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1.
Anticancer Res ; 40(5): 2497-2507, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366394

RESUMO

BACKGROUND: Spectrin αII contributes to cisplatin and carboplatin resistance in ovarian serous carcinoma cells, and its expression in surgical specimens is a valid predictor of prognosis. We sought to identify effective drugs for spectrin αII-mediated cisplatin-resistant cells. MATERIALS AND METHODS: We employed SKOV3 cells with small interfering RNA-mediated spectrin αII downregulation, serous carcinoma cells (NOS2), cisplatin-resistant cells (NOS2CR2), and oxaliplatin-resistant cells (NOS2OXR). RESULTS: In the drug-sensitivity test, oxaliplatin was not affected by the inhibition of spectrin αII expression and was effective for cisplatin-resistant NOS2CR2 cells. NOS2OXR cells did not express higher levels of spectrin αII compared to NOS2 in western blot analysis. Six non-platinum anticancer drugs were not affected by the inhibition and was effective for resistant NOS2CR2 and NOS2OXR cells. Doxorubicin exhibited potent cytotoxicity at 2 µM against both resistant cell lines. CONCLUSION: Pegylated liposomal doxorubicin/oxaliplatin regimen may be effective for cisplatin-resistant ovarian carcinoma with spectrin αII-overexpression.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Doxorrubicina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Ovarianas/genética , Espectrina/genética , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Polietilenoglicóis/farmacologia , RNA Interferente Pequeno/genética
2.
Cancer Immunol Immunother ; 69(1): 103-114, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31811336

RESUMO

We previously reported that CD200 overexpression in the host decreases progression and metastasis of the highly aggressive metastatic 4THM breast carcinoma. We have explored a possible synergistic interaction between the CD200 mimetic PEG-M49 and pegylated liposomal doxorubicin (Peg-Dox) in wild-type CD200 knockout (CD200-/-) and CD200 Receptor 1 knockout (CD200R1-/-) mice for the first time. A 4THM breast carcinoma model and three groups of BALB/c mice (wild type, CD200-/- and CD200R1-/-) were used. Five days after injection of tumor cells, mice were injected with Peg-Dox (ip, once a week) and PEG-M49 or a control aptamer (iv, every 3 days). Necropsies were performed either 12 (mid-point) or 24 (endpoint) days after injection and the extent of tumor growth, visceral metastasis and changes in the tumor-directed immune response were evaluated. PEG-M49 and Peg-Dox co-treatment induced complete tumor regression and loss of macroscopic lung metastasis in four out of seven WT mice. This synergistic anti-tumoral effect is thought to be due to Peg-M49-induced inhibition of Gr1 + CD11b + cells and Peg-Dox-induced increases in tumor-infiltrating CD8 + and CD8CD4 double-positive cells. Similar changes were observed in CD200R1-/- mice indicating that the primary effects of Peg-M49 are mediated by non-CD200R1 receptors. We also demonstrated for the first time that tumor growth, metastasis, and tumor infiltrating GR1 + CD11b + cells were markedly increased in CD200R1-/- mice, indicating an anti-inflammatory and protective role of CD200. CD200 mimetics might be a safe and effective immunomodulatory treatment in conjunction with classical chemotherapeutics for therapy of aggressive metastatic breast carcinoma.


Assuntos
Antígenos CD/genética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Aptâmeros de Nucleotídeos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/análogos & derivados , Animais , Antígenos CD/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aptâmeros de Nucleotídeos/uso terapêutico , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Sinergismo Farmacológico , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptores de Orexina/genética , Receptores de Orexina/imunologia , Polietilenoglicóis/farmacologia , Polietilenoglicóis/uso terapêutico
3.
BMC Infect Dis ; 19(1): 848, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615436

RESUMO

BACKGROUND: Pegylated liposomal doxorubicin plays an important role in the treatment of patients with severe refractory human immunodeficiency virus (HIV)-associated Kaposi sarcoma (KS). High cumulative doses of conventional doxorubicin exceeding 500 mg/m2 are known to cause cardiac toxicity. However, the safe cumulative dose of pegylated liposomal doxorubicin is unclear. CASE PRESENTATION: A 40-year-old Japanese man with HIV infection presented with pain, edema, and multiple skin nodules on both legs which worsened over several months. He was diagnosed with HIV-associated KS. He received long-term pegylated liposomal doxorubicin combined with antiretroviral therapy for advanced, progressive KS. The cumulative dose of pegylated liposomal doxorubicin reached 980 mg/m2. The patient's left ventricular ejection fraction remained unchanged from baseline during treatment. After he died as a result of cachexia and wasting, caused by recurrent sepsis and advanced KS, an autopsy specimen of his heart revealed little or no evidence of histological cardiac damage. We also conducted a literature review focusing on histological changes of the myocardium in patients treated with a cumulative dose of pegylated liposomal doxorubicin exceeding 500 mg/m2. CONCLUSIONS: This case report and literature review suggest that high (> 500 mg/m2) cumulative doses of pegylated liposomal doxorubicin may be used without significant histological/clinical cardiac toxicity in patients with HIV-associated KS.


Assuntos
Doxorrubicina/análogos & derivados , Infecções por HIV/patologia , Sarcoma de Kaposi/tratamento farmacológico , Adulto , Antirretrovirais/uso terapêutico , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Coração/diagnóstico por imagem , Humanos , Masculino , Miocárdio/patologia , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/química , Polietilenoglicóis/uso terapêutico , Sarcoma de Kaposi/diagnóstico , Sarcoma de Kaposi/etiologia
4.
Molecules ; 24(19)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31574945

RESUMO

Glioma is one of the most aggressive and common malignant brain tumors. Due to the presence of the blood-brain barrier (BBB), the effectiveness of therapeutics is greatly affected. In this work, to develop an efficient anti-glioma drug with targeting and which was able to cross the BBB, cell-penetrating peptides (R8) and transferrin co-modified doxorubicin (DOX)-loaded liposomes (Tf-LPs) were prepared. Tf-LPs possessed a spherical shape and uniform size with 128.64 nm and their ξ-potential was 6.81 mV. Tf-LPs were found to be stable in serum within 48 h. Uptake of Tf-LPs in both U87 and GL261 cells was analyzed by confocal laser scanning microscopy and by flow cytometry. Tf-LPs were efficiently taken up by both U87 and GL261 cells. Moreover, Tf-LPs exhibited sustained-release. The cumulative release of DOX from Tf-LPs reached ~50.0% and showed excellent anti-glioma efficacy. Histology of major organs, including brain, heart, liver, spleen, lungs and kidney, and the bodyweight of mice, all indicated low toxicity of Tf-LPs. In conclusion, Tf-LPs showed great promise as an anti-glioma therapeutic agent.


Assuntos
Antineoplásicos/administração & dosagem , Peptídeos Penetradores de Células/metabolismo , Glioma/tratamento farmacológico , Glioma/metabolismo , Transferrina/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/química , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Sistemas de Liberação de Medicamentos , Humanos , Lipossomos , Camundongos , Polietilenoglicóis/administração & dosagem , Transferrina/química , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Gynecol Oncol ; 155(2): 301-304, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31575390

RESUMO

OBJECTIVE: Pegylated liposomal doxorubicin (PLD) has similar reported clinical efficacy compared with conventional doxorubicin with less cardiotoxicity. The manufacturer of PLD advises that cardiac function should be evaluated with endomyocardial biopsy, echocardiography or multigated radionucleotide scan (MUGA) pre-treatment and during therapy. This study was designed to assess the necessity of pre-treatment cardiac evaluation in patients receiving PLD. METHODS: After IRB approval, a retrospective study of all women with gynecologic cancer who received PLD from 2006 to 2018 was performed. Demographic information, treatment records, cardiac risk factors, and cardiac surveillance testing were examined. Wilcoxon signed rank sum test and logistic regression were used to evaluate the association of cumulative PLD exposure with cardiotoxicity. RESULTS: A total of 235 patients received PLD for gynecologic cancer. Patients received a median of 3 cycles of PLD with a cumulative dosage of 237 mg over a median follow-up time of 24 months. Sixteen patients in the cohort (7%) had no cardiac surveillance at all. Of the remaining patients who underwent cardiac testing, 183 (84%) received MUGA scans and 36 (16%) had echocardiography. Of the 56 patients who had both pre- and post-treatment cardiac testing, there was no significant difference in median ejection fraction (p = 0.17). Three patients developed PLD-associated cardiac toxicity but only one patient had severe manifestations requiring discontinuation of PLD therapy. CONCLUSIONS: Routine cardiac testing before, during or after treatment with PLD may be unnecessary. Cardiac testing may be more appropriate for individual patients for whom the clinical suspicion of PLD-related cardiac toxicity is high.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/análogos & derivados , Neoplasias dos Genitais Femininos/tratamento farmacológico , Cardiopatias/induzido quimicamente , Doxorrubicina/efeitos adversos , Substituição de Medicamentos , Ecocardiografia/métodos , Feminino , Cardiopatias/fisiopatologia , Cardiopatias/prevenção & controle , Humanos , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Polietilenoglicóis/efeitos adversos , Angiografia Cintilográfica/métodos , Estudos Retrospectivos , Volume Sistólico/efeitos dos fármacos
6.
Pediatr Surg Int ; 35(12): 1369-1378, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31559456

RESUMO

PURPOSE: To investigate the possibility that the antioxidant stress protein Heme oxygenase-1 (HO-1) is involved in the acquisition of chemoresistance in cisplatin and pirarubicin (CITA) therapy. METHODS: Human hepatoblastoma-derived cell line (HepG2) was used to generate a knockdown cell line of HO-1 by small interfering RNA (siRNA). Expression of HO-1, epidermal growth factor receptor (EGFR), Akt, and extracellular signal-regulated kinase1/2 (ERK1/2) was examined by Western blot. The cytotoxic effect of cisplatin, pirarubicin, and EGFR inhibitor was examined by trypan blue staining. In human hepatoblastoma specimens (n = 5), changes of HO-1 expression were examined immunohistochemically before and after CITA therapy. RESULTS: HO-1 expression in HepG2 cells was increased by the treatment of cisplatin (CDDP) and pirarubicin (THP) dose-dependently. In HO-1 knockdown HepG2 cells, the HO-1 was not expressed and the percentage of trypan blue-positive cells (dead cells) was significantly increased after treatment of CDDP and THP. The EGFR inhibitor decreased the levels of HO-1, phospho-Akt and phospho-ERK1/2 in HepG2 cells. Combination treatment of EGFR inhibitor with CDDP and THP increased the cytotoxic effect in HepG2 cells. In human hepatoblastoma specimens, 4 of the 5 patients (80%) showed HO-1 expression changed much stronger in the viable tumor cells after CITA therapy. CONCLUSION: The cytotoxic effects of CDDP and THP were both enhanced under HO-1 knockdown conditions as well as under conditions that inhibit the activation pathway of HO-1 by EGFR inhibitors. EGFR/HO-1 axis may be involved in acquiring chemoresistance in HepG2 cell lines as well as in human hepatoblastoma.


Assuntos
Cisplatino/farmacologia , Doxorrubicina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo , Heme Oxigenase-1/metabolismo , Hepatoblastoma/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Antineoplásicos/farmacologia , Linhagem Celular , Células Cultivadas , Pré-Escolar , Doxorrubicina/farmacologia , Feminino , Células Hep G2 , Humanos , Lactente , Masculino
7.
Anal Bioanal Chem ; 411(27): 7087-7094, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31471684

RESUMO

Accurate measurement and understanding of therapeutic uptake and metabolism is key in the drug development process. This work examines the amount of doxorubicin that can penetrate into spheroids after being encapsulated in a liposomal configuration in comparison with free drug. Through a process known as serial trypsinization, three distinct cellular populations of a spheroid were successfully separated and a small molecule extraction was used to isolate the chemotherapeutic. Doxorubicin showed a time-dependent permeability into spheroids with the most drug accumulating in the core at 24 h of treatment. Entrapment of the chemotherapeutic delayed the permeability of the drug and resulted in reduced amounts quantified at the earlier time points. These findings validate the claim that liposomal therapeutics have the ability to alter the pharmacokinetics and pharmacodynamics profiles of a drug while also demonstrating the combined power of mass spectrometry and three-dimensional cell cultures to evaluate drug penetration and metabolism. Graphical abstract.


Assuntos
Antibióticos Antineoplásicos/metabolismo , Doxorrubicina/análogos & derivados , Esferoides Celulares/metabolismo , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/metabolismo , Doxorrubicina/farmacocinética , Células HCT116 , Humanos , Espectrometria de Massas , Polietilenoglicóis/metabolismo , Polietilenoglicóis/farmacocinética , Tripsina/metabolismo
8.
Biomed Res Int ; 2019: 2486783, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31531348

RESUMO

The incidence of gastric cancer is extremely high in China, prompting the development of effective therapeutic strategies. Sodium selenite (SS) affects the proliferation and redifferentiation of gastric cancer cells and the Adriamycin prodrug Ac-Phe-Lys-PABC-ADM (PADM) reduces toxicity in gastric cancer treatment. However, the mechanisms involved therein remain unclear. In this study, nude mice were transplanted with SGC-7901 gastric cancer cells to construct a tumor xenograft model. After administration of SS and PADM, tumor weight and size were reduced. In addition, the levels of alanine aminotransferase, aspartate transaminase, creatinine, and lactate dehydrogenase were decreased, indicating improved hepatic and renal function and inhibited cancer cell metabolism. Furthermore, combined treatment of SS and PADM downregulated the expression of cell cycle-related proteins (cyclin-dependent kinase 4, Ki67, cyclin E, and cyclin D1), elevated that of proapoptosis proteins (Bax, cleaved caspase-3, cleaved caspase-9, and P53), and upregulated that of mitochondrial apoptosis-associated proteins (apoptotic protease activating factor 1 and second mitochondria-derived activator of caspases). In conclusion, combined treatment of SS and PADM effectively promoted apoptosis in gastric cancer xenografts via the mitochondrial apoptosis pathway.


Assuntos
Apoptose/efeitos dos fármacos , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacologia , Xenoenxertos/efeitos dos fármacos , Oligopeptídeos/farmacologia , Pró-Fármacos/farmacologia , Selenito de Sódio/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Caspases/metabolismo , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Xenoenxertos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias Gástricas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
9.
BMJ Case Rep ; 12(9)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31537597

RESUMO

AIDS-related Kaposi sarcoma (KS) is a malignancy seen in patients with HIV/AIDS that results from unrestrained human herpesvirus 8 infection. It can have an atypical presentation and an aggressive clinical course in patients with uncontrolled HIV infection. We present an interesting case of AIDS-related KS with an atypical initial presentation with skin nodules and debilitating lymphoedema. Patient was successfully managed with supportive measures, antiretroviral therapy and systemic chemotherapy.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Síndrome de Imunodeficiência Adquirida/diagnóstico , Infecções por HIV/complicações , Sarcoma de Kaposi/diagnóstico , Neoplasias Cutâneas/patologia , Infecções Oportunistas Relacionadas com a AIDS/patologia , Infecções Oportunistas Relacionadas com a AIDS/terapia , Síndrome de Imunodeficiência Adquirida/patologia , Adulto , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Humanos , Linfedema/patologia , Masculino , Cuidados Paliativos/métodos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , Sarcoma de Kaposi/patologia , Sarcoma de Kaposi/terapia , Resultado do Tratamento
10.
Drug Deliv ; 26(1): 898-917, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31526065

RESUMO

Although intraperitoneal chemotherapy (IPC) has been suggested as a promising method for the management of peritoneal dissemination (PD) of ovarian or colorectal cancers, the actual clinical use of this method has been restricted due to such problems as poor drug penetration into the tumor and high side effects. It is, therefore, necessary to develop new strategies to improve the efficacy of this approach. In the present work, a new strategy is proposed based on intraperitoneal (IP) injection of thermosensitive liposomal doxorubicin (TSL-Dox) with triggered release by mild hyperthermia induced by high intensity focused ultrasound (HIFU). A computational model is developed to evaluate the proposed drug delivery system. Results show an order of magnitude increase in drug penetration depth into the tumor compared to the conventional IP delivery. Furthermore, the effects of thermal conditions applied to the tumor, TSL size, tumor vessel permeability, and tumor size are investigated. Results indicate an improved efficiency of the drug delivery by expanding the heated region, yet, it increases the risk of unintentional TSL drug load release in the peritoneal cavity. Results also indicate that smaller TSLs have better treatment outcome. However, there is a significant reduction in treatment efficacy for TSLs with sizes smaller than the vessel wall pore size. Thus, tuning the size of TSL should be based on the tumor microvascular permeability. The simulation results suggest that the TSL-Dox delivery system in smaller tumors is far advantageous than larger ones. Results of our model can be used as guidelines for future preclinical studies.


Assuntos
Antibióticos Antineoplásicos/química , Doxorrubicina/análogos & derivados , Lipossomos/química , Antibióticos Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Hipertermia Induzida/métodos , Injeções Intraperitoneais , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Temperatura , Distribuição Tecidual
11.
Cir Cir ; 87(S1): 28-32, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31501620

RESUMO

Background: The successful performance of ostomies for the treatment of different diseases has been described since 1706. We report herein the first case of successful ostomy utilizing a synthetic stoma created in a patient with peritoneal carcinomatosis. Clinical case: A 40-year-old woman presented with abdominal carcinomatosis due to psammomatous papillotubular adenocarcinoma consistent with primary ovarian carcinoma. The patient had negative estrogen and progesterone receptors and Ki-67 proliferative activity was 83%. She was initially treated with cytoreduction therapy, chemotherapy, and hyperthermic intraperitoneal chemotherapy. Because the patient presented with enteric perforations and the extensive tumor invasion and adhesions in all the intestinal segments made it impossible to create autologous decompression stomas, a synthetic stoma was constructed. Conclusions: Synthetic stomas can be a good treatment option when autologous stomas can not be created.


Assuntos
Adenocarcinoma Papilar/secundário , Drenagem/instrumentação , Neoplasias Intestinais/secundário , Perfuração Intestinal/cirurgia , Neoplasias Ovarianas/cirurgia , Estomas Cirúrgicos , Adenocarcinoma Papilar/tratamento farmacológico , Adenocarcinoma Papilar/etiologia , Adenocarcinoma Papilar/cirurgia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Coagulação com Plasma de Argônio , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução/métodos , Docetaxel/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Evolução Fatal , Feminino , Humanos , Hipertermia Induzida , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/etiologia , Neoplasias Intestinais/cirurgia , Perfuração Intestinal/etiologia , Mitomicina/administração & dosagem , Polietilenoglicóis/administração & dosagem
12.
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
13.
J Cancer Res Ther ; 15(4): 773-783, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31436231

RESUMO

Background: Lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox) consists of doxorubicin encapsulated contained within a heat-sensitive liposome. Aims and Objectives: We sought to evaluate whether the use of combined radiofrequency ablation (RFA) and LTLD would result in larger coagulation volume and longer overall survival (OS) compared with the use of RFA alone in patients with 3-7 cm unresectable hepatocellular carcinoma (HCC). Materials and Methods: Between 2010 and 2012, 22 HCC patients were randomly assigned to one of two treatments in our center: (1) ultrasound-guided percutaneous RFA plus intravenous (IV) infusion of LTLD (combination, n = 11) or (2) RFA plus IV dummy (RFA, n = 11). Four patients withdrew from the study, and the remaining 18 patients entered the final analysis. There were 14 male and 4 female patients with an average age of 61.1 ± 9.3 years (range: 40-73 years). The average tumor size was 4.2 ± 1.0 cm (range: 3.1-6.1 cm). One-month enhanced computed tomography was used to evaluate the ablation efficacy and coagulation volume after RFA. Regular follow-up after RFA was performed to assess toxicity, local response rates, and OS rates. Results: A major complication (empyema) occurred in one case in the combination group. Combination treatment region did not induce any additional toxicity beyond doxorubicin. The primary ablation success rate was 93.3% (14/15 tumors) in the combination group and 77.8% (7/9 tumors) in the RFA group (P = 0.308). The difference in coagulation volume between pre- and post-RFA in the combination group was significantly larger than that of the RFA group (105.7 ± 73.8 cm 3 vs. 37.3 ± 8.5 cm 3, P = 0.013). The follow-up period ranged from 11 to 80 months (average: 49.1 ± 24.8 months). The local progression rate was 6.7% (1/15 tumors) in the combination group and 22.2% (2/9 tumors) in the RFA group. The mean OS for the combination group was 68.5 ± 7.2 months, which was significantly greater compared with the RFA group (46.0 ± 10.6 months, P = 0.045). Conclusions: RFA with heat target delivery chemotherapy facilitated better tumor coagulation necrosis without additional toxicity. This combined treatment may improve the clinical efficacy of RFA or free doxorubicin and prolong survival in patients with medium to large HCC.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/mortalidade , Doxorrubicina/análogos & derivados , Neoplasias Hepáticas/mortalidade , Ablação por Radiofrequência/mortalidade , Adulto , Idoso , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Terapia Combinada , Método Duplo-Cego , Doxorrubicina/uso terapêutico , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida
14.
Dermatol Clin ; 37(4): 443-454, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31466585

RESUMO

Primary cutaneous B-cell lymphomas are a group of diseases with indolent and aggressive behavior. The goal of the initial workup is to evaluate for systemic involvement, provide adequate staging, and guide therapy. Histopathological studies are a critical part of the workup for classification of these lymphomas because they are similar to their nodal counterparts. There are limited data for treatment guidelines, and thus, therapy differs among institutions. Overall, localized therapies are preferred for indolent types and chemotherapy or immunotherapy for the aggressive forms.


Assuntos
Antineoplásicos/uso terapêutico , Procedimentos Cirúrgicos Dermatológicos , Linfoma de Células B/terapia , Neoplasias Cutâneas/terapia , Administração Cutânea , Corticosteroides/uso terapêutico , Antibacterianos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bexaroteno/uso terapêutico , Borrelia burgdorferi , Ciclofosfamida/uso terapêutico , Procedimentos Cirúrgicos de Citorredução , Gerenciamento Clínico , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapêutico , Humanos , Injeções Intralesionais , Doença de Lyme/tratamento farmacológico , Linfoma de Células B/diagnóstico , Linfoma de Células B/patologia , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/microbiologia , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma de Zona Marginal Tipo Células B/terapia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Mecloretamina/uso terapêutico , Polietilenoglicóis/uso terapêutico , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Vincristina/uso terapêutico
15.
Int J Hyperthermia ; 36(1): 868-875, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31452420

RESUMO

Objective: To compare the efficacy and safety of a novel thermochemotherapy scheme and the instillation of pirarubicin (THP) without hyperthermia in patients with intermediate- and high-risk nonmuscle-invasive bladder cancer (NMIBC). Materials and methods: Between June 2012 and December 2016, 300 patients with urothelial carcinoma of the bladder undergoing intravesical adjuvant therapy with THP after transurethral resection of bladder tumors (TURBT) were enrolled in the study. These patients were divided into the CTHC group (thermochemotherapy composed of three consecutive sessions in which only the second hyperthermia was combined with THP, followed by intravesical instillation with THP without using hyperthermia) and the THP group (instillation of THP without hyperthermia). Cystoscopy and urinary cytology were repeated every 3 months. The primary endpoint was 24-month recurrence-free survival (RFS). Secondary endpoints included 24-month progression-free survival (PFS) and adverse event (AE) rates. Results: Baseline characteristics of the CTHC (n = 76) and THP (n = 85) groups were well-balanced. The 24-month RFS was 82.9% in the CTHC group and 63.5% in the THP group (log-rank p = .008). A significantly higher percentage of patients in the CTHC group achieved PFS than in the THP group (97.4% versus 87.1%; log-rank p = .011). There was no significant difference in AEs between the two groups (p > .05). Based on Cox proportional hazards models, CTHC was the only factor that contributed independently to improved RFS (hazard ratio, 0.422; 95% confidence interval, 0.214-0.835; p = .013). Conclusion: The CTHC scheme is a safe and effective adjuvant treatment option after TURBT for patients with intermediate- and high-risk NMIBC.


Assuntos
Antineoplásicos/uso terapêutico , Doxorrubicina/análogos & derivados , Hipertermia Induzida , Neoplasias da Bexiga Urinária/terapia , Administração Intravesical , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Doxorrubicina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Procedimentos Cirúrgicos Urológicos
16.
Int J Hyperthermia ; 36(1): 817-826, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31451077

RESUMO

Objective: Thermosensitive liposomal doxorubicin (TSL-Dox) is a promising stimuli-responsive nanoparticle drug delivery system that rapidly releases the contained drug in response to hyperthermia (HT) (>40 °C). Combined with localized heating, TSL-Dox allows highly localized delivery. The goals of this study were to demonstrate that real-time fluorescence imaging can visualize drug uptake during delivery, and can predict tumor drug uptake. Methods: Nude mice carrying subcutaneous tumors (Lewis lung carcinoma) were anesthetized and injected with TSL-Dox (5 mg/kg dose). Localized HT was induced by heating tumors for 15, 30 or 60 min via a custom-designed HT probe placed superficially at the tumor location. In vivo fluorescence imaging (excitation 523 nm, emission 610 nm) was performed before, during, and for 5 min following HT. After imaging, tumors were extracted, drug uptake was quantified by high-performance liquid chromatography, and correlated with in vivo fluorescence. Plasma samples were obtained before and after HT to measure TSL-Dox pharmacokinetics. Results: Local drug uptake could be visualized in real-time during HT. Compared to unheated control tumors, fluorescence of heated tumors increased by 4.6-fold (15 min HT), 9.3-fold (30 min HT), and 13.2-fold (60 min HT). HT duration predicted tumor drug uptake (p = .02), with tumor drug concentrations of 4.2 ± 1.3 µg/g (no HT), 7.1 ± 5.9 µg/g (15 min HT), 14.1 ± 6.7 µg/g (30 min HT) and 21.4 ± 12.6 µg/g (60 min HT). There was good correlation (R2 = 0.67) between fluorescence of the tumor region and tumor drug uptake. Conclusions: Real-time in vivo fluorescence imaging can visualize drug uptake during delivery, and can predict tumor drug uptake.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Lewis/diagnóstico por imagem , Carcinoma Pulmonar de Lewis/terapia , Doxorrubicina/análogos & derivados , Hipertermia Induzida , Imagem Óptica , Animais , Antibióticos Antineoplásicos/sangue , Antibióticos Antineoplásicos/farmacocinética , Carcinoma Pulmonar de Lewis/metabolismo , Doxorrubicina/administração & dosagem , Doxorrubicina/sangue , Doxorrubicina/farmacocinética , Sistemas de Liberação de Medicamentos , Feminino , Camundongos Endogâmicos BALB C , Camundongos Nus , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , Temperatura
18.
Am J Chin Med ; 47(5): 1075-1097, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31311298

RESUMO

Pirarubicin (THP) is an anthracycline antibiotic, frequently used for the treatment of various human cancers. Unfortunately, the clinical effectiveness of THP is limited by its dose-related cardiotoxicity. Apocynum leaf extract is an extract of the dried leaves of Apocynum venetum L. (a member of the Apocynaceae family, AVLE) that has many positive effects on the cardiovascular system and is widely consumed as tea in China. In this study we established a cardiactoxicity rat model, which showed that pretreatment with AVLE attenuated THP-induced myocardial histopathological injury, electrocardiogram abnormalities, and cardiac dysfunction. AVLE also significantly reduced serum levels of malondialdehyde (MDA), brain natriuretic peptide (BNP), creatine kinase (CK-MB), cardiac troponin (CTnT), and lactate dehydrogenase (LDH); and increased serum superoxide dismutase (SOD) levels. Treatment with AVLE or dexrazoxane (DZR) resulted in an increase Cytochrome C (cytc) in the mitochondria and reduced Cytc and cleaved-caspase-3 levels (p<0.05) in cytoplasm. We also found that AVLE significantly reduced voltage-dependent anion channel 1 (VDAC1), adenosine nucleotide transporter 1 (ANT1), and cyclophilin D (CYPD) mRNA expression (p<0.05). Furthermore, AVLE appeared to exert therapeutic effects in a dose-dependent manner. Our study suggests the anti-oxidant and anti-apoptotic properties of AVLE may be responsible for the observed cardioprotective effects.


Assuntos
Antioxidantes/administração & dosagem , Apocynum/química , Cardiotoxicidade/prevenção & controle , Medicamentos de Ervas Chinesas/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/fisiopatologia , Creatina Quinase/genética , Creatina Quinase/metabolismo , Doxorrubicina/efeitos adversos , Doxorrubicina/análogos & derivados , Humanos , Masculino , Malondialdeído/metabolismo , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Encefálico/metabolismo , Folhas de Planta/química , Ratos , Ratos Wistar , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Troponina/genética , Troponina/metabolismo
19.
Oncol Rep ; 42(3): 1057-1065, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322247

RESUMO

Although bevacizumab maintenance following bevacizumab in combination with chemotherapy has demonstrated significant prolongation of progression-free survival in clinical studies in patients with ovarian cancer, the majority of the cancer cases in the study were of the serous histotype; therefore, data regarding clear cell carcinoma is limited. Furthermore, the efficacy of bevacizumab beyond progression has not yet been demonstrated in ovarian cancer. A xenograft model using the human ovarian clear cell carcinoma cell line RMG-I was used to investigate the antitumor effects and the mechanisms of bevacizumab in maintenance treatment and bevacizumab when administered beyond disease progression. In the RMG-I model, bevacizumab maintenance following bevacizumab in combination with paclitaxel exhibited increased tumor suppression, compared with its absence, and inhibited the increase of microvessel density (MVD) in tumors. Following disease progression during bevacizumab maintenance, continued bevacizumab treatment in combination with PEGylated liposomal doxorubicin as a secondary chemotherapeutic agent had increased efficacy, compared with PEGylated liposomal doxorubicin alone, and resulted in lower MVD accompanied with lower levels of insulin-like growth factor binding protein-3, which is reported to have angiogenic activity. Continuous suppression of angiogenesis by bevacizumab may contribute to the superior efficacy of bevacizumab maintenance and bevacizumab beyond progression in ovarian cancer.


Assuntos
Adenocarcinoma de Células Claras/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neovascularização Patológica/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adenocarcinoma de Células Claras/irrigação sanguínea , Adenocarcinoma de Células Claras/patologia , Animais , Apoptose , Bevacizumab/administração & dosagem , Proliferação de Células , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/patologia , Neoplasias Ovarianas/irrigação sanguínea , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Polietilenoglicóis/administração & dosagem , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Drug Dev Ind Pharm ; 45(9): 1556-1564, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31271317

RESUMO

Objective: This study was aimed to develop DOX-TPP loaded acetal-PEG-PCCL micelles to improve the clinical efficacy of drug resistance tumor. Significance: Chemotherapy is one of the main treatments for breast cancer but is plagued by multidrug resistance (MDR). DOX-TPP-loaded micelles can enhance the specific concentration of drugs in the tumor and improve the efficacy and overcome MDR. Methods: In this study, DOX-TPP-loaded micelles based on acetal-PEG-PCCL were prepared and their physicochemical properties were characterized. The cellular uptake and ability to induce apoptosis of the micelles was confirmed by flow cytometry in MCF-7/ADR cells. In addition, cytotoxicity of the micelles was studied in MCF-7 cells and MCF-7/ADR cells. Confocal is used to study the subcellular distribution of DOX. Free DOX-TPP or DOX-TPP-loaded acetal-PEG-PCCL micelles were administered via intravenous injection in the tail vain for the biodistribution study in vivo. Results: The diameter of micelles was about 102.4 nm and their drug-loading efficiency is 61.8%. The structural characterization was confirmed by 1H NMR. The micelles exhibited better antitumor efficacy compared to free doxorubicin in MCF-7/ADR cells by MTT assay. The apoptotic rate and the cellular uptake of micelles were significantly higher than free DOX and DOX-TPP. Micelles can efficiently deliver mitochondria-targeting DOX-TPP to tumor cells. The result of bio-distribution showed that the micelles had stronger tumor infiltration ability than free drugs. Conclusions: In this study, mitochondriotropic DOX-TPP was conjugated to the nanocarrier acetal-PEG-PCCL via ionic interaction to form a polymer, which spontaneously formed spherical micelles. The cytotoxicity and cellular uptake of the micelles are superior to free DOX and exhibit mitochondrial targeting and passive tumor targeting, indicating that they have potential prospects.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/administração & dosagem , Nanoconjugados/química , Compostos Organofosforados/administração & dosagem , Acetais/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacocinética , Composição de Medicamentos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Micelas , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Compostos Organofosforados/química , Compostos Organofosforados/farmacocinética , Poliésteres/química , Polietilenoglicóis/química , Distribuição Tecidual
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