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1.
Anticancer Res ; 41(9): 4535-4542, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475080

RESUMO

BACKGROUND/AIM: Due to the SARS-CoV-2 pandemic, many scientific committees proposed neoadjuvant therapy (NACT) bridging treatment as a novel strategy and indication. The aim of the study was to evaluate the impact of COVID-19 pandemic on breast cancer patients undergoing NACT. PATIENTS AND METHODS: All breast cancer patients referred to two Breast Units during COVID-19-pandemic were enrolled. RESULTS: Out of 814 patients, 43(5.3%) were enrolled in the COVID-19-group and compared with 94 (7.9%) similar Pre-COVID-19 patients. We observed a reduction in the number of patients undergoing NACT, p=0.0019. No difference was reported in terms of clinical presentation, indications, and tumor response. In contrast, a higher number of vascular adverse events was reported (6.9% vs. 0% p=0.029). Immediate breast cancer reconstructions following invasive surgery suffered a significant slowdown (5.9% vs. 47.7%, p=0.019). CONCLUSION: COVID-19 caused a reduction in the number of patients undergoing NACT, with no changes in terms of indications, clinical presentation, and tumor response. Furthermore, there was an increased incidence of vascular events.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , COVID-19/epidemiologia , Mamoplastia/estatística & dados numéricos , Terapia Neoadjuvante/estatística & dados numéricos , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , COVID-19/complicações , Tratamento Farmacológico/estatística & dados numéricos , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Pandemias , Estudos Retrospectivos , Resultado do Tratamento
2.
Anticancer Res ; 41(9): 4555-4562, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475083

RESUMO

BACKGROUND/AIM: While there is increasing evidence supporting the role of several first- and second-line treatment regimens for advanced hepatocellular carcinomas (HCC), the clinical relevance of rechallenge treatment with previously administered drugs, however, remains to be explored. PATIENTS AND METHODS: Five consecutive patients with advanced HCC who received lenvatinib rechallenge treatment after ramucirumab were assessed. RESULTS: All patients were clinically diagnosed with failure after ramucirumab treatment, and the frequencies of ramucirumab administration before lenvatinib re-administration ranged from 3 to 11. The alfa-fetoprotein level in four of five patients decreased 1 month after the lenvatinib rechallenge. Radiological findings via the modified Response Evaluation Criteria in Solid Tumors showed stable diseases in four patients and a partial response in one. CONCLUSION: Rechallenge treatment with lenvatinib after ramucirumab can be effective, and may be a treatment option for HCC in cases wherein the disease progressed after an initial response to lenvatinib treatment.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Quinolinas/administração & dosagem , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Estudos Retrospectivos , Falha de Tratamento , Resultado do Tratamento , alfa-Fetoproteínas/metabolismo
3.
Isr Med Assoc J ; 23(9): 556-562, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34472230

RESUMO

BACKGROUND: Early referral to palliative care services in patients with advanced cancer is widely accepted. In addition, the use of futile intervention at the end of life is a pivotal aspect of assessing quality of care at that time. OBJECTIVES: To evaluate the use of palliative care and aggressive treatments during the last month of life in women with gynecological malignancies. METHODS: The study was designed in two steps. The first step included a retrospective analysis of a gynecologic oncology cohort that underwent end-of-life (EOL) care. In the second part, a questionnaire regarding EOL care was completed by family members. Since our palliative care service became more active after 2014, we compared data from the years 2013-2014 to the years 2015-2019. RESULTS: We identified 89 patients who died from gynecological malignancy during study period; 21% received chemotherapy and 40% underwent invasive procedures during their last month of life. A palliative care consultation was documented for 49% of patients more than one week before their death. No statistical difference was achieved between the two time periods regarding the use of chemotherapy or invasive procedures in the last month of life. Nonetheless, after the incorporation of palliative medicine more women had palliative care consultations and had EOL discussions. Most of the patients' relatives were satisfied with EOL care. CONCLUSIONS: Many aggressive interventions were given during the last month of life. EOL discussions were documented in the medical charts of most patients and the rates increased with time.


Assuntos
Neoplasias dos Genitais Femininos/terapia , Cuidados Paliativos/métodos , Assistência Terminal/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Estudos de Coortes , Feminino , Humanos , Israel , Pessoa de Meia-Idade , Satisfação do Paciente/estatística & dados numéricos , Encaminhamento e Consulta , Estudos Retrospectivos , Inquéritos e Questionários
4.
BMJ ; 374: n1959, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34497044

RESUMO

OBJECTIVES: To investigate the regulatory handling of cancer drugs that were granted accelerated approval by the US Food and Drug Administration (FDA) but failed to improve the primary endpoint in post-approval trials and to evaluate the extent to which negative post-approval trials changed the recommendations in treatment guidelines. DESIGN: Retrospective observational study. SETTING: FDA and National Comprehensive Cancer Network (NCCN) reports. INCLUDED DRUGS: Cancer drugs that received accelerated approval from the FDA and had negative post-approval trials. MAIN OUTCOME MEASURES: Regulatory outcomes, including withdrawal, conversion to regular approval, and no action. RESULTS: 18 indications for 10 cancer drugs that received accelerated approval but failed to improve the primary endpoint in post-approval trials were identified. Of these, 11 (61%) were voluntarily withdrawn by the manufacturer and one (bevacizumab for breast cancer) was revoked by the FDA. Of the 11 withdrawals, six occurred in 2021 alone. The remaining six (33%) indications remain on the label. The NCCN guidelines provide a high level of endorsement (category 1 endorsement for one and category 2A endorsement for seven) for accelerated approval drugs that have failed post-approval trials, sometimes even after the approval has been withdrawn or revoked. CONCLUSION: Cancer drug indications that received accelerated approval often remained on formal FDA approved drug labelling and continued to be recommended in clinical guidelines several years after statutorily required post-approval trials showed no improvement in the primary efficacy endpoint. Clinical guidelines should better align with the results of post-approval trials of cancer drugs that received accelerated approval.


Assuntos
Antineoplásicos/efeitos adversos , Aprovação de Drogas , Neoplasias/tratamento farmacológico , Antineoplásicos/administração & dosagem , Bases de Dados Factuais , Intervalo Livre de Doença , Rotulagem de Medicamentos , Determinação de Ponto Final , Humanos , Intervalo Livre de Progressão , Estudos Retrospectivos , Retirada de Medicamento Baseada em Segurança/estatística & dados numéricos , Fatores de Tempo , Incerteza , Estados Unidos , United States Food and Drug Administration
6.
Molecules ; 26(15)2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34361634

RESUMO

Prolonging in vivo circulation has proved to be an efficient route for enhancing the therapeutic effect of rapidly metabolized drugs. In this study, we aimed to construct a nanocrystal-loaded micelles delivery system to enhance the blood circulation of docetaxel (DOC). We employed high-pressure homogenization to prepare docetaxel nanocrystals (DOC(Nc)), and then produced docetaxel nanocrystal-loaded micelles (DOC(Nc)@mPEG-PLA) by a thin-film hydration method. The particle sizes of optimized DOC(Nc), docetaxel micelles (DOC@mPEG-PLA), and DOC(Nc)@mPEG-PLA were 168.4, 36.3, and 72.5 nm, respectively. The crystallinity of docetaxel was decreased after transforming it into nanocrystals, and the crystalline state of docetaxel in micelles was amorphous. The constructed DOC(Nc)@mPEG-PLA showed good stability as its particle size showed no significant change in 7 days. Despite their rapid dissolution, docetaxel nanocrystals exhibited higher bioavailability. The micelles prolonged the retention time of docetaxel in the circulation system of rats, and DOC(Nc)@mPEG-PLA exhibited the highest retention time and bioavailability. These results reveal that constructing nanocrystal-loaded micelles may be a promising way to enhance the in vivo circulation and bioavailability of rapidly metabolized drugs such as docetaxel.


Assuntos
Antineoplásicos/farmacocinética , Docetaxel/farmacocinética , Portadores de Fármacos/farmacocinética , Nanopartículas/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Docetaxel/administração & dosagem , Masculino , Micelas , Ratos , Ratos Sprague-Dawley
7.
Medicine (Baltimore) ; 100(31): e26801, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34397833

RESUMO

RATIONALE: At present, the prognosis of patients with giant lung squamous cell carcinoma (LSCC) is poor, and there is no safe and effective treatment for elderly patients with large LSCC. PATIENT CONCERNS: Here, we reported a 77-year-old man admitted to the hospital with cough for 3 months and significant chest pain. Computed tomography (CT) imaging showed a large mass in the left lung with pleural effusion. DIAGNOSES: Chest CT scan revealed a 12.5 cm × 7.3 cm mass in the left upper lobe adjacent to the pulmonary vein, with left pleural effusion. Pulmonary tumor markers were significantly elevated, and CT-guided percutaneous lung mass biopsy specimens showed LSCC. INTERVENTIONS: After diagnosis, the patient was treated with sintilimab combined with endostar and nab-paclitaxel. After 2 cycles of treatment, the lung mass in the patient shrank rapidly and the clinical symptoms were relieved. OUTCOMES: The patient's tumor dramatically shrank, and the pleural effusion was decreased after 4 cycles of treatment without any adverse effects. Meanwhile, the high-level tumor marker resumed normal. LESSONS: Sintilimab combined with endostar and nab-paclitaxel may be a good treatment option for lung squamous cell cancer, especially for that in elderly patients.


Assuntos
Albuminas/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Carcinoma de Células Escamosas , Endostatinas/administração & dosagem , Neoplasias Pulmonares , Paclitaxel/administração & dosagem , Derrame Pleural , Proteínas Recombinantes/administração & dosagem , Idoso , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biópsia/métodos , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/fisiopatologia , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/fisiopatologia , Masculino , Estadiamento de Neoplasias , Derrame Pleural/diagnóstico por imagem , Derrame Pleural/etiologia , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Carga Tumoral
8.
Medicine (Baltimore) ; 100(31): e26820, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34397843

RESUMO

ABSTRACT: Real-world clinical cases of molecularly targeted agent (MTA) administration to patients with advanced hepatocellular carcinoma (HCC) with ≥50% liver occupation have been reported, but treatment outcomes have rarely been described. We have encountered several cases in which albumin-bilirubin (ALBI) scores deteriorated markedly and C-reactive protein (CRP) levels elevated in the early post-dose period. The present study therefore investigated early clinical changes in ALBI score and CRP levels after initiating MTA in advanced HCC patients with ≥50% liver occupation, focusing on antitumor response at 6 weeks.This retrospective study included 46 HCC patients with liver occupation ≥50% and 191 patients with <50%, Child-Pugh score ≤7, and Eastern Cooperative Oncology Group Performance Status scores of 0 or 1, who were treated with sorafenib or lenvatinib as first-line systemic therapy at our hospital between June 2011 and January 2020. We analyzed their medical records up to March 2020 and investigated the outcomes and changes in CRP and ALBI scores classified according to antitumor response at 6 weeks.Overall survival was significantly longer in patients with partial response (PR) + stable disease (SD) (13.7 months) than in patients with progressive disease (PD) (1.7 months, P < .001) in the ≥50% group. Patients with antitumor response of PR + SD at 6 weeks in the ≥50% group showed more marked deterioration of ALBI score at 2 weeks than those in the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. Focusing on patients with PD at 6 weeks, ALBI score deteriorated over time in both groups. Regarding CRP, on 6-week PR + SD patients, a significant increase in CRP levels at 1 and 2 weeks was evident in the >50% group compared to the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. In PD patients, no difference between groups in CRP elevation occurred at 1 and 2 weeks.In MTA treatment for patients with ≥50% liver occupation, to obtain an antitumor response of PR + SD, adequate management might be important considering transient deteriorated ALBI scores and elevated CRP levels.


Assuntos
Bilirrubina/análise , Carcinoma Hepatocelular , Neoplasias Hepáticas , Compostos de Fenilureia , Quinolinas , Albumina Sérica/análise , Sorafenibe , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biomarcadores Farmacológicos/análise , Proteína C-Reativa/análise , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Correlação de Dados , Monitoramento de Medicamentos/métodos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Humanos , Japão/epidemiologia , Fígado/diagnóstico por imagem , Fígado/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Terapia de Alvo Molecular/métodos , Estadiamento de Neoplasias , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Sorafenibe/administração & dosagem , Sorafenibe/efeitos adversos
9.
Medicine (Baltimore) ; 100(31): e26844, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34397857

RESUMO

RATIONALE: Primary signet ring cell carcinoma of the uterine cervix is extremely rare and the clinical characteristics and prognosis are not well known and there are no specific guidelines for treatment. PATIENT CONCERNS: A 43-year-old woman was referred to our hospital for abnormal uterine bleeding lasting 1 month. DIAGNOSES: Histological examination revealed a signet ring cell carcinoma of the uterine cervix. After evaluation of extragenital origin, the patient was diagnosed International Federation of Gynecology and Obstetrics stage IIIC1 primary signet ring cell carcinoma or the uterine cervix. INTERVENTION: The patient was prescribed concomitant chemo-radiation followed by intracavitary brachytherapy. OUTCOMES: She showed no evidence of disease after treatment but, it recurred after 7 months of last treatment. LESSONS: Different approaches to diagnosis and treatment of this rare disease are needed and molecular pathological studies related to the onset of the disease are required.


Assuntos
Carcinoma de Células em Anel de Sinete , Colo do Útero , Quimiorradioterapia/métodos , Cisplatino/administração & dosagem , Neoplasias do Colo do Útero , Esfregaço Vaginal/métodos , Adulto , Antineoplásicos/administração & dosagem , Biópsia/métodos , Braquiterapia/métodos , Carcinoma de Células em Anel de Sinete/patologia , Carcinoma de Células em Anel de Sinete/fisiopatologia , Carcinoma de Células em Anel de Sinete/terapia , Colo do Útero/diagnóstico por imagem , Colo do Útero/patologia , Evolução Fatal , Feminino , Humanos , Recidiva Local de Neoplasia/patologia , Papillomaviridae/isolamento & purificação , Retratamento/métodos , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/fisiopatologia , Neoplasias do Colo do Útero/terapia , Hemorragia Uterina/diagnóstico , Hemorragia Uterina/etiologia
10.
Pan Afr Med J ; 39: 18, 2021.
Artigo em Francês | MEDLINE | ID: mdl-34394809

RESUMO

Introduction: cancer is a major cause of death in the world. The purpose of this study is to evaluate the epidemiological, clinical, therapeutic and prognostic features of cancers of the pancreas (CP) at the National Hospital and University Center of Cotonou. Methods: we conducted a cross-sectional descriptive and analytical study with a prospective and retrospective data collection over a period of ten years, from 1 October 2009 to 31 October 2019. Results: out of 15.102 hospitalizations, we identified 72 cases of CP, reflecting a hospitalization rate of 0.5%. The average age of patients was 59 years. The sex-ratio (H/F) was 1.5. The main reason for consultation was abdominal pain. More than half (51.4%) of patients had metastatic tumor at the time of diagnosis. Histological evidence of adenocarcinoma was only reported in 15.1% of cases. The rate of operable patients was 37.5% while the rate of resectable patients was 2.7%. Palliative chemotherapy was given to 13.9% of patients. The average cost of treatment was 955.882,4 FCFA (23.9 times the Guaranteed Interprofessional Minimum Wage in Benin). Median overall survival was 6 months. Mortality rate was 86.9% (53/61), survival rate at one year was 31.4%, and zero at five years. Palliative surgery (p = 0.021) and chemotherapy (p = 0.023) improved patient survival. Conclusion: cancer of the pancreas, due to its non-specific signs and insidious outcome, is often diagnosed at a late stage. A metastatic tumor and the limited individual and institutional therapeutic possibilities lead to more pejorative prognosis.


Assuntos
Adenocarcinoma/epidemiologia , Hospitalização/estatística & dados numéricos , Cuidados Paliativos/métodos , Neoplasias Pancreáticas/epidemiologia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Benin , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida
11.
Medicine (Baltimore) ; 100(32): e26138, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397868

RESUMO

RATIONALE: Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy that is almost always fatal and lacks effective systemic treatment options. Current treatments of ATC include surgery, radiation, and chemotherapy, used in combination when possible. In the aspect of immunotherapy, the biomarker of TMB-H and MSI-H may suggest that patients benefit from pembrolizumab. Programmed cell death-ligand 1 (PD-L1) is highly expressed in ATC but has not been written into the guidelines or approved by the FDA as a biomarker for thyroid cancer immunotherapy. PATIENT CONCERNS: A 55-year-old woman was admitted to our hospital because of a slight right-sided neck enlargement in November 2019. DIAGNOSES: The clinical diagnosis was ATC, pT3bN0M0, and stage IVB. INTERVENTIONS: Oral administration of apatinib (250 mg 3 times daily) was initiated after surgery, but some unpleasant side effects emerged after 1 month of treatment. Next-generation sequencing revealed that the tumor harbored 2 mutations, HRAS p.Q61R and TP53 p.P278S, and PD-L1 staining was positive with a high expression. Thus, camrelizumab (programmed cell death protein 1 inhibitor) was combined with apatinib, and apatinib was changed to 250 mg once a day from March 2020. OUTCOMES: No adverse reactions were observed after the treatment immunotherapy combined with antiangiogenic drugs. Currently, the survival time of patients is more than 11 months, and the quality of life is not affected. CONCLUSION: This case suggests that immunotherapy in patients with ATC based upon PD-L1 evaluation provides a therapeutic option. Targeting programmed cell death protein 1/PD-L1 may provide a much-needed treatment option for patients with advanced ATC.


Assuntos
Imunoterapia/métodos , Piridinas/administração & dosagem , Carcinoma Anaplásico da Tireoide/terapia , Neoplasias da Glândula Tireoide/terapia , Administração Oral , Antineoplásicos/administração & dosagem , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Feminino , Humanos , Pessoa de Meia-Idade , Carcinoma Anaplásico da Tireoide/diagnóstico , Carcinoma Anaplásico da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/diagnóstico
12.
Medicine (Baltimore) ; 100(32): e26845, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397891

RESUMO

RATIONALE: Despite the development of human papillomavirus vaccines and significant improvement in cervical cancer screening over the past few years, cervical cancer remains the fourth most common cancer in women of childbearing age after breast cancer, melanoma, and thyroid cancer. PATIENT CONCERNS: In this case report, the patients are all cervical cancer with stage IB2 and IB3 during pregnancy, the management constitutes a major medical challenge related to the impact of treatment on both maternal and fetal outcomes. Neoadjuvant chemotherapy (NACT) is an innovative option for cervical cancer patients with stage IB2 and IB3 before cesarean delivery and radical hysterectomy, and many chemotherapeutic agents are available, cisplatin plus paclitaxel yielded good maternal and fetal outcomes to the authors' knowledge. DIAGNOSES: Masses were discovered in the cervix of 4 pregnant women with a history of vaginal bleeding. Biopsy examination of the masses revealed cervical carcinoma, which was staged in accordance with the International Federation of Gynecology and Obstetrics (i.e., FIGO) system. INTERVENTIONS: The patients were treated with paclitaxel plus cisplatin, followed by cesarean delivery and radical hysterectomy. OUTCOMES: The 4 patients were treated successfully, with no recurrence during follow-up periods of 14 to 56 months, and all of the children were doing well with no anomalies. LESSONS: Although further data are required, in pregnant women with invasive cervical cancer, NACT with cisplatin plus paclitaxel followed by cesarean delivery and radical hysterectomy was a practical treatment option.


Assuntos
Cisplatino , Histerectomia/métodos , Paclitaxel , Complicações Neoplásicas na Gravidez , Neoplasias do Colo do Útero , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biópsia/métodos , Colo do Útero/patologia , Cesárea/métodos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Feminino , Humanos , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Gravidez , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Complicações Neoplásicas na Gravidez/patologia , Complicações Neoplásicas na Gravidez/cirurgia , Resultado da Gravidez , Resultado do Tratamento , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/cirurgia
13.
J Enzyme Inhib Med Chem ; 36(1): 1839-1859, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34338119

RESUMO

A series of [1]benzothieno[2,3-c]pyridines was synthesised. Most compounds were chosen by NCI-USA to evaluate their anticancer activity. Compounds 5a-c showed prominent growth inhibition against most cell lines. 5c was selected at five dose concentration levels. It exhibited potent broad-spectrum anticancer activity with a GI50 of 4 nM-37 µM. Cytotoxicity of 5a-c was further evaluated against prostate, renal, and breast cancer cell lines. 5c showed double and quadruple the activity of staurosporine and abiraterone, respectively, against the PC-3 cell line with IC50 2.08 µM. The possible mechanism of anti-prostate cancer was explored via measuring the CYP17 enzyme activity in mice prostate cancer models compared to abiraterone. The results revealed that 5c suppressed the CYP17 enzyme to 15.80 nM. Moreover, it was found to be equipotent to abiraterone in testosterone production. Cell cycle analysis and apoptosis were performed. Additionally, the ADME profile of compound 5c demonstrated both good oral bioavailability and metabolic stability.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Piridinas/química , Piridinas/farmacologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Linhagem Celular Tumoral , Simulação por Computador , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Humanos , Masculino , Camundongos , Neoplasias da Próstata/patologia , Piridinas/síntese química , Piridinas/farmacocinética , Análise Espectral/métodos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Nat Commun ; 12(1): 5001, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408151

RESUMO

As a basic structure of most polypyridinal metal complexes, [Ru(bpy)3]2+, has the advantages of simple structure, facile synthesis and high yield, which has great potential for scientific research and application. However, sonodynamic therapy (SDT) performance of [Ru(bpy)3]2+ has not been investigated so far. SDT can overcome the tissue-penetration and phototoxicity problems compared to photodynamic therapy. Here, we report that [Ru(bpy)3]2+ is a highly potent sonosensitizer and sonocatalyst for sonotherapy in vitro and in vivo. [Ru(bpy)3]2+ can produce singlet oxygen (1O2) and sono-oxidize endogenous 1,4-dihydronicotinamide adenine dinucleotide (NADH) under ultrasound (US) stimulation in cancer cells. Furthermore, [Ru(bpy)3]2+ enables effective destruction of mice tumors, and the therapeutic effect can reach deep tissues over 10 cm under US irradiation. This work paves a way for polypyridinal metal complexes to be applied to the noninvasive precise sonotherapy of cancer.


Assuntos
Antineoplásicos/química , Neoplasias/terapia , Rutênio/química , Terapia por Ultrassom , Animais , Antineoplásicos/administração & dosagem , Humanos , Camundongos , Camundongos Endogâmicos BALB C , NAD/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Oxirredução/efeitos da radiação , Porfirinas/química , Rutênio/administração & dosagem , Oxigênio Singlete/metabolismo , Ondas Ultrassônicas
15.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360829

RESUMO

Pancreatic cancer (PC), one of the most lethal solid tumors in humans, has a five-year survival rate of only 4%. Surgical treatment is the only accepted therapy with curative intent because the vast majority of these tumors are chemoresistant. Unfortunately, due to the aggressive nature of these tumors, fewer than 20% are resectable when the first symptoms occur. Novel therapies are required to overcome all these therapeutic issues, and the development of active nanocarriers represents an exciting opportunity to improve PC outcomes. The present review focuses on recent advances in the field of nanotechnology with application in PC treatment.


Assuntos
Nanopartículas/uso terapêutico , Nanotecnologia/métodos , Neoplasias Pancreáticas , Animais , Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/tratamento farmacológico
16.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443443

RESUMO

Cytostatic chemotherapeutics provide a classical means to treat cancer, but conventional treatments have not increased in efficacy in the past years, warranting a search for new approaches to therapy. The aim of the study was, therefore, to obtain methacrylic acid (MAA) (co)polymers and to study their immunopharmacological properties. 4-Cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl] pentanoic acid (CDSPA) and 2-cyano-2-propyl dodecyl trithiocarbonate (CPDT) were used as reversible chain transfer agents. Experiments were carried out in Wistar rats. The MTT assay was used to evaluate the cytotoxic effect of the polymeric systems on peritoneal macrophages. An experimental tumor model was obtained by grafting RMK-1 breast cancer cells. Serum cytokine levels of tumor-bearing rats were analyzed. The chain transfer agents employed in classical radical polymerization substantially reduced the molecular weight of the resulting polymers, but a narrow molecular weight distribution was achieved only with CDSPA and high CPDT concentrations. Toxicity was not observed when incubating peritoneal macrophages with polymeric systems. In tumor-bearing rats, the IL-10 concentration was 1.7 times higher and the IL-17 concentration was less than half that of intact rats. Polymeric systems decreased the IL-10 concentration and normalized the IL-17 concentration in tumor-bearing rats. The maximum effect was observed for a MAA homopolymer with a high molecular weight. The anion-active polymers proposed as carrier constituents are promising for further studies and designs of carrier constituents of drug derivatives.


Assuntos
Antineoplásicos/imunologia , Antineoplásicos/farmacologia , Portadores de Fármacos/química , Ácidos Polimetacrílicos/farmacologia , Animais , Antineoplásicos/administração & dosagem , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Citocinas/metabolismo , Feminino , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Peso Molecular , Ácidos Polimetacrílicos/administração & dosagem , Ratos Wistar
17.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445380

RESUMO

Cholangiocarcinoma (CC) is an aggressive malignancy with an inferior prognosis due to limited systemic treatment options. As preclinical models such as CC cell lines are extremely rare, this manuscript reports a protocol of cholangiocarcinoma patient-derived organoid culture as well as a protocol for the transition of 3D organoid lines to 2D cell lines. Tissue samples of non-cancer bile duct and cholangiocarcinoma were obtained during surgical resection. Organoid lines were generated following a standardized protocol. 2D cell lines were generated from established organoid lines following a novel protocol. Subcutaneous and orthotopic patient-derived xenografts were generated from CC organoid lines, histologically examined, and treated using standard CC protocols. Therapeutic responses of organoids and 2D cell lines were examined using standard CC agents. Next-generation exome and RNA sequencing was performed on primary tumors and CC organoid lines. Patient-derived organoids closely recapitulated the original features of the primary tumors on multiple levels. Treatment experiments demonstrated that patient-derived organoids of cholangiocarcinoma and organoid-derived xenografts can be used for the evaluation of novel treatments and may therefore be used in personalized oncology approaches. In summary, this study establishes cholangiocarcinoma organoids and organoid-derived cell lines, thus expanding translational research resources of cholangiocarcinoma.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/genética , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Organoides/citologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/genética , Linhagem Celular Tumoral , Colangiocarcinoma/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Técnicas de Cultura de Órgãos/métodos , Organoides/efeitos dos fármacos , Organoides/patologia , Organoides/transplante , Medicina de Precisão , Análise de Sequência de RNA , Células Tumorais Cultivadas , Sequenciamento Completo do Exoma , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Int J Mol Sci ; 22(15)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34361101

RESUMO

Currently, carbon nanoparticles play a large role as carriers of various types of drugs, and also have applications in other fields of medicine, e.g., in tissue engineering, where they are used to reconstruct bone tissue. They also contribute to the early detection of cancer cells, and can act as markers in imaging diagnostics. Their antibacterial and anti-inflammatory properties are also known. This feature is particularly important in dental implantology, where various types of bacterial infections and implant rejection often occur. The search for newer and more effective treatments may lead to future use of nanoparticles on a large scale. In this work, the current state of knowledge on the possible use of nanotubes, nanodiamonds, and fullerenes in therapy is reviewed. Both advantages and disadvantages of the use of carbon nanoparticles in therapy and diagnostics have been indicated.


Assuntos
Antineoplásicos/administração & dosagem , Carbono/química , Sistemas de Liberação de Medicamentos , Nanomedicina , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Medicina Regenerativa , Animais , Antineoplásicos/química , Humanos , Nanopartículas/química
19.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360564

RESUMO

In recent decades, studies on the functional features of Se nanoparticles (SeNP) have gained great popularity due to their high biocompatibility, stability, and pronounced selectivity. A large number of works prove the anticarcinogenic effect of SeNP. In this work, the molecular mechanisms regulating the cytotoxic effects of SeNP, obtained by laser ablation, were studied by the example of four human cancer cell lines: A-172 (glioblastoma), Caco-2, (colorectal adenocarcinoma), DU-145 (prostate carcinoma), MCF-7 (breast adenocarcinoma). It was found that SeNP had different concentration-dependent effects on cancer cells of the four studied human lines. SeNP at concentrations of less than 1 µg/mL had no cytotoxic effect on the studied cancer cells, with the exception of the A-172 cell line, for which 0.5 µg/mL SeNP was the minimum concentration affecting its metabolic activity. It was shown that SeNP concentration-dependently caused cancer cell apoptosis, but not necrosis. In addition, it was found that SeNP enhanced the expression of pro-apoptotic genes in almost all cancer cell lines, with the exception of Caco-2 and activated various pathways of adaptive and pro-apoptotic signaling pathways of UPR. Different effects of SeNP on the expression of ER-resident selenoproteins and selenium-containing glutathione peroxidases and thioredoxin reductases, depending on the cell line, were established. In addition, SeNP triggered Ca2+ signals in all investigated cancer cell lines. Different sensitivity of cancer cell lines to SeNP can determine the induction of the process of apoptosis in them through regulation of the Ca2+ signaling system, mechanisms of ER stress, and activation of various expression patterns of genes encoding pro-apoptotic proteins.


Assuntos
Antineoplásicos/administração & dosagem , Apoptose , Citotoxinas/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Selênio/química , Antineoplásicos/química , Citotoxinas/química , Humanos , Nanopartículas/química , Transdução de Sinais , Células Tumorais Cultivadas
20.
Int J Nanomedicine ; 16: 4597-4614, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34267515

RESUMO

Malignant gliomas (MGs) are the most common and devastating primary brain tumor. At present, surgical interventions, radiotherapy, and chemotherapy are only marginally effective in prolonging the life expectancy of patients with MGs. Inherent heterogeneity, aggressive invasion and infiltration, intact physical barriers, and the numerous mechanisms underlying chemotherapy and radiotherapy resistance contribute to the poor prognosis for patients with MGs. Various studies have investigated methods to overcome these obstacles in MG treatment. In this review, we address difficulties in MG treatment and focus on promising polymeric local drug delivery systems. In contrast to most local delivery systems, which are directly implanted into the residual cavity after intratumoral injection or the surgical removal of a tumor, some rapidly developing and promising nanotechnological methods-including surface-decorated nanoparticles, magnetic nanoparticles, and focused ultrasound assist transport-are administered through (systemic) intravascular injection. We also discuss further synergistic and multimodal strategies for heightening therapeutic efficacy. Finally, we outline the challenges and therapeutic potential of these polymeric drug delivery systems.


Assuntos
Portadores de Fármacos , Glioma/tratamento farmacológico , Polímeros , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Terapia Combinada , Portadores de Fármacos/química , Humanos , Polímeros/química
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