous targeting of PLK1.


Assuntos
Acetanilidas/administração & dosagem , Neoplasias Cerebelares/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Meduloblastoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/química , Pteridinas/administração & dosagem , Acetanilidas/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Sinergismo Farmacológico , Amplificação de Genes , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Meduloblastoma/genética , Meduloblastoma/metabolismo , Camundongos , Estabilidade Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/genética , Pteridinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Cancer Lett ; 439: 56-65, 2018 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-30243708

RESUMO

Anaplastic thyroid cancer (ATC) is among the most lethal malignancies. The mitotic kinase PLK1 is overexpressed in the majority of ATCs and PLK1 inhibitors have shown preclinical efficacy. However, they also cause mitotic slippage and endoreduplication, leading to the generation of tetraploid, genetically unstable cell populations. We hypothesized that PI3K activity may facilitate mitotic slippage upon PLK1 inhibition, and thus tested the effect of combining PLK1 and PI3K inhibitors in ATC models, in vitro and in vivo. Treatment with BI6727 and BKM120 resulted in a significant synergistic effect in ATC cells, independent of the levels of AKT activity. Combination of the two drugs enhanced growth suppression at doses for which the single drugs showed no effect, and led to a massive reduction of the tetraploid cells population. Furthermore, combined treatment in PI3Khigh cell lines showed a significant induction of apoptosis. Finally, combined inhibition of PI3K and PLK1 was extremely effective in vivo, in an immunocompetent allograft model of ATC. Our results demonstrate a clear therapeutic potential of combining PLK1 and PI3K inhibitors in anaplastic thyroid tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/antagonistas & inibidores , Endorreduplicação/efeitos dos fármacos , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Aminopiridinas/administração & dosagem , Animais , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Endorreduplicação/genética , Humanos , Camundongos , Morfolinas/administração & dosagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Pteridinas/administração & dosagem , Carcinoma Anaplásico da Tireoide/genética , Carcinoma Anaplásico da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo
7.
J Viral Hepat ; 25(11): 1331-1340, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29851204

RESUMO

Vesatolimod is an oral agonist of toll-like receptor 7 designed to minimize systemic exposure and side effects. We assessed the safety and efficacy of vesatolimod in viremic chronic hepatitis B (CHB) patients not currently on oral antiviral treatment (OAV) in a phase 2, multicentre, double-blind, randomized, placebo-controlled study. A total of 192 patients stratified by HBeAg status and alanine aminotransferase level were randomized 2:2:2:1 to receive oral vesatolimod (1-, 2- or 4-mg) or placebo once weekly for 12 weeks; tenofovir disoproxil fumarate (300-mg daily) was administered daily for 48 weeks. Efficacy was assessed by quantitative serum HBsAg decline at Week 24 from baseline. In addition to safety assessments, changes in whole-blood interferon-stimulated gene (ISG) transcripts and serum cytokines were explored. Most patients were male (64.1%) and HBeAg-negative (60.9%) at baseline. Among vesatolimod-treated patients, most (60.4%-69.1%) experienced ≥1 treatment-emergent adverse event; the majority were mild or moderate in severity. No clinically meaningful differences in HBsAg changes from baseline were observed between treatment groups. No patients experienced HBsAg loss, while 3 patients experienced HBeAg loss and hepatitis B e-antibody seroconversion at week 48. HBV DNA suppression rates were similar across all treatment arms at Week 24. ISG15 induction was dose-dependent and did not correlate with HBsAg changes. A small proportion of patients exhibited dose-dependent interferon-α induction that correlated with grade of influenza-like adverse events. Overall, vesatolimod is safe and well tolerated in CHB patients. Although consistent dose-dependent pharmacodynamic induction of ISGs was demonstrated, it did not result in clinically significant HBsAg decline.


Assuntos
Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Pteridinas/administração & dosagem , Pteridinas/farmacologia , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/farmacologia , Citocinas/sangue , Citocinas/imunologia , DNA Viral/sangue , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/sangue , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Interferon-alfa/sangue , Interferon-alfa/imunologia , Masculino , Pessoa de Meia-Idade , Pteridinas/efeitos adversos , Soroconversão , Tenofovir/administração & dosagem , Tenofovir/efeitos adversos , Tenofovir/farmacologia , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Adulto Jovem
8.
Ther Innov Regul Sci ; 52(4): 416-422, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29714574

RESUMO

Volasertib is a selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase (Plk). A potential for prolonged QT intervals was indicated with volasertib in preclinical studies and preliminary clinical data. As a result, electrocardiograms (ECGs) have been collected in all volasertib clinical trials to monitor potential cardiac effects. This article describes strategic and statistical methods prospectively planned to perform an integrated analysis of ECG data from available trials to evaluate volasertib's effect on cardiac repolarization, as reflected by changes in the duration of QT interval and other ECG-related endpoints. Methods to effectively cope with heterogeneity between trials (ie, differences in study designs) are discussed. These strategies may be useful for other investigational drugs for which QT risk assessment is required, but a thorough QT/QTc trial is not feasible, resulting in the need for an alternative approach. Volasertib therapy relevantly prolonged adjusted mean QTcF change from administration baseline following the first and subsequent infusions. The integrated analysis revealed that the volasertib effects on the mean QTc changes from baseline were transient and had resolved at 24 hours after start of the first infusion. There was no evidence for a long-term impact on the QTcF interval following multiple infusions with volasertib.


Assuntos
Síndrome do QT Longo/diagnóstico , Inibidores de Proteínas Quinases/efeitos adversos , Pteridinas/efeitos adversos , Ensaios Clínicos como Assunto , Drogas em Investigação , Eletrocardiografia , Humanos , Síndrome do QT Longo/induzido quimicamente , Estudos Prospectivos , Inibidores de Proteínas Quinases/administração & dosagem , Pteridinas/administração & dosagem , Projetos de Pesquisa
9.
Antiviral Res ; 153: 39-48, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29425831

RESUMO

Human enterovirus 71 (EV71) is the second most common cause of hand, foot, and mouth disease (HFMD), which can occur as a severe epidemic especially among children under 5-years old. New and improved treatment strategies to control EV71 infection are therefore urgently required. The heterocyclic compound GS-9620, a potent and selective agonist of Toll-like receptor 7 (TLR7), has been reported to activate plasmacytoid dendritic cells (pDCs), and suppress HBV as well as HIV replication. In this study, we indicated that GS-9620 also could inhibit EV71 replication in the mouse model of EV71 infection. With three-days treatment after EV71 infection, the levels of proinflammatory cytokines/chemokines, like IFN-α, IFN-γ and MCP-1, were sharply reduced in serum compared to those without treatment. Furthermore, GS-9620 activated TLR7 in the limb muscle cells, which stimulated the NF-κB and PI3K/AKT signaling pathways. When NF-κB or PI3K/AKT inhibitors were used, the antiviral effect of the GS-9620 was impacted. Overall, our data implied GS-9620 probably activates NF-κB and PI3K/AKT signaling pathways to clear the virus.


Assuntos
Antivirais/administração & dosagem , Enterovirus Humano A/efeitos dos fármacos , Doença de Mão, Pé e Boca/tratamento farmacológico , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Pteridinas/administração & dosagem , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/farmacologia , Citocinas/sangue , Modelos Animais de Doenças , Enterovirus Humano A/crescimento & desenvolvimento , Doença de Mão, Pé e Boca/patologia , Camundongos , Pteridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
10.
Gastroenterology ; 154(6): 1764-1777.e7, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29378197

RESUMO

BACKGROUND & AIMS: The oral Toll-like receptor (TLR) 7 agonist GS-9620 has antiviral effects in woodchuck and chimpanzee models of chronic hepatitis B virus (HBV) infection. We investigated, in a clinical trial, the capacity of this agent to reconstitute protective immunity in patients with chronic HBV infection. METHODS: We performed a prospective study of 28 patients with suppression of HBV infection by nucleos(t)ide analogue therapy and who tested negative for hepatitis B e antigen at 4 medical centers in Italy. Patients were randomly assigned (1:3:3:3) to groups given placebo or different doses of GS-9620 (1, 2, and 4 mg, weekly for 12 weeks). We added data from 8 patients receiving nucleos(t)ide analogue therapy to the placebo group (controls); 13 treatment-naïve patients with chronic HBV infection and 15 subjects who spontaneously recovered from an acute HBV infection served as additional controls. Peripheral blood mononuclear cells were collected at baseline, during administration of GS-9620 or placebo, and 12 weeks afterward. Phenotype and function of natural killer (NK) and HBV-specific T cells were analyzed by flow cytometry. T cells were expanded by incubation with peptides from the entire HBV proteome and studied after overnight or 10 days culture. NK-cell inhibition of T-cell responses was measured by assessing cytokine production by T cells stimulated with peptides in the presence or absence of NK cells. RESULTS: T cells collected at baseline before addition of GS-9620, when patients were receiving only nucleos(t)ide therapy, had greater responses to HBV than T cells from treatment-naïve patients, based on cytokine production in response to HBV peptides. However, during or after administration of GS-9620, T cells produced higher levels of cytokines compared to baseline. NK-cell activation and function increased after patients were given GS-9620, but the ability of NK cells to suppress T-cell responses was lower during GS-9620 therapy than before. Changes in T-cell or NK-cell function did not correlate with levels of hepatitis B surface antigen. Serum levels of hepatitis B surface antigen did not decrease significantly compared to baseline in patients given any dose of GS-9620. CONCLUSIONS: Twelve weeks administration of GS-9620 had no significant effect on serum hepatitis B surface antigen levels, but did appear to increase T-cell and NK-cell responses and reduce the ability of NK to suppress T cells. GS-9620 might therefore be included in therapies to increase the immune response to HBV.


Assuntos
Antivirais/administração & dosagem , Vírus da Hepatite B/imunologia , Hepatite B Crônica/tratamento farmacológico , Células Matadoras Naturais/efeitos dos fármacos , Pteridinas/administração & dosagem , Linfócitos T/efeitos dos fármacos , Adulto , Feminino , Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Nucleosídeos/uso terapêutico , Estudos Prospectivos , Receptor 7 Toll-Like/agonistas
11.
J Hepatol ; 68(3): 431-440, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29104121

RESUMO

BACKGROUND & AIMS: Vesatolimod (GS-9620) is an oral agonist of toll-like receptor 7, an activator of innate and adaptive immune responses. Herein the safety and efficacy of vesatolimod is assessed after once-weekly treatment in patients with chronic hepatitis B (CHB) infection suppressed on oral antiviral treatment. METHODS: In a phase II, double-blind, randomized, placebo (PBO)-controlled study, 162 patients stratified by hepatitis B surface antigen (HBsAg) levels and serum hepatitis B e antigen (HBeAg) status were randomized 1:3:3:3 to once-weekly oral PBO or vesatolimod (1-, 2-, or 4-mg doses) for 4, 8 or 12 weeks per cohort. Efficacy was assessed by change in baseline HBsAg (log10 IU/ml) at the primary endpoint (Week 24). Safety assessments included adverse events (AE) and laboratory abnormality monitoring. Pharmacodynamic assessments included peripheral cytokine level quantification and interferon-stimulated gene (ISG) mRNA expression evaluation. RESULTS: The majority of patients were male (76%) and HBeAg-negative (79%) at baseline. Most (41-80%) experienced ≥1 AE during the study with the majority of AEs mild or moderate in severity. No significant declines in HBsAg were observed at the primary (Week 24) or secondary endpoints (Weeks 4, 8, 12, and 48). ISG15 induction was dose-dependent and consistent after repeat dosing, returning closer to baseline by one week after treatment at all dose levels; no patient demonstrated significant serum interferon alpha (IFNα) expression at any timepoint evaluated. Multivariate analyses showed that ≥2-fold ISG15 induction is associated with 2- or 4-mg vesatolimod dose and female sex. CONCLUSIONS: Vesatolimod was safe and well-tolerated in patients with CHB, demonstrating consistent dose-dependent pharmacodynamic induction of ISG15 without significant systemic induction of IFNα expression or related symptoms. However, no significant HBsAg declines were observed. LAY SUMMARY: In a phase II study, vesatolimod, an oral, once-weekly, experimental immune-activating drug for the treatment of hepatitis B virus (HBV), is safe and well-tolerated in chronic HBV patients who are virally suppressed on oral antiviral treatment. Despite demonstrating on-target biomarker responses in patients, no significant declines in hepatitis B surface antigen were observed. Clinical Trial Number: GS-US-283-1059; NCT 02166047.


Assuntos
Vírus da Hepatite B , Hepatite B Crônica , Pteridinas , Imunidade Adaptativa/efeitos dos fármacos , Administração Oral , Adulto , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/farmacocinética , Método Duplo-Cego , Monitoramento de Medicamentos/métodos , Feminino , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Masculino , Pessoa de Meia-Idade , Monitorização Imunológica/métodos , Pteridinas/administração & dosagem , Pteridinas/efeitos adversos , Pteridinas/farmacocinética , Receptor 7 Toll-Like/agonistas , Resultado do Tratamento
12.
Clin Pharmacokinet ; 57(3): 379-392, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28631179

RESUMO

BACKGROUND: Volasertib, a potent and selective polo-like kinase inhibitor, has shown to increase response rates and improve survival with a clinically manageable safety profile, administered alone and in combination with cytarabine in patients with acute myeloid leukaemia. OBJECTIVES: The objectives of this analysis were to describe the pharmacokinetics of volasertib and cytarabine, administered as single agents or in combination. METHODS: Three thousand, six hundred and six plasma volasertib concentrations from 501 patients receiving either volasertib alone, or in combination with cytarabine, and 826 plasma cytarabine concentrations from 650 patients receiving cytarabine as multiple subcutaneous injections per cycle either alone, or in combination with volasertib, were analysed using NONMEM Version 7.3. Covariates evaluated included demographic and disease-related parameters. RESULTS: The pharmacokinetics of volasertib were found to be dose independent from 150 to 550 mg. Body surface area and ethnicity showed significant effects in all the patients. This is reflected as an increase in drug exposure for Japanese patients, although this finding has to be interpreted with caution because only 7% of patients were part of that population group. Volasertib showed low-to-mild inter-individual variability in total clearance. For the case of cytarabine, its pharmacokinetics was affected by body surface area. Finally, volasertib and cytarabine did not influence the pharmacokinetic characteristics of each other. CONCLUSIONS: The pharmacokinetics of volasertib in patients with acute myeloid leukaemia alone or in combination with cytarabine is predictable and associated with low-to-mild patient variability with the exception of the high variability associated with the volume of distribution of the central compartment, having no effect on the area under the plasma concentration-time curve.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Pteridinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Superfície Corporal , Citarabina/administração & dosagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pteridinas/farmacocinética , Distribuição Tecidual
13.
Lung Cancer ; 104: 126-130, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28212994

RESUMO

OBJECTIVES: This phase II, open-label study was designed to evaluate the response rate to the polo-like kinase 1 (Plk-1) inhibitor BI 2536 in patients with sensitive-relapsed small cell lung cancer (SCLC). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, and safety. MATERIALS AND METHODS: Patients were treated with the recommended phase II dose of 200mg of BI 2536 intravenously every 21days. This was a two-stage design with an early stopping rule in place if responses were not seen in at least 2 of the first 18 enrolled patients. RESULTS AND CONCLUSION: Twenty-three patients were enrolled in the study and 21 patients were evaluable for response. No responses were observed and all 23 patients have progressed. The median PFS was 1.4 months. Treatment was generally well tolerated and the most frequent adverse events were neutropenia, fatigue, nausea, vomiting, and constipation. BI 2536 is not effective in the treatment of sensitive relapsed SCLC. The criteria for expanding the trial to the second stage were not achieved, and the study was terminated for a lack of efficacy.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pteridinas/administração & dosagem , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Administração Intravenosa , Adulto , Idoso , Proteínas de Ciclo Celular/efeitos adversos , Proteínas de Ciclo Celular/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Proteínas Serina-Treonina Quinases/efeitos adversos , Proteínas Serina-Treonina Quinases/uso terapêutico , Proteínas Proto-Oncogênicas/efeitos adversos , Proteínas Proto-Oncogênicas/uso terapêutico , Pteridinas/efeitos adversos , Pteridinas/farmacologia , Recidiva , Carcinoma de Pequenas Células do Pulmão/patologia , Fumar/epidemiologia , Falha de Tratamento , Resultado do Tratamento
14.
Oncotarget ; 7(30): 47998-48010, 2016 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-27384992

RESUMO

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective against non-small cell lung cancer (NSCLC) with activating EGFR mutations, but resistance is inevitable. Mechanisms of acquired resistance include T790M mutations and epithelial-mesenchymal transition (EMT). One potential strategy for overcoming this resistance is the inhibition of polo-like kinase 1 (PLK1) based on our previous studies showing that mesenchymal NSCLC cell lines are more sensitive to PLK1 inhibition than epithelial cell lines. To determine the extent to which PLK1 inhibition overcomes EGFR TKI resistance we measured the effects of the PLK1 inhibitor volasertib alone and in combination with the EGFR inhibitor erlotinib in vitro and in vivo in EGFR mutant NSCLC cell lines with acquired resistance to erlotinib. Two erlotinib-resistant cell lines that underwent EMT had higher sensitivity to volasertib, which caused G2/M arrest and apoptosis, than their parental cells. In all NSCLC cell lines with T790M mutations, volasertib markedly reduced erlotinib resistance. All erlotinib-resistant NSCLC cell lines with T790M mutations had higher sensitivity to erlotinib plus volasertib than to erlotinib alone, and the combination treatment caused G2/M arrest and apoptosis. Compared with either agent alone, the combination treatment also caused significantly more DNA damage and greater reductions in tumor size. Our results suggest that PLK1 inhibition is clinically effective against NSCLC that becomes resistant to EGFR inhibition through EMT or the acquisition of a T790M mutation. These results uncover new functions of PLK1 inhibition in the treatment of NSCLC with acquired resistance to EGFR TKIs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas de Ciclo Celular/antagonistas & inibidores , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pteridinas/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Cloridrato de Erlotinib/administração & dosagem , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Pteridinas/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Med Res Rev ; 36(4): 749-86, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27140825

RESUMO

Considering the important side effects of conventional microtubule targeting agents, more and more research focuses on regulatory proteins for the development of mitosis-specific agents. Polo-like kinase 1 (Plk1), a master regulator of several cell cycle events, has arisen as an intriguing target in this research field. The observed overexpression of Plk1 in a broad range of human malignancies has given rise to the development of several potent and specific small molecule inhibitors targeting the kinase. In this review, we focus on volasertib (BI6727), the lead agent in category of Plk1 inhibitors at the moment. Numerous preclinical experiments have demonstrated that BI6727 is highly active across a variety of carcinoma cell lines, and the inhibitor has been reported to induce tumor regression in several xenograft models. Moreover, volasertib has shown clinical efficacy in multiple tumor types. As a result, Food and Drug Administration (FDA) has recently awarded volasertib the Breakthrough Therapy status after significant benefit was observed in acute myeloid leukemia (AML) patients treated with the Plk1 inhibitor. Here, we discuss both preclinical and clinical data available for volasertib administered as monotherapy or in combination with other anticancer therapies in a broad range of tumor types.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pteridinas/farmacologia , Animais , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Pteridinas/administração & dosagem , Pteridinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
Strahlenther Onkol ; 192(4): 260-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26952039

RESUMO

PURPOSE: This study examined the efficacy of polo-like kinase 1 (PLK1) inhibition on radiosensitivity in vitro and in vivo by a pharmacologic approach using the highly potent PLK1 inhibitor volasertib. METHODS AND MATERIALS: Human esophageal squamous cell carcinoma (ESCC) cell lines KYSE 70 and KYSE 150 were used to evaluate the synergistic effect of volasertib and irradiation in vitro using cell viability assay, colony formation assay, cell cycle phase analysis, and western blot, and in vivo using ectopic tumor models. RESULTS: Volasertib decreased ESCC cell proliferation in a dose- and time-dependent manner. Combination of volasertib and radiation caused G2/M cell cycle arrest, increased cyclin B levels, and induced apoptosis. Volasertib significantly enhanced radiation-induced death in ESCC cells by a mechanism involving the enhancement of histone H3 phosphorylation and significant cell cycle interruption. The combination of volasertib plus irradiation delayed the growth of ESCC tumor xenografts markedly compared with either treatment modality alone. CONCLUSIONS: The in vitro results suggested that targeting PLK1 might be a viable approach to improve the effects of radiation in ESCC. In vivo studies showed that PLK1 inhibition with volasertib during irradiation significantly improved local tumor control when compared to irradiation or drug treatment alone.


Assuntos
Carcinoma de Células Escamosas/radioterapia , Proteínas de Ciclo Celular/antagonistas & inibidores , Sobrevivência Celular/efeitos da radiação , Neoplasias Esofágicas/radioterapia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pteridinas/administração & dosagem , Radiossensibilizantes , Animais , Apoptose/efeitos da radiação , Western Blotting , Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Quimiorradioterapia , Terapia Combinada , Xenoenxertos , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/radioterapia , Ensaio Tumoral de Célula-Tronco
17.
Anticancer Res ; 36(2): 599-609, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26851014

RESUMO

BACKGROUND: Polo-like kinase 1 (PLK1) controls the main cell-cycle checkpoints, suggesting utility of its inhibition for cancer treatment, including of highly proliferative pediatric cancer. This preclinical study explored the selective PLK1 inhibitor volasertib (BI 6727) alone and combined with chemotherapy in pediatric malignancies. MATERIALS AND METHODS: Inhibition of proliferation was explored in vitro using dimethylthiazol carboxymethoxyphenyl sulfophenyl tetrazolium (MTS) assay. Mice bearing human xenografts were treated with weekly intravenous injections of volasertib. RESULTS: Volasertib inhibited proliferation in all 40 cell lines tested, with a mean half-maximal growth inhibitory concentration of 313 nmol/l (range: 4-5000 nmol/l). Volasertib was highly active against RMS-1 alveolar rhabdomyosarcoma xenografts, resulting in 100% tumor regression. Activity was associated with complete and prolonged G2/M arrest and subsequent apoptotic cell death. Volasertib showed synergistic activity with vincristine but antagonistic effects with etoposide. CONCLUSION: These findings support the further exploration of volasertib for pediatric malignancies, particularly alveolar rhabdomyosarcoma, and its combination with mitotic spindle poison.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Sinergismo Farmacológico , Neoplasias/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/patologia , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Criança , Feminino , Citometria de Fluxo , Humanos , Meduloblastoma/tratamento farmacológico , Meduloblastoma/enzimologia , Meduloblastoma/patologia , Camundongos , Camundongos Nus , Neoplasias/enzimologia , Neoplasias/patologia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/enzimologia , Neuroblastoma/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Pteridinas/administração & dosagem , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/enzimologia , Rabdomiossarcoma/patologia , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/enzimologia , Sarcoma de Ewing/patologia , Células Tumorais Cultivadas , Vincristina/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Clin Oncol ; 34(7): 706-13, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26755507

RESUMO

PURPOSE: Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. This phase II trial evaluated volasertib or single-agent chemotherapy in patients with platinum-resistant or -refractory ovarian cancer who experienced failure after treatment with two or three therapy lines. PATIENTS AND METHODS: Patients were randomly assigned to receive either volasertib 300 mg by intravenous infusion every 3 weeks or an investigator's choice of single-agent, nonplatinum, cytotoxic chemotherapy. The primary end point was 24-week disease control rate. Secondary end points included best overall response, progression-free survival (PFS), safety, quality of life, and exploratory biomarker analyses. RESULTS: Of the 109 patients receiving treatment, 54 received volasertib and 55 received chemotherapy; demographics were well balanced. The 24-week disease control rates for volasertib and chemotherapy were 30.6% (95% CI, 18.0% to 43.2%) and 43.1% (95% CI, 29.6% to 56.7%), respectively, with partial responses in seven (13.0%) and eight (14.5%) patients, respectively. Median PFS was 13.1 weeks and 20.6 weeks for volasertib and chemotherapy (hazard ratio, 1.01; 95% CI, 0.66 to 1.53). Six patients (11%) receiving volasertib achieved PFS fore more than 1 year, whereas no patient receiving chemotherapy achieved PFS greater than 1 year. No relationship between the expression of the biomarkers tested and their response was determined. Patients treated with volasertib experienced more grade 3 and 4 drug-related hematologic adverse events (AEs) and fewer nonhematologic AEs than did patients receiving chemotherapy. Discontinuation resulting from AEs occurred in seven (13.0%) and 15 (27.3%) patients in the volasertib and chemotherapy arms, respectively. Both arms showed similar effects on quality of life. CONCLUSION: Single-agent volasertib showed antitumor activity in patients with ovarian cancer. AEs in patients receiving volasertib were mainly hematologic and manageable.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Pteridinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Carboplatina/uso terapêutico , Cisplatino/uso terapêutico , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Pteridinas/administração & dosagem , Qualidade de Vida , Resultado do Tratamento
19.
Int J Cancer ; 138(2): 497-506, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26260582

RESUMO

Since polo-like kinase 1 (PLK1) is highly expressed in Ewing sarcoma (ES), we evaluated the therapeutic potential of the PLK1 inhibitor BI 6727. Here, we identify a synergistic induction of apoptosis by BI 6727 and several microtubule-interfering drugs in ES cells, including vincristine (VCR), vinblastine (VBL), vinorelbine (VNR) and eribulin. Synergistic drug interaction is confirmed by calculation of combination index (CI). Also, BI 6727 and VCR act in concert to reduce long-term clonogenic survival. Mechanistically, BI 6727/VCR co-treatment cooperates to trigger mitotic arrest, phosphorylation of BCL-2 and BCL-XL and downregulation of MCL-1. This inactivation of anti-apoptotic BCL-2 family proteins in turn promotes activation of BAX and BAK, activation of caspase-9 and -3 and caspase-dependent apoptosis. Overexpression of BCL-2 or simultaneous knockdown of BAX and BAK significantly rescue BI 6727/VCR-induced apoptosis, indicating that engagement of the mitochondrial pathway is critical for BI 6727/VCR-mediated apoptosis. The clinical relevance of PLK1 inhibitor-based combination therapies is underscored by the fact that BI 6727 is currently evaluated in phase I clinical trials in childhood cancer. In conclusion, PLK1 inhibitors such as BI 6727 may provide a new strategy to chemosensitize ES.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/patologia , Sarcoma de Ewing/patologia , Western Blotting , Proteínas de Ciclo Celular/antagonistas & inibidores , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pteridinas/administração & dosagem , Interferência de RNA , Moduladores de Tubulina/administração & dosagem
20.
Invest New Drugs ; 34(1): 66-74, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26627079

RESUMO

PURPOSE: This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical effects of volasertib, a selective Polo-like kinase inhibitor that induces mitotic arrest and apoptosis, in Japanese patients with advanced solid tumors (NCT01348347; 1230.15). METHODS: In this phase I, open-label, dose-escalation trial, sequential patient cohorts (3 + 3 dose-escalation design) received volasertib (200-350 mg) as a single dose by intravenous infusion over 2 h on day 1 every 21 days until disease progression or unacceptable toxicity. The primary endpoint was the MTD of volasertib in Japanese patients with an advanced solid tumor; secondary endpoints included safety, pharmacokinetics, and clinical benefit. RESULTS: Fifteen patients with an advanced solid tumor were treated. Dose-limiting toxicities of grade 4 neutropenia for ≥7 days and grade 4 thrombocytopenia were both experienced by 2/6 patients in the 350 mg cohort. The MTD of volasertib in Japanese patients was 300 mg. The most common (≥3 patients) drug-related non-hematologic adverse events included fatigue, decreased appetite, and nausea. Exposure to volasertib and its metabolite increased with increasing doses. A partial response in a patient with gastric cancer and stable disease in eleven patients were observed. CONCLUSIONS: Volasertib had a manageable safety profile up to the MTD determined as 300 mg. Exposure to volasertib and its metabolite increased with increasing doses. The safety profile of volasertib in Japanese patients is comparable with those previously obtained in Caucasian patients. These data support enrollment of Japanese patients in global clinical trials without dose modification.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pteridinas/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Grupo com Ancestrais do Continente Asiático , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pteridinas/efeitos adversos , Pteridinas/farmacocinética
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