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1.
Yakugaku Zasshi ; 140(10): 1243-1249, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32999203

RESUMO

Here the author describes the tumor-selective delivery of a fluorescence photosensitizing agent and an antitumor agent, based on the polymer effect of an N-(2-hydroxypropyl)methacrylamide (HPMA) based copolymer, by utilizing the enhanced permeability and retention (EPR) effect seen in solid tumors. Firstly, the tumor distribution of the photosensitizer, zinc-protoporphyrin IX (ZnPP), was significantly increased by conjugation with the HPMA polymer (P-ZnPP). The P-ZnPP suppressed tumor growth by local generation of cytotoxic singlet oxygen, and the tumor tissue was visualized by fluorescence upon light irradiation. Subsequently, a two-step mechanism for tumor selectivity was observed for the cytotoxic anthracycline, pirarubicin (THP), which conjugated the HPMA-based copolymer via a hydrazone bond (P-THP). The EPR-dependent accumulation of P-THP and the tumor-selective release of THP in the tumor tissues led to highly tumor-selective toxicity. Rapid cell uptake of THP compared to other anthracyclines, and deeper P-THP penetration of the tumor cell spheroid were attributed to the superior antitumor activity of P-THP. The molecular weight of P-THP affected its antitumor activity; oligomeric P-THP derivatives with higher molecular weights, DP-THP and SP-THP, showed even higher antitumor activity. P-THP was effective for both implanted tumor and autochthonous tumor models. These results indicate that nano-sized anticancer drugs based on polymer effect are promising clinical therapeutics.


Assuntos
Antineoplásicos , Sistemas de Liberação de Medicamentos , Desenvolvimento de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fármacos Fotossensibilizantes , Polímeros , Protoporfirinas , Animais , Antraciclinas/química , Antraciclinas/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Doxorrubicina/análogos & derivados , Doxorrubicina/química , Doxorrubicina/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Metacrilatos/química , Terapia de Alvo Molecular , Peso Molecular , Neoplasias/patologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/metabolismo , Protoporfirinas/química , Protoporfirinas/metabolismo
2.
Yonsei Med J ; 61(9): 750-761, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32882759

RESUMO

PURPOSE: Gastric cancer (GC) is a malignant tumor with a high mortality rate. Drug resistance is a major obstacle to GC therapy. This study aimed to investigate the role and mechanism of exosomal circPRRX1 in doxorubicin resistance in GC. MATERIALS AND METHODS: HGC-27 and AGS cells were exposed to different doses of doxorubicin to construct doxorubicin-resistant cell lines. Levels of circPRRX1, miR-3064-5p, and nonreceptor tyrosine phosphatase 14 (PTPN14) were detected by quantitative real-time PCR or Western blot assay. Then, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, transwell, and Western blot assays were used to explore the function of circPRRX1 in GC cells. Interactions among circPRRX1, miR-3064-5p, and PTPN14 were confirmed by dual-luciferase reporter assay. The in vivo function of circPRRX1 was analyzed in a xenograft tumor model. RESULTS: CircPRRX1 was highly expressed in doxorubicin-resistant GC cell lines. Knockdown of circPRRX1 reversed doxorubicin resistance in doxorubicin-resistant GC cells. Additionally, extracellular circPRRX1 was carried by exosomes to spread doxorubicin resistance. CircPRRX1 silencing reduced doxorubicin resistance by targeting miR-3064-5p or regulating PTPN14. In GC patients, high levels of circPRRX1 in serum exosomes were associated with poor responses to doxorubicin treatment. Moreover, depletion of circPRRX1 reduced doxorubicin resistance in vivo. CONCLUSION: CircPRRX1 strengthened doxorubicin resistance by modulating miR-3064-5p/PTPN14 signaling and might be a therapeutic target for GC patients.


Assuntos
Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Linhagem Celular Tumoral , Exossomos/genética , Exossomos/metabolismo , Exossomos/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio , Humanos , MicroRNAs/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
3.
Zhonghua Bing Li Xue Za Zhi ; 49(10): 1046-1051, 2020 Oct 08.
Artigo em Chinês | MEDLINE | ID: mdl-32992421

RESUMO

Objective: To investigate the protective effect of dihydromyricetin (DHM) on doxorubicin (DOX)-induced myocardial injury and its mechanism. Methods: Twenty-four healthy male SD rats were divided into 4 groups: control group, DOX group, DOX+DHM100 group and DOX+DHM200 group. Echocardiography was used to measure cardiac function. At the end of the 6th week, the rats were anesthetized and sacrificed, and the pathological changes of the cardiac tissues were observed by HE staining, Masson staining and WGA staining. Cardiomyocyte apoptosis was observed by TUNEL staining, and protein levels of NLRP3, caspase-1, IL-1ß, bax and bcl-2 were detected by Western blot and immunohistochemistry. Results: Compared with the control group, the left ventricular ejection fraction and left ventricular fractional shortening decreased significantly in DOX group, while left ventricular internal dimension at systole and left ventricular internal dimension at diastole increased. In DOX+DHM group, both left ventricular ejection fraction and left ventricular fractional shortening increased, while left ventricular internal dimension at systole and left ventricular internal dimension at diastole decreased (P<0.05). Furthermore, DOX group showed significant myocardial injury histologically, while DOX+DHM group significantly inhibited DOX-induced myocardial injury in rats. Meanwhile, cardiomyocyte hypertrophy was found in the DOX group, while the cardiomyocyte hypertrophy was notably inhibited in the DOX+DHM group. Compared with the control group, the apoptotic rates of cardiomyocytes and the levels of bax/bcl-2 ratio were significantly increased in DOX group, which were significantly alleviated in the DOX+DHM group (P<0.05). In addition, the levels of NLRP3, caspase-1 and IL-1ß were increased as compared with control group, while the levels of the above indicators were remarkably reversed in DOX+DHM group as compared with DOX group (P<0.05). Conclusion: DHM alleviates DOX-induced myocardial injury in rats by inhibiting NLRP3 inflammasome and reducing cardiomyocyte apoptosis.


Assuntos
Inflamassomos , Função Ventricular Esquerda , Animais , Doxorrubicina , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Ratos , Ratos Sprague-Dawley , Volume Sistólico
4.
Zhonghua Zhong Liu Za Zhi ; 42(8): 617-623, 2020 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-32867451

RESUMO

As a new type of anthracyclines, pegylated liposomal doxorubicin (PLD) is widely used in the treatment of a variety of malignant tumors, including soft tissue sarcoma, ovarian cancer, breast cancer, multiple myeloma, and so on. Compared with traditional anthracyclines, PLD can significantly decrease the incidences of adverse events such as cardiac toxicity and alopecia. However, the use of PLD will be accompanied with toxic side effects such as hand-foot syndrome, oral mucositis, and infusion reaction. This consensus will mainly focus on the mechanism, prevention and treatment of adverse events of PLD, in order to improve the therapeutic efficacy of PLD and life quality of patients.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Doxorrubicina/análogos & derivados , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Síndrome Mão-Pé/complicações , Neoplasias/tratamento farmacológico , Estomatite/complicações , Antibióticos Antineoplásicos/uso terapêutico , Consenso , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Humanos , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Guias de Prática Clínica como Assunto
5.
Zhonghua Zhong Liu Za Zhi ; 42(8): 692-696, 2020 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-32867464

RESUMO

Objective: To evaluate the efficacy and safety of polyethylene glycol liposome doxorubicin (PLD) in the treatment of osteosarcoma. Methods: This study was a single-center retrospective clinical study. Two hundreds and seventy-six classical osteosarcoma treated in Beijing Jishuitan Hospital from 2015 to 2016 were enrolled. There were 213 patients who received combined chemotherapy of high dose methotrexate, ifosfamide, cisplatin and doxorubicin (ADM) were classified in ADM group. Other 63 patients received the same types, doses and cycles of chemotherapy drugs except ADM replaced by PLD were identified as PLD group. Clinical and imaging evaluation and surgical treatment were performed after neoadjuvant chemotherapy. Tumor necrosis rate was examined according to Huvos method. The efficacy of neoadjuvant chemotherapy was evaluated based on 90% necrosis rate. The recurrence, metastasis and survival were followed up regularly after operation. The adverse reactions of hematology, hepatorenal toxicity, gastrointestinal reaction and cardiotoxicity were evaluated. Results: There were no significant differences between PLD group and ADM group in age, sex, location, stage and surgical margin (all P>0.05). There were no significant differences in clinical symptoms and imaging evaluation between PLD group and ADM group after preoperative chemotherapy (all P>0.05). The tumor necrosis rate was detected in 134 cases. Among 27 cases of PLD group, tumor necrosis rates more than 90% were 11 cases, while among 107 cases of ADM group, tumor necrosis rates more than 90% were 45 cases. No significant difference of tumor necrosis rate between this two group was observed (P=0.901). The recurrence rates of PLD group and ADM group were 7.8% (4/51) and 7.3% (12/164), the metastasis rates were 19.6% (10/51) and 16.5% (27/164), the median progression free survival (PFS) were 42 and 37 months, respectively, without significant differences (all P>0.05). The incidence of granulocytopenia and decrease degree of granulocytes in PLD group were significantly lower than those in ADM group (P<0.001). There were no significant differences in the incidences of thrombocytopenia, anemia, gastrointestinal reaction, liver function damage and stomatitis between two groups (all P>0.05). Conclusions: PLD and ADM have similar chemotherapeutic effects in osteosarcoma. The incidences of adverse reactions of PLD are lower, especially the hematological toxicity represented by granulocytopenia is significantly reduced. PLD has a better application prospect.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/terapia , Lipossomos/uso terapêutico , Osteossarcoma/tratamento farmacológico , Neoplasias Ósseas/patologia , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Extremidades , Humanos , Ifosfamida/administração & dosagem , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Recidiva Local de Neoplasia , Osteoblastos/efeitos dos fármacos , Osteoblastos/patologia , Osteossarcoma/patologia , Polietilenoglicóis , Prognóstico , Estudos Retrospectivos
6.
Anticancer Res ; 40(10): 5371-5378, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988856

RESUMO

BACKGROUND/AIM: 18 kDa Translocator protein (TSPO) is a mitochondrial protein up-regulated in colorectal carcinoma (CRC). Our purpose was to develop a TSPO-targeted doxorubicin prodrug (Dox-TSPO) which can be loaded onto drug-eluting beads for transarterial chemoembolization. Furthermore, we evaluated its loading and release kinetics and effects on cell viability. MATERIALS AND METHODS: N-Fmoc-DOX-14-O-hemiglutarate was coupled with a TSPO ligand, 6-TSPOmbb732, using classical N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate coupling to produce Dox-TSPO. Loading and elution studies were performed using DC beads™. Cell viability studies were performed using CellTiter-Glo® Luminescent Cell Viability Assay. RESULTS: Dox-TSPO was successfully synthesized and readily loaded onto and eluted from DC beads™, albeit at a slower rate than free doxorubicin. CRC cell lines expressing TSPO were 2- to 4- fold more sensitive to Dox-TSPO compared to free doxorubicin at 72 h. CONCLUSION: Dox-TSPO is a promising candidate for targeted and directed cancer treatment of CRC liver metastases.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Doxorrubicina/farmacologia , Pró-Fármacos/farmacologia , Receptores de GABA/genética , Proteínas de Transporte/química , Proteínas de Transporte/farmacologia , Linhagem Celular Tumoral , Quimioembolização Terapêutica/métodos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Humanos , Pró-Fármacos/química , Receptores de GABA/química
7.
Medicine (Baltimore) ; 99(33): e21440, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32871991

RESUMO

RATIONALE: Follicular non-Hodgkin lymphoma (fNHL) is a neoplasm characterized by an indolent course and chemosensitivity, but also by disease recurrence. Bendamustine is often used as frontline treatment or second line. HEADING DIAGNOSIS:: fNHL. PATIENT CONCERNS: A 63-year-old Caucasian male with diagnosis of fNHL lymphoma underwent to cyclophosphamide, doxorubicin, vincristine, and prednisone associated with rituximab chemoimmunotherapy, during which interim reevaluation showed progressive disease and severe toxicity. INTERVENTIONS: Early switch to rituximab-bendamustine. OUTCOMES: This regimen was well tolerated, patient compliance was optimal, there were no delays in administration and no infectious episodes. An interim reevaluation after 3 courses revealed that the patient was fit, the blood cell count was normal, and lymphadenopathies and nocturnal sweating had completely regressed. Of note, the PET/CT scan did not show fluorodeoxyglucose pathological uptake, clearly confirming disease regression. LESSONS: Early switching to a bendamustine-rituximab-based scheme, even during conventional chemotherapy, decreases toxicity and reduces the risk of treatment interruption or delay, with favorable effects on overall response and prognosis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Cloridrato de Bendamustina/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Rituximab/uso terapêutico , Ciclofosfamida , Doxorrubicina , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona , Vincristina
8.
Lancet Haematol ; 7(10): e765-e771, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32976753

RESUMO

Over the past 30 years, the scientific community has made little progress in changing the natural history of peripheral T-cell lymphomas. Of the haematological malignancies, T-cell lymphomas have an extremely poor prognosis. One reason for this poor outcome has been that no treatment programme has ever been developed specifically for the broader category of the disease-peripheral T-cell lymphoma-let alone any of the specific subtypes, except advances made for patients with CD30-positive anaplastic large cell lymphoma. Decades of effort have focused on retrofitting chemotherapy programmes used for other diseases, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for diffuse large B-cell lymphoma, which have not been associated with much progress, and have universally produced far more toxicity than benefit. A remarkable heterogeneity, a paucity of cases, and the absence of peripheral T-cell lymphoma-specific drugs, until recently at least, have limited the field's ability to make substantive and innovative advances. Over the past few years, however, it appears the field is beginning to make progress. Lineage and disease-specific novel-to-novel platforms are producing, although perhaps not unsurprisingly, compelling results suggesting that the path to a cure for this rare orphan disease might be heading in a different direction.


Assuntos
Linfoma de Células T Periférico/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Imunoterapia/métodos , Medicina de Precisão/métodos , Prednisona/uso terapêutico , Resultado do Tratamento , Vincristina/uso terapêutico
10.
Anticancer Res ; 40(9): 5237-5243, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878812

RESUMO

BACKGROUND/AIM: Adult T-cell leukemia/lymphoma (ATLL) is a relatively refractory CD4-positive peripheral T-cell lymphoma. VCAP-AMP-VECP (mLSG15) is one of the standard chemotherapeutic regimens for patients with aggressive ATLL. Mogamulizumab (moga), a monoclonal antibody for C-C chemokine receptor 4 antigen expressed on the cell surface, has recently been poised for use as monotherapy and in combination with chemotherapy. However, to date, a significant survival benefit has not been obtained with the combination of moga + mLSG15 therapy. PATIENTS AND METHODS: We retrospectively analyzed 77 patients diagnosed with aggressive ATLL. Of them, 22 were treated with moga + a chemotherapy regimen comprised of etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisolone (EPOCH), 16 with moga + mLSG15, and 39 with chemotherapy alone. RESULTS: A risk reduction of approximately 30% was obtained with moga + EPOCH compared with moga + mLSG15. CONCLUSION: The addition of moga to chemotherapy did not result in a survival benefit compared with chemotherapy alone. However, a statistically significant overall survival benefit was observed in patients with moga-induced skin disorders.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma de Células T do Adulto/diagnóstico , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Esquema de Medicação , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Feminino , Humanos , Leucemia-Linfoma de Células T do Adulto/mortalidade , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Prognóstico , Modelos de Riscos Proporcionais , Retratamento , Estudos Retrospectivos , Resultado do Tratamento , Vincristina/efeitos adversos , Vincristina/uso terapêutico
11.
Anticancer Res ; 40(9): 5295-5299, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878820

RESUMO

BACKGROUND: To assess the prophylactic efficacy of postoperative single intravesical instillation with pirarubicin (THP) and mitomycin C (MMC) for low-risk non-muscle-invasive bladder cancer (NMBC). PATIENTS AND METHODS: A total of 103 clinically low-risk NMBC patients were preoperatively randomized into either THP (n=49) or MMC (n=54) groups. The primary endpoint was recurrence-free survival. RESULTS: The median follow-up periods of the THP and MMC groups were 955 and 1008 days, respectively (p=0.76). Twelve patients (24.5%) in the THP group and 7 (13%) in the MMC group had bladder cancer recurrences. The two-year recurrence-free survival of the THP group and the MMC group was 77.8% and 86.4%, respectively (p=0.20). Neither groups had severe toxicity. CONCLUSION: In low-risk NMBC, the prophylactic effect against postoperative single intravesical instillation with THP was not superior to that with MMC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cuidados Pós-Operatórios , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Cistoscópios , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Gradação de Tumores , Estadiamento de Neoplasias , Recidiva , Resultado do Tratamento , Carga Tumoral , Neoplasias da Bexiga Urinária/diagnóstico
12.
Ann Hematol ; 99(11): 2589-2598, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32892275

RESUMO

The induction therapy containing ixazomib, an oral proteasome inhibitor, has shown favorable efficacy and safety in clinical trials, but its experience in real-life remains limited. In routine practice, few patients received ixazomib-based induction therapy due to reasons including (1) patients' preference on oral regimens, (2) concerns on adverse events (AEs) of other intravenous/subcutaneous regimens, (3) requirements for less center visits, and (4) fears of COVID-19 and other infectious disease exposures. With the aim of assessing the real-life effectiveness and safety of ixazomib-based induction therapy, we performed this multi-center, observational study on 85 newly diagnosed multiple myeloma (NDMM) patients from 14 medical centers. Ixazomib-based regimens included ixazomib-lenalidomide-dexamethasone (IRd) in 44.7% of patients, ixazomib-dexamethasone (Id) in 29.4%, and Id plus another agent (doxorubicin, cyclophosphamide, thalidomide, or daratumumab) in 25.9%. Different ixazomib-based therapies were applied due to (1) financial burdens or limitations on local health insurance coverage, (2) concerns on treatment tolerance, and (3) drug accessibility issue. Ten patients received ixazomib maintenance. The median age was 67 years; 43.5% had ISS stage III disease; 48.2% had an Eastern Cooperative Oncology Group performance score ≥ 2; and 17.6% with high-risk cytogenetic abnormalities. Overall response rate for all 85 patients was 95.3%, including 65.9% very good partial response or better and 29.5% complete responses. The median time to response was 30 days. The response rate was similar across different ixazomib-based regimens. Median progression-free survival was not reached. Severe AEs (≥ grade 3) were reported in 29.4% of patients. No grade 3/4 peripheral neuropathy (PN) occurred. Patients received a median of 6 (range 1-20) cycles of ixazomib treatment; 56.6% remained on treatment at data cutoff; 15.3% discontinued treatment due to intolerable AEs. These results support that the ixazomib-based frontline therapy was highly effective with acceptable toxicity in routine practice and the ixazomib oral regimens could be good alternative options for NDMM patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Compostos de Boro/administração & dosagem , Glicina/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos de Boro/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Indução de Remissão , Análise de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Resultado do Tratamento
13.
J Biomed Nanotechnol ; 16(5): 721-738, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32919491

RESUMO

Oral squamous cell carcinoma (OSCC) is one of the most common cancers in developing countries particularly in those aged over 50. Traditional treatment is with surgery, radiotherapy, chemotherapy, or a combination of these which often results in considerable discomfort to the patient. Here we describe a potential alternative which employs a near-infrared (NIR) responsive dissolvable microneedle system (HMPBs&DOX@HA MNs) made of hyaluronic acid (HA) with hollow mesoporous Prussian blue nanoparticles (HMPBs) loaded with doxorubicin (DOX). HMPBs&DOX@HA MNs can easily penetrate the skin, and shows the ability to heat and maintain the internal temperature of tumor tissue at more than 60 C under the irradiation of an NIR laser. Besides, the DOX release behavior can also be regulated by the NIR laser. HMPBs&DOX@HA MNs reveals not only strong cell inhibition in vitro, but also prominent antitumor efficacy in vivo with all tumor-bearing mice cured in just one treatment and with no recurrence. This innovative transdermal drug delivery system minimizes the side effects while eliminating tumors. It has great potential to be an effective clinical treatment of OSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Animais , Linhagem Celular Tumoral , Doxorrubicina , Ferrocianetos , Humanos , Ácido Hialurônico , Nanopartículas Metálicas , Camundongos , Recidiva Local de Neoplasia
14.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 49(3): 364-374, 2020 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-32762172

RESUMO

OBJECTIVE: To design and synthesize folate-modified pH-responsive chitosan-based nanomicelles and investigate the in vitro anti-tumor activity of the drug-loaded micelles. METHODS: CHI-DMA was obtained by reductive amination reaction of aldehyde-based chitosan and hydrophilic amine compounds, and CHI-DMA-LA was obtained by condensation reaction with lauric acid; FA-CHI-DMA-LA was obtained after modification with folic acid (FA). The drug-loaded nanomicelles FA-CHI-DMA-LA/DOX were assembled by solvent change method. The physicochemical properties of polymers were characterized by hydrogen nuclear magnetic resonance and transmission electron microscope. The particle size and surface potential were determined by dynamic light scattering method. Folic acid access rate, doxorubicin (DOX) loading rate and entrapped efficiency were measured by UV-vis spectrophotometer. The drug release properties of DOX-loaded micelles in vitro were monitored by fluorescence spectrophotometer at different pHs (7.4, 6.5, 5.0). The cytotoxicity against human oral cancer KB cells was detected by MTT assay. Fluorescence microscope and flow cytometry were applied to investigate the phagocytosis of DOX-loaded micelles on KB cells. RESULTS: FA-CHI-DMA-LA was synthesized. The particle sizes of FA-CHI-DMA-LA-1 and FA-CHI-DMA-LA-2 micelles which used for the subsequent experiments were (73±14) nm and (106±15) nm, zeta potential were (15.59±1.98) mV and (21.20±2.35) mV, respectively. The drug loading rates of drug-loaded micelles FA-CHI-DMA-LA-1/DOX and FA-CHI-DMA-LA-2/DOX are (4.08±1.12)%and (4.12±0.44)%, respectively. In vitro drug release is pH-responsive, with cumulative release of DOX up to 37%and 36%at pH 5.0, which is about 1.5 times higher than that of pH 7.4. For FA-CHI-DMA-LA micelles with 1.25 to 125 µg/mL concentration, the survival rate of KB cells is more than 70%after incubation for 24 hours. The cell uptake of FA-CHI-DMA-LA/DOX micelles was enhanced compared to CHI-DMA-LA/DOX, and the cell uptake was higher in incubation without FA medium than that with FA. Compared with free DOX or CHI-DMA-LA/DOX, FA-CHI-DMA-LA/DOX nanomicelles showed higher cyctoxicity to KB cells, especially the FA-CHI-DMA-LA-2/DOX nanomicelles, the cell survival rate was about 17% after incubation for 24 hours. CONCLUSIONS: FA-modified chitosan-based nanomicelle with good biocompatibility was successfully prepared, which exhibits tumor microenvironmental pH responsive drug release and tumor targeting.


Assuntos
Nanoestruturas , Antineoplásicos , Quitosana , Doxorrubicina , Portadores de Fármacos , Ácido Fólico , Humanos , Micelas , Polímeros
15.
Int J Nanomedicine ; 15: 4825-4845, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32753868

RESUMO

Background: Nanosized drug delivery systems (NDDSs) have shown excellent prospects in tumor therapy. However, insufficient penetration of NDDSs has significantly impeded their development due to physiological instability and low passive penetration efficiency. Methods: Herein, we prepared a core cross-linked pullulan-modified nanosized system, fabricated by visible-light-induced diselenide bond cross-linked method for transporting ß-Lapachone and doxorubicin prodrug (boronate-DOX, BDOX), to improve the physiological stability of the NDDSs for efficient passive accumulation in tumor blood vessels (ß-Lapachone/BDOX-CCS). Additionally, ultrasound (US) was utilized to transfer ß-Lapachone/BDOX-CCS around the tumor vessel in a relay style to penetrate the tumor interstitium. Subsequently, ß-Lapachone enhanced ROS levels by overexpressing NQO1, resulting in the transformation of BDOX into DOX. DOX, together with abundant levels of ROS, achieved synergistic tumor therapy. Results: In vivo experiments demonstrated that ultrasound (US) + cross-linked nanosized drug delivery systems (ß-Lapachone/BDOX-CCS) group showed ten times higher DOX accumulation in the tumor interstitium than the non-cross-linked (ß-Lapachone/BDOX-NCS) group. Conclusion: Thus, this strategy could be a promising method to achieve deep penetration of NDDSs into the tumor.


Assuntos
Doxorrubicina/uso terapêutico , Nanopartículas/química , Naftoquinonas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Ultrassonografia , Animais , Ácidos Borônicos/química , Permeabilidade Capilar/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Reagentes para Ligações Cruzadas/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Endocitose/efeitos dos fármacos , Feminino , Glucanos/química , Células Hep G2 , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Naftoquinonas/farmacocinética , Tamanho da Partícula , Pró-Fármacos/farmacocinética , Espécies Reativas de Oxigênio/metabolismo , Distribuição Tecidual/efeitos dos fármacos
16.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1096-1104, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798383

RESUMO

OBJECTIVE: To compare the expression of miR-199a-5p between ADM-resistant AML cell (K562/ADM)and ADM-sensitive AML cell (K562), and to investigate the effect of miR-199a-5p on regulating AML drug resistance as well as its molecular mechanism. METHODS: MTT method was used to detect the proliferation inhibition effect of ADM on K562 and K562/ADM cells, the IC50 was calculated. miR-199a-5p expression in cell lines (K562 and K562/ADM) and bone marrow sample (refractory/relapsed AML patients and complete remission AML patients) was detected by RT-qPCR. K562/ADM and K562 cells were transfected by miR-199a-5p mimic and miR-199a-5p inhibitor respectively to ensure that miR-199a-5p expression in K562/ADM cells was increased and that in K562 cells was decreased. Then proliferation inhibition effect of ADM on both cells was detected by CCK-8 and mRNA and protein DRAM1 expression in both cells was measured by real time RT-PCR and Western blot respectively. Dual luciferase reporter assay was used to detect wether there were direct binding sites between miR-199a-5p and DRAM1 3' UTR. CCK-8 was used to measure the proliferation inhibition effect of ADM on K562/ADM cells when DRAM1 was downregulated by siRNA. RESULTS: The IC50 of ADM for K562/ADM and K562 cells was 146.14±0.079 and 3.08±0.056 µg/ml respectively. As compared with patients in complete remission group, MiR-199a-5p expression in refractory/ relapsed AML patients significantly decreased, and the MiR-199a-5p expression in K562/ADM cells was also dramatically downregulated, compared with K562 cells (P<0.05). When the expression of miR-199a-5p was upregulated in K562/ADM cells, the proliferation inhibition effect of ADM on cells elevated and both DRAM1 mRNA and protein expressions decreased. Conversely, when miR-199a-5p expression was downregulated in K562 cells, the proliferation inhibition effect of ADM on cells obviously reduced and both DRAM1 mRNA and protein expression increased (P<0.05). Dual luciferase reporter Assay showed a direct interaction between miR-199a-5p and its binding site within DRAM1 mRNA. Both DRAM1 mRNA and protein expression in K562/ADM were markedly higher than those in K562 cells (P<0.05). The ADM chemosensitivity of K562/ADM cells was improved significantly when DRAM1 expression was downregulated (P<0.05). CONCLUSION: miR-199a-5p is downregulated in chemoresistant AML cells. miR-199a-5p expression plays an important role in regulating the sensitivity of AML cells to ADM treatment. DRAM1 is a functional target gene for miR-199a-5p modulating AML chemoresistance.


Assuntos
Leucemia Mieloide Aguda , MicroRNAs , Animais , Doxorrubicina , Humanos , Células K562 , Masculino , RNA Mensageiro
17.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1210-1214, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798400

RESUMO

OBJECTIVE: To analyze the clinical efficacy and safety of rituximab therapy for patients with Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (DLBCL), and to explore the factors influencing the clinical efficacy. METHODS: According to therapeutic regimen, 66 patients with EBV-positive DLBCL were divided into two groups: CHOP group (32 cases) and R-CHOP group (CHOP+ rituximab, 34 cases). The clinical efficacy and the incidence of complication were compared between two groups. The clinical risk factors for the clinical efficacy in patients with EBV-positive DLBCL were confirmed by multivariate Logistic analysis. RESULTS: Compared with CHOP group, the complete remission rate, partial remission rate and the overall effective rate in R-CHOP group all were high (P<0.05), moreover the disease progression rate in R-CHOP group were low (P<0.05). The occurrences rate of myelotoxicity, hepatic injury and gastrointestinal reaction were not statistically significantly different between two groups (P>0.05). Multivariate Logistic analysis showed that the Ann Arbor staging, IPI risk score and Ki-67 positive rate were independent risk factors for the clinical efficacy in patients with EBV-positive DLBCL (OR=2.689, P=0.038; OR=3.232, P=0.025; OR=2.919, P=0.023). CONCLUSION: The clinical efficacy and safety of the therapy with rituximab on the patients with EBV-positive DLBCL are better. The poor Ann Arbor stage, high IPI risk score and the Ki-67 positive rate are factors affecting the clinical efficacy for the patients with EBV-positive DLBCL.


Assuntos
Herpesvirus Humano 4 , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Resultado do Tratamento , Vincristina/uso terapêutico
20.
Ann Hematol ; 99(10): 2255-2263, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32766934

RESUMO

We aimed to clarify the clinical characteristics, prognostic factors, and effectiveness of the HLH-94/2004 regimens and hematopoietic stem cell transplantation (HSCT) in pediatric patients with primary hemophagocytic lymphohistiocytosis (pHLH) in China. A retrospective analysis was performed on 38 patients with pHLH at Beijing Children's Hospital. PRF1 (34.2%) and UNC13D (31.6%) were the most common mutations in the pHLH. Thirty-eight patients were treated with the HLH-94/2004 regimens after diagnosis. Twenty-six patients (72.2%) responded to first-line treatment (complete response: 55.5%, partial response: 16.7%). The median survival time was 23 months. The overall survival (OS) rate at 3 years was 74.7%. There was no significant difference in the response rate (72% vs. 63.6%, P = 0.703) or 3-year OS (83.6% vs. 66.7%, P = 0.443) between the patients treated with the HLH-94 regimen and those treated with the HLH-2004 regimen. The incidences of all side effects in patients treated with the HLH-94 or HLH-2004 regimen were 32.0% and 18.2%, respectively (P = 0.394). Among 15 patients treated with HSCT, neither the preconditioning regimen nor the donor type affected patient prognosis (P = 0.205 and P = 0.161, respectively). The disease status (remission or nonremission) before preconditioning did not affect prognosis or the incidence of GVHD. Furthermore, a higher bilirubin level (≥ 30 µmol/L) was correlated with a poorer prognosis in pHLH patients (P = 0.026). The effectiveness rates of the HLH-94 and HLH-2004 regimens, chemotherapy, and HSCT were similar in pHLH patients. A bilirubin level ≥ 30 µmol/L might be an adverse prognostic factor in pHLH.


Assuntos
Ciclosporina/uso terapêutico , Doxorrubicina/uso terapêutico , Etoposídeo/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Linfo-Histiocitose Hemofagocítica/terapia , Metilprednisolona/uso terapêutico , Criança , Pré-Escolar , China/epidemiologia , Terapia Combinada , Intervalo Livre de Doença , Quimioterapia Combinada , Seguimentos , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/epidemiologia , Linfo-Histiocitose Hemofagocítica/genética , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Condicionamento Pré-Transplante , Resultado do Tratamento
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