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1.
Anticancer Res ; 39(10): 5703-5707, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570470

RESUMO

BACKGROUND/AIM: Anthracyclines, such as doxorubicin, though widely used in anticancer therapy, they are associated with cardiotoxic side-effects. The aim of this trial was to investigate long-term follow-up cardiotoxicity findings in patients treated with doxorubicin and concomitant metoprolol or enalapril 10 years earlier. PATIENTS AND METHODS: Overall, 147 patients were randomized into the treatment arms. A total of 125 patients treated with doxorubicin without evidence of heart disease at the start of chemotherapy were analyzed. They were followed-up for up to 10 years after treatment start. RESULTS AND CONCLUSION: A total of 47 patients completed the follow-up and 21 patients died, none due to cardiotoxicity events. Clinical signs of heart failure were not seen in any patients and no statistically significant differences between baseline and 10-year findings were seen for echocardiographic variables. No evidence of long-term cardiotoxicity was seen and nor metoprolol or enalapril offered an additional benefit.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxicidade/prevenção & controle , Doxorrubicina/efeitos adversos , Enalapril/uso terapêutico , Linfoma/tratamento farmacológico , Metoprolol/uso terapêutico , Adolescente , Antraciclinas/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Cardiotoxicidade/etiologia , Doxorrubicina/uso terapêutico , Ecocardiografia/métodos , Feminino , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Estudos Prospectivos
2.
Hautarzt ; 70(9): 700-706, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31428802

RESUMO

BACKGROUND: Whilst cutaneous angiosarcoma is rare tumour which primarily affects elderly patients, its management presents a significant therapeutic challenge. Indeed, complete surgical excision is often not possible due to the location and the diffuse and extensive nature of the tumour. Therefore, current treatment strategies often include chemo- and/or radiotherapy. METHODS: We report our experience of combined chemo- and radiotherapy in the clinical course of 6 patients with cutaneous angiosarcoma who were treated between 2007 and 2018. RESULTS: All patients presented non-resectable tumours and were treated with radiotherapy in combination with the administration of liposomal, pegylated doxrubicin (25 mg/m2 every 2 weeks). The mean duration of progression-free survival was 8 months (5-14 months), corresponding to an overall survival of 13 months (13-34 months). A partial response was seen in 4 patients and 1 patient developed progressive disease. One patient abandoned therapy after one administration. Two patients developed severe adverse events which led to termination of therapy after 1.5 months and 7 months, i.e. after 4 and 15 cycles respectively. DISCUSSION: Combined radio- and chemotherapy with liposomal, pegylated doxorubicin is a useful therapeutic option in the management of cutaneous angiosarcoma. Given the short-lived response rate, new treatment options are urgently required.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Quimiorradioterapia/métodos , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapêutico , Hemangiossarcoma/terapia , Neoplasias Cutâneas/terapia , Administração Metronômica , Idoso , Hemangiossarcoma/patologia , Humanos , Lipossomos , Polietilenoglicóis/uso terapêutico , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Resultado do Tratamento
3.
Medicine (Baltimore) ; 98(31): e16688, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31374054

RESUMO

The objectives of this study were to analyze the clinical features of patients with bone involved lymphoma and identify the prognostic factors and to explore the optimized treatment strategy for bone involved lymphoma.A total of 1948 patients with lymphoma in our cancer center from September 2006 to October 2017 were retrospectively evaluated. Among these, 109 patients with skeletal involvement in lymphoma were enrolled. According to the pathologic subtypes, the patients were divided into 3 subgroups: classic Hodgkin lymphoma (cHL), B-cell non-Hodgkin lymphoma (B-NHL), and T-cell non-Hodgkin lymphoma (T-NHL). The clinical characteristics and overall survival (OS) of 3 groups of patients were reviewed, and the prognostic factors were analyzed.There were 9 (3 unifocal, 6 multifocal) patients with primary bone lymphoma. The 5-year OS of cHL, B-NHL, and T-NHL patients was 88.24%, 54.09%, and 61.58%, respectively. Advanced stage, elevated lactate dehydrogenase (LDH), age above 60, high International Prognostic Index score, and treatment without radiotherapy for the bone involved were significant poor prognostic factors for OS of all patients in univariate analysis. There was a trend toward better OS not only in limited-stage but also in advanced-stage patients with radiotherapy for the bone involved compared with the patients without radiotherapy. Elevated LDH level and age above 60 were the independent unfavorable prognostic factor in multivariate analysis.Elevated LDH level and age above 60 predict the poor prognosis of patients with bone involvement. The potential for long-term survival suggests that additional consolidative radiotherapy for the site of skeleton involvement may have a better chance of long-term success.


Assuntos
Neoplasias Ósseas/radioterapia , Doença de Hodgkin/radioterapia , Linfoma de Células B/radioterapia , Linfoma de Células T/radioterapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Estudos de Casos e Controles , Terapia Combinada , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/mortalidade , Humanos , Estimativa de Kaplan-Meier , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/mortalidade , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Estudos Retrospectivos , Vincristina/uso terapêutico
4.
Ann Hematol ; 98(9): 2025-2033, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31312929

RESUMO

Outcomes for patients with non-Hodgkin's lymphoma (NHL) that proves refractory to treatment remain poor. Treatment of such patients is individualized and can include enrolment in a clinical trial of novel agents or use of one of a wide array of drug regimens. Initial treatment with anthracyclines such as doxorubicin limits options at later stages of treatment because of anthracycline-related cumulative cardiotoxicity. The aza-anthracenedione pixantrone was developed to reduce the likelihood of cardiotoxicity without compromising efficacy and is currently conditionally approved for use as monotherapy in patients with multiply-relapsed or refractory aggressive B cell NHL. The use of pixantrone in combination therapy, often to replace doxorubicin or mitoxantrone, has or is currently being investigated in numerous studies in patients with aggressive or indolent NHL and is the focus of this review. These include the R-CPOP regimen (rituximab, cyclophosphamide, pixantrone, vincristine, prednisone) for aggressive NHL in the first-line setting, including a study in elderly patients with limited cardiac function, and for patients with relapsed NHL with prior anthracycline exposure; the PSHAP regimen (pixantrone, cytarabine, prednisone, cisplatin), also in the latter setting; the PREBen/PEBen regimen (pixantrone, bendamustine and etoposide with or without rituximab) as salvage therapy; and pixantrone in combination with fludarabine, dexamethasone, and rituximab (FPD-R) for relapsed indolent NHL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Isoquinolinas/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Mitoxantrona/uso terapêutico , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Terapia de Salvação/métodos , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Vincristina/uso terapêutico
5.
Chem Commun (Camb) ; 55(58): 8434-8437, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31259350

RESUMO

Phosphatidylcholine is the main component of liposomes and other phospholipid-based nanocarriers in drug delivery. However, the functions and applications of these nanocarriers are extremely limited by conventional phospholipids. Here we report novel disulfide phosphatidylcholines (SS-PCs) and SS-PC based liposomes (SS-LPs) used as alternatives to traditional phospholipids and liposomes.


Assuntos
Dissulfetos/química , Portadores de Fármacos/química , Lipossomos/química , Fosfatidilcolinas/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Dissulfetos/síntese química , Dissulfetos/metabolismo , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Humanos , Lipossomos/síntese química , Lipossomos/metabolismo , Camundongos , Oxirredução , Fosfatidilcolinas/síntese química , Fosfatidilcolinas/metabolismo
6.
Rev Med Chil ; 147(4): 437-443, 2019 Apr.
Artigo em Espanhol | MEDLINE | ID: mdl-31344204

RESUMO

BACKGROUND: Hodgkin lymphoma has a high rate of curability, even in advanced stages. AIM: To assess the results of Hodgkin lymphoma treatment using the ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy regimen. MATERIAL AND METHODS: Analysis of a database held by the Chilean Ministry of Health, including all patients treated at accredited cancer treatment centers. RESULTS: Data for 915 patients, median age 35 years (range 15-86 years) and followed for a median of 97 months (range 1-347 months) were analyzed. Forty-one percent had localized disease. Overall survival at five years for localized and advanced stages was 92% and 74%, respectively. The figures for progression free survival were 87% and 64%, respectively. Patients with relapse who received autologous stem cell transplantation (ASCT) had a five year overall survival of 92%, compared to 64% among those who did not undergo this procedure (p < 0.01). The Guarantees in Health Program set up by the Ministry of Health, was associated with earlier stage disease at diagnosis. CONCLUSIONS: The ABVD regimen achieves high rates of cure in localized stages of the disease but the results in advanced stages are not optimal. ASCT significantly improves survival in patients with relapse. The Guarantees in Health Program is associated with earlier diagnosis of the disease.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bleomicina/uso terapêutico , Chile , Dacarbazina/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Vimblastina/uso terapêutico , Adulto Jovem
7.
Planta Med ; 85(11-12): 997-1007, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31288278

RESUMO

Silymarin-enriched extract (SEE) is obtained from Silybum marianum (Asteraceae). Doxorubicin (DXR) is a widely used chemotherapeutical yet with severe side effects. The goal of the present study was to assess the pharmacologic effect of SEE and its bioactive components silibinin and silychristine when administrated alone or in combination with DXR in the human prostate cancer cells (PC-3). PC-3 cells were treated with SEE, silibinin (silybins A and B), silychristine, alone, and in combination with DXR, and cell proliferation was assessed by the MTT assay. Cell cycle, apoptosis, and autophagy rate were assessed by flow cytometry. Expression levels of autophagy-related genes were quantified by qRT-PCR, ELISA and western blot while transmission electron microscopy was performed to reveal autophagic structures. Finally, NMR spectrometry was used to identify specific metabolites related to autophagy. SEE inhibited PC-3 cell proliferation in a dose-dependent manner while the co-treatment (DXR-SEE) revealed an additive cytotoxic effect. Cell cycle, apoptosis, and autophagy variations were observed in addition to altered expression levels of autophagy related genes (LC3, p62, NBR1, Beclin1, ULK1, AMBRA1), while several modifications in autophagic structures were identified after DXR-SEE co-treatment. Furthermore, treated cells showed a different metabolic profile, with significant alterations in autophagy-related metabolites such as branched-chain amino acids. In conclusion, the DXR-SEE co-treatment provokes perturbations in the autophagic mechanism of prostate cancer cells (PC-3) compared to DXR treatment alone, causing an excessive cell death. These findings propose the putative use of SEE as an adjuvant cytotoxic agent.


Assuntos
Doxorrubicina/uso terapêutico , Cardo Mariano/química , Extratos Vegetais/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Silimarina/uso terapêutico , Western Blotting , Sinergismo Farmacológico , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Masculino , Células PC-3/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Silimarina/isolamento & purificação
8.
Chem Commun (Camb) ; 55(61): 9015-9018, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31290867
9.
Int J Nanomedicine ; 14: 4961-4974, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308666

RESUMO

Background: Lipid polymer hybrid nanoparticles (LPHNPs) for the controlled delivery of hydrophilic doxorubicin hydrochloride (DOX.HCl) and lipophilic DOX base have been fabricated by the single step modified nanoprecipitation method. Materials and methods: Poly (D, L-lactide-co-glicolide) (PLGA), lecithin, and 1,2-distearoyl-Sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000 (DSPE-PEG 2000) were selected as structural components. Results: The mean particle size was 173-208 nm, with an encapsulation efficiency of 17.8±1.9 to 43.8±4.4% and 40.3±0.6 to 59. 8±1.4% for DOX.HCl and DOX base, respectively. The drug release profile was in the range 33-57% in 24 hours and followed the Higuchi model (R2=0.9867-0.9450) and Fickian diffusion (n<0.5). However, the release of DOX base was slower than DOX.HCl. The in vitro cytotoxicity studies and confocal imaging showed safety, good biocompatibility, and a higher degree of particle internalization. The higher internalization of DOX base was attributed to higher permeability of lipophilic component and better hydrophobic interaction of particles with cell membranes. Compared to the free DOX, the DOX.HCl and DOX base loaded LPHNPs showed higher antiproliferation effects in MDA-MB231 and PC3 cells. Conclusion: Therefore, LPHNPs have provided a potential drug delivery strategy for safe, controlled delivery of both hydrophilic and lipophilic form of DOX in cancer cells.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/uso terapêutico , Interações Hidrofóbicas e Hidrofílicas , Lipídeos/química , Nanopartículas/química , Polímeros/química , Varredura Diferencial de Calorimetria , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Coloides/química , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Feminino , Humanos , Cinética , Nanopartículas/ultraestrutura , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática
10.
Int J Nanomedicine ; 14: 3893-3909, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239663

RESUMO

Background: Photothermal and chemotherapy treatment has been frequently studied for cancer therapy; however, chemotherapy is equally toxic to both normal and cancer cells. The clinical application value of most kinds of photothermal transforming agents remains limited, due to their poor degradation and minimal accumulation in tumors. Materials and methods: We reported the synthesis of photothermal transforming agents (MoS2) and chemotherapeutic (doxorubicin, DOX) co-loaded electrospun nanofibers using blend electrospinning for the treatment of postoperative tumor recurrence. Results: Under the irradiation of an 808 nm laser, the as-prepared chitosan/polyvinyl alcohol/MoS2/DOX nanofibers showed an admirable photothermal conversion capability with a photothermal conversion efficiency of 23.2%. These composite nanofibers are in vitro and in vivo biocompatible. In addition, they could control the sustained release of DOX and the generated heat can sensitize the chemotherapeutic efficacy of DOX via enhancing its release rate. Their chemo-/photothermal combined therapy efficiency was systematically studied in vitro and in vivo. Instead of circulating with the body fluid, MoS2 was trapped by the nanofibrous matrix in the tumor and so its tumor-killing ability was not compromised, thus rendering this composite nanofiber a promising alternative for future clinical translation within biomedical application fields. Conclusion: Chitosan/polyvinyl alcohol/MoS2/DOX nanofibers showed an excellent photothermal conversion capability with a photothermal conversion efficiency of 23.2% and can completely inhibit the postoperative tumor reoccurrence.


Assuntos
Dissulfetos/química , Doxorrubicina/uso terapêutico , Molibdênio/química , Nanofibras/química , Nanotecnologia/métodos , Neoplasias/terapia , Fototerapia , Animais , Materiais Biocompatíveis/farmacologia , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Reagentes para Ligações Cruzadas/química , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Células HT29 , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanofibras/ultraestrutura , Recidiva Local de Neoplasia/patologia , Neoplasias/sangue , Neoplasias/patologia , Neoplasias/cirurgia , Padrões de Referência , Resultado do Tratamento
11.
Int J Nanomedicine ; 14: 4105-4121, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239670

RESUMO

Purpose: Doxorubicin (DOX) encapsulated O-succinyl chitosan graft Pluronic® F127 (OCP) copolymer nanoparticles conjugated with an anti-HER2 monoclonal antibody were developed as targeted drug delivery vehicles for the treatment of HER2-overexpressing breast cancer. Methods: Five percent and 10% (w/w) of O-succinyl chitosan was grafted onto Pluronic® F127 using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) as mediated cross-linking agents. DOX was added to the copolymer solution to form DOX-nanoparticles before conjugation with anti-HER2 on the surface of the nanoparticles. Results: DOX was encapsulated within the NP matrices at an encapsulation efficiency of 73.69 ± 0.53% to 74.65 ± 0.44% (the initial DOX concentration was 5 µg/mL). Anti-HER2 was successfully conjugated onto the surface of the nanoparticles at a moderately high conjugation efficiency of approximately 57.23 ± 0.38% to 61.20 ± 4.42%. In the in vitro DOX dissolution study, the nanoparticle formulations exhibited a biphasic drug release with an initial burst release followed by a sustained release profile at both pH 5.0 and pH 7.4. The drug was rapidly and completely released from the nanoparticles at pH 5.0. In the in vitro cytotoxicity, the anti-HER2 conjugated OCP copolymer nanoparticles showed the lowest IC50, which indicated an increase in the therapeutic efficacy of DOX to treat human breast cancer cells with the HER2 overexpression. Conclusion: Our study shows that anti-HER2 conjugated OCP copolymer nanoparticles have the potential for the development of anticancer drug carriers.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quitosana/análogos & derivados , Doxorrubicina/uso terapêutico , Nanopartículas/química , Receptor ErbB-2/metabolismo , Animais , Neoplasias da Mama/patologia , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cercopithecus aethiops , Quitosana/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Feminino , Humanos , Ligantes , Células MCF-7 , Micelas , Tamanho da Partícula , Células Vero
12.
J Clin Pathol ; 72(9): 630-635, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31189540

RESUMO

AIMS: Heightened B-cell receptor (BCR) activity in diffuse large B-cell lymphoma (DLBCL) is well established, and a subset of patients with relapsed DLBCL can benefit from BCR-targeted therapies. Universal outreach of such emerging therapies mandates forming a global landscape of BCR molecular signalling in DLBCL, including Southeast Asia. METHODS: 79 patients with DLBCL (nodal, 59% and extranodal, 41%) treated with rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) therapy were selected. Expression levels of BCR and linked signalling pathway molecules were inter-related with Lymph2Cx-based cell of origin (COO) types and overall survival (OS). RESULTS: Activated B-cell (ABC) type DLBCL constituted 49% (39/79) compared with germinal centre B-cell (GCB) type DLBCL (29/79; 37%) and revealed poor prognosis (p=0.013). In ABC-DLBCL, high BTK expression exerted poor response to R-CHOP, while OS in ABC-DLBCL with low BTK expression was similar to GCB-DLBCL subtype (p=0.004). High LYN expression coupled with a poor OS for ABC-DLBCL as well as GCB-DLBCL subtypes (p=0.001). Furthermore, high coexpression of BTK/LYN (BTK high/LYN high) showed poor OS (p=0.019), which linked with upregulation of several genes associated with BCR repertoire and nuclear factor-kappa B pathway (p<0.01). In multivariate analysis, high BTK and LYN expression retained prognostic significance against established clinical predictive factors such as age, International Prognostic Index and COO (p<0.05). CONCLUSIONS: Our data provide a clear association between high BCR activity in DLBCL and response to therapy in a distinct population. Molecular data provided here will pave the pathway for the provision of promising novel-targeted therapies to patients with DLBCL in Southeast Asia.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Medicina de Precisão/métodos , Receptores de Antígenos de Linfócitos B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/efeitos adversos , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Tumorais/imunologia , Tomada de Decisão Clínica , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/etnologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Malásia/epidemiologia , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Prevalência , Receptores de Antígenos de Linfócitos B/imunologia , Sistema de Registros , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento , Vincristina/efeitos adversos , Vincristina/uso terapêutico
13.
Int J Nanomedicine ; 14: 4029-4044, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213813

RESUMO

Purpose: As well as functioning as a ligand that is selectively internalized by cells overexpressing human epidermal growth factor receptor-2 (HER2), HApt can exert cytotoxic effects by inducing cross-linking and subsequent translocation of HER2 to cytoplasmic vesicles, such downregulation of HER2 inhibits cell proliferation and induces apoptosis. We aimed to exploit the potential of HApt as both a targeting agent and antagonist to maximize the efficacy of mesoporous silica nanoparticle (MSN)-based drug release systems for HER2-positive breast cancer. Materials and methods: We fabricated novel HApt aptamer-functionalized pH-sensitive ß-cyclodextrin (ß-CD)-capped doxorubicin (DOX)-loaded mesoporous silica nanoparticles (termed MSN-BM/CD-HApt@DOX) for targeted delivery and selective targeting of HER2-positive cells. MSN-functionalized benzimidazole (MSN-BM) was used to load and achieve pH stimuli-responsive release of the chemotherapeutic agent doxorubicin (DOX). ß-cyclodextrin was introduced as a gatekeeper for encapsulated DOX and HApt as a selective HER2-targeting moiety and biotherapeutic agent. Results: Physical and chemical characterizations (FT-IR, XRD, TEM and BET) confirmed successful construction of MSN-BM/CD-HApt@DOX nanoparticles. In vitro release assays verified pH-sensitive DOX release. MSN-BM/CD-HApt@DOX (relative DOX concentration, 3.6 µg/mL) underwent HER2-mediated endocytosis and was more cytotoxic to HER2-positive SKBR3 cells than HER2-negative MCF7 cells. MSN-BM/CD-HApt@DOX also exhibited better uptake and stronger growth inhibition in SKBR3 cells than the control MSN-BM/CD-NCApt@DOX functionalized with a scrambled nucleotide sequence on CD. Overall, intracellular delivery of DOX and the biotherapeutic agent HApt resulted in synergistic cytotoxic effects in HER2-positive cancer cells in comparison to either DOX or HApt alone. Conclusion: MSN-BM/CD-HApt@DOX enables HER2-mediated targeting and biotherapeutic effects as well as pH-responsive DOX drug release, resulting in synergistic cytotoxic effects in HER2-overexpressing cells in vitro. This novel nanocarrier could potentially enable specific targeting to improve the efficacy of chemotherapy for HER2-positive cancer.


Assuntos
Neoplasias da Mama/patologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Receptor ErbB-2/metabolismo , Dióxido de Silício/química , Apoptose/efeitos dos fármacos , Benzimidazóis/química , Neoplasias da Mama/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Endocitose , Feminino , Humanos , Concentração de Íons de Hidrogênio , Nanopartículas/ultraestrutura , Porosidade , Padrões de Referência , Espectroscopia de Infravermelho com Transformada de Fourier , beta-Ciclodextrinas/química
14.
Int J Nanomedicine ; 14: 3615-3627, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190815

RESUMO

Purpose: Modified top-down procedure was successfully employed in the synthesis of aragonite nanoparticles (NPs) from cheaply available natural seawater cockle shells. This was with the aim of developing a pH-sensitive nano-carrier for effective delivery of doxorubicin (DOX) on MCF-7 breast cancer cell line. Methods: The shells were cleaned with banana pelts, ground using a mortar and pestle, and stirred vigorously on a rotary pulverizing blending machine in dodecyl dimethyl betane solution. This simple procedure avoids the use of stringent temperatures and unsafe chemicals associated with NP production. The synthesized NPs were loaded with DOX to form DOX-NPs. The free and DOX-loaded NPs were characterized for physicochemical properties using field emission scanning electron microscopy, transmission electron microscopy, zeta potential analysis, Fourier transform infrared spectroscopy, and X-ray diffraction. The release profile, cytotoxicity, and cell uptake were evaluated. Results: NPs had an average diameter of 35.50 nm, 19.3% loading content, 97% encapsulation efficiency, and a surface potential and intensity of 19.1±3.9 mV and 100%, respectively. A slow and sustained pH-specific controlled discharge profile of DOX from DOX-NPs was observed, clearly showing apoptosis/necrosis induced by DOX-NPs through endocytosis. The DOX-NPs had IC50 values 1.829, 0.902, and 1.0377 µg/mL at 24, 48, and 72 hrs, while those of DOX alone were 0.475, 0.2483, and 0.0723 µg/mL, respectively. However, even at higher concentration, no apparent toxicity was observed with the NPs, revealing their compatibility with MCF-7 cells with a viability of 92%. Conclusions: The modified method of NPs synthesis suggests the tremendous potential of the NPs as pH-sensitive nano-carriers in cancer management because of their pH targeting ability toward cancerous cells.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Materiais Biocompatíveis/química , Neoplasias da Mama/patologia , Carbonato de Cálcio/química , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Musa/química , Nanopartículas/ultraestrutura , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Difração de Raios X
15.
Medicine (Baltimore) ; 98(25): e15873, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31232921

RESUMO

RATIONALE: Ameloblastoma is generally characterized as a benign tumor originating in odontogenic epithelium. However, few cases of metastatic malignant ameloblastoma have also been reported. Due to the low incidence of malignant ameloblastoma, there is no established treatment regimen. To explore effective treatment for malignant ameloblastoma, we reported this case study. PATIENTS CONCERNS: This report described a case of a 28-year-old malignant ameloblastoma female patient with multiple metastasis (brain and lung). DIAGNOSES: The patient presented ameloblastoma of the left mandible in 2012. Three years later, local recurrence and brain metastasis was observed during a follow-up examination. Five years later, malignant ameloblastoma was detected by imaging and immunohistochemistry in the bilateral multiple pulmonary nodules and mediastinal lymph nodes. INTERVENTIONS: The patient was initially treated with tumor resection. Three years later after local recurrence and brain metastasis, she was accepted the extensive mandibulectomy supplemented with brain stereotactic body radiotherapy (SBRT). When diagnosed with pulmonary metastasis, the patient received combined chemotherapy regimen of MAID (mesna, adriamycin, ifosfamide and dacarbazine) for 6 cycles. OUTCOMES: The efficacy evaluation was partial remission (PR) after the 6 cycles of MAID. The last patient follow-up was July 24th 2018, and no evidence of progression was observed. The progression-free survival (PFS) of the patient was more than 9 months. LESSONS: Surgical resection is the optimal treatment for locally recurrent ameloblastoma. SBRT may be an effective treatment for unresectable oligometastasis of malignant ameloblastoma. Finally, combined chemotherapy of MAID showed encouraging effects in the management of metastatic malignant ameloblastoma.


Assuntos
Ameloblastoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Maxilomandibulares/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Ameloblastoma/diagnóstico por imagem , Ameloblastoma/secundário , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/secundário , Dacarbazina/administração & dosagem , Dacarbazina/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Feminino , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/uso terapêutico , Neoplasias Maxilomandibulares/diagnóstico por imagem , Neoplasias Maxilomandibulares/patologia , Neoplasias Pulmonares/secundário , Mesna/administração & dosagem , Mesna/uso terapêutico , Metástase Neoplásica , Resultado do Tratamento
16.
Cancer Sci ; 110(9): 2690-2699, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31250942

RESUMO

Senescence is a state of growth arrest induced not only in normal cells but also in cancer cells by aging or stress, which triggers DNA damage. Despite growth suppression, senescent cancer cells promote tumor formation and recurrence by producing cytokines and growth factors; this state is designated as the senescence-associated secretory phenotype. In this study, we examined the susceptibility of senescent human breast cancer cells to immune cell-mediated cytotoxicity. Doxorubicin (DXR) treatment induced senescence in 2 human breast cancer cell lines, MDA-MB-231 and BT-549, with the induction of γH2AX expression and increased expression of p21 or p16. Treatment with DXR also induced the expression of senescence-associated ß-galactosidase and promoted the production of pro-inflammatory cytokines. Importantly, DXR-treated senescent MDA-MB-231 cells showed increased sensitivity to 2 types of immune cell-mediated cytotoxicity: cytotoxicity of activated CD4+ T cells and Ab-dependent cellular cytotoxicity by natural killer cells. This increased sensitivity to cytotoxicity was partially dependent on tumor necrosis factor-related apoptosis-inducing ligand and perforin, respectively. This increased sensitivity was not observed following treatment with the senescence-inducing cyclin-dependent kinase-4/6 inhibitor, abemaciclib. In addition, treatment with DXR, but not abemaciclib, decreased the expression of antiapoptotic proteins in cancer cells. These results indicated that DXR and abemaciclib induced senescence in breast cancer cells, but that they differed in their sensitivity to immune cell-mediated cytotoxicity. These findings could provide an indication for combining anticancer immunotherapy with chemotherapeutic drugs or molecular targeting drugs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linfócitos T CD4-Positivos/imunologia , Senescência Celular/imunologia , Células Matadoras Naturais/imunologia , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Proteínas Reguladoras de Apoptose/metabolismo , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Recidiva Local de Neoplasia
17.
Int J Nanomedicine ; 14: 2619-2636, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31043778

RESUMO

Background: Chemotherapy as an important tool for cancer treatment faces many obstacles such as multidrug resistance and adverse toxic effects on healthy tissues. Drug delivery systems has opened a new window to overcome these problems. There has been a strong interest development of new platform and system for delivof chemotherapeutic agents. Purpose: In the present study, a green synthesis method was chosen and performed for preparation of a novel amphoteric calix[4]arene (Calix) macrocycle with low toxicity to the human body. Materials and methods: The amphoteric Calix was coated on the surface of Fe3O4 magnetic nanoparticles and used as a magnetic nanocarrier for simultaneous delivery of two anticancer agents, doxorubicin and methotrexate, against MCF7 cancer cells. Several chemical characterizations were done for validation of prepared nanocarrier, and in vitro loading and release studies of drugs were performed with good encapsulation efficiency. Results: In vitro biological studies including hemolysis assay, erythrocytes sedimentation rate, red blood cells aggregation, cyto cellular internalization, and apoptosis evaluations were performed. Based on results, the developed nanocarrier has many advantages and capability for an efficient codelivery of DOX and MTX, which has a highly potent ability to kill cancer cells. Conclusion: All these results persuade us, this nanocarrier could be effectively used for cancer therapy of MCF7 breast cancer cells and is suitable for use in further animal studies in future investigations.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Calixarenos/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas de Magnetita/química , Fenóis/química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Calixarenos/síntese química , Varredura Diferencial de Calorimetria , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Difusão Dinâmica da Luz , Endocitose , Feminino , Humanos , Células MCF-7 , Nanopartículas de Magnetita/ultraestrutura , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Tamanho da Partícula , Fenóis/síntese química , Espectroscopia de Infravermelho com Transformada de Fourier
18.
Phytomedicine ; 59: 152921, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31055231

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with poor prognosis. Various chemotherapeutics are used in treatment of HCC, but most of them have significant toxicity to patients. Thus, it is urgently needed to develop new therapeutic strategies to achieve high specificity and tolerable adverse effects. As a natural polyphenol, ellagic acid (EA) demonstrates inhibitory effects in cancers. PURPOSE: The goal of the present study to investigate the anticancer activity of EA with a focus on its stimulating effects on doxorubicin hydrochloride (DOX) and cisplatin (DDP) in HCC treatment. METHODS: HepG2, SMMC-7721 and HL-7702 cells were treated with EA, DOX, DDP or their combinations. Cell viability and apoptosis were examined to evaluate the cytotoxicity of these treatments. Western blot analysis and immunofluorescent assays were used to determine expression of genes related to the mitochondrial apoptosis pathway. To assess the anticancer activities and systemic toxicity of EA, DOX and EA+DOX treatments, a xenograft mouse model with inoculated HepG2 cells was employed, followed by immunohistochemical and histopathological evaluation. RESULTS: EA could both markedly potentiate anticancer activities of DOX and DDP to HCC HepG2 and SMMC-7721 cells, and reduce their cytotoxicity to normal liver HL-7702 cells. EA and its combination with DOX or DDP induced cell apoptosis through a pathway mediated by mitochondrial cytochrome c release. In nude mice, EA combination with a relatively low dosage of DOX effectively inhibited tumor growth without causing cardiotoxicity observed in mice treated by a high dosage of DOX. CONCLUSION: We discovered that EA synergistically potentiated DOX and DDP in suppressing HCC with significantly reduced side effects and this may represent a novel strategy in HCC therapies with both high anticancer efficiencies and low systemic toxicity in patients.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Ácido Elágico/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Cardiotoxicidade , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Humanos , Camundongos , Camundongos Nus , Neoplasias Experimentais , Fitoterapia
19.
Rev Med Chil ; 147(2): 247-250, 2019 Feb.
Artigo em Espanhol | MEDLINE | ID: mdl-31095175

RESUMO

Patients transplanted from solid organs have an increased risk of cancer, especially lymphomas. Lymphomas correspond to 4 to 5% of malignant neoplasms in the general population and in solid organ transplant patients it reaches an incidence of 21%. The incidence of non-Hodgkin lymphomas is 10 times higher than in the non-transplanted population. We report the case of a 68-year-old man with a kidney transplant who 6 years after transplantation, developed a non-Hodgkin diffuse large cells B lymphoma with lymph node and pulmonary involvement, with markers of very poor prognosis (triple MYC expressor, BCL2 and BCL6). and its evolution with chemotherapy with DA R EPOCH.


Assuntos
Linfoma Difuso de Grandes Células B/genética , Linfoma não Hodgkin/genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Etoposídeo/uso terapêutico , Genes myc/genética , Humanos , Transplante de Rim/efeitos adversos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/etiologia , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/etiologia , Masculino , Prednisona/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Vincristina/uso terapêutico
20.
Int J Nanomedicine ; 14: 2533-2542, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114189

RESUMO

Background: Drug delivery systems (DDS) capable of targeting both cell and organelle levels are highly desirable for effective cancer therapy. In this study, we developed a novel enzyme-responsive, multistage-targeted anticancer DDS based on mesoporous silica nanoparticles (MSNs), which possessed both CD44-targeting and mitochondrial-targeting properties. Materials and methods: Triphenylphosphine (TPP), a mitochondria-targeting compound, was grafted onto the surface of MSNs firstly. Then, Doxorubicin (Dox) was encapsulated into the pore of MSNs, followed by capping with tumor-targeting molecules hyaluronic acid (HA) through electrostatic interactions to form the final product consist of Dox loaded, TPP attached, HA capped mesoporous silica nanoparticles (MSN-DPH). Results: Our results suggested that MSN-DPH was preferentially taken up by cancer cells via CD44 receptor-mediated endocytosis. Moreover, MSN-DPH mainly accumulated in mitochondria owing to the mitochondrial-targeting ability of TPP. Degradation of HA by overexpressed HAase facilitated the release of Dox in cancer cells. Thus, MSN-DPH efficiently killed the cancer cells while exhibited much lower cytotoxicity to normal cells. Conclusion: This study demonstrates a promising multistage-targeted DDS for cancer chemotherapy.


Assuntos
Sistemas de Liberação de Medicamentos , Mitocôndrias/metabolismo , Nanopartículas/química , Neoplasias/patologia , Dióxido de Silício/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Humanos , Ácido Hialurônico/química , Nanopartículas/ultraestrutura , Neoplasias/tratamento farmacológico , Porosidade
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