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1.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198613

RESUMO

Breast cancer is the most common cancer in females. The aim of this study was to determine the effect of paclitaxel (PTX) and doxorubicin (DOX) therapy on the ßIII-tubulin, carbonic anhydrase IX (CA IX), and survivin expression in chemically-induced rat mammary tumors. Animals with induced mammary carcinogenesis were randomly divided into treatment groups and an untreated group. The total proportion of tumors, the proportion of carcinoma in situ (CIS), and invasive carcinoma (IC) were evaluated. Protein expression in tumor tissue was determined using IHC. Statistical analysis of the data, evaluated by Fisher-exact test and unpaired t-test. Significantly increased levels of proteins in the tumor cells were confirmed using the IHC method for all studied proteins. The expression of ßIII-tubulin, CA IX, and survivin increased significantly after treatment with both cytostatics (PTX and DOX). Depending on the type of tumor, a significant increase in all proteins was observed in IC samples after PTX treatment, and CA IX expression after DOX treatment. In CIS samples, a significant increase of ßIII-tubulin and survivin expression was observed after a DOX treatment. The results suggest that ßIII-tubulin, survivin, and CA IX may be significant drug resistance markers and the clinical regulation of their activity may be an effective means of reversing this resistance.


Assuntos
Anidrase Carbônica IX/metabolismo , Doxorrubicina/uso terapêutico , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/metabolismo , Paclitaxel/uso terapêutico , Survivina/metabolismo , Tubulina (Proteína)/metabolismo , Animais , Doxorrubicina/farmacologia , Feminino , Paclitaxel/farmacologia , Ratos Sprague-Dawley
2.
Rinsho Ketsueki ; 62(6): 631-640, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34219091

RESUMO

Intravascular large B-cell lymphoma is a rare disease entity of extranodal large B-cell lymphoma and is characterized by selective growth of tumor cells in the lumina of small vessels in systemic organs. The challenge in obtaining sufficient tumor cells from biopsy specimens has hampered the elucidation of underlying biology. Recent advances in xenograft models and plasma cell-free DNA have revealed that the intravascular large B-cell lymphoma has genetic features similar to those of activated B-cell-like diffuse large B-cell lymphoma and frequent genetic alterations in immune-check point related genes. In terms of clinical aspects, considering the improvement in the clinical outcomes and higher risk of secondary central nervous system (CNS) involvement in the rituximab era, phase 2 trial of R-CHOP therapy combined with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy was conducted. The trial, named the PRIMEUR-IVL study, displayed good progression-free survival and low cumulative incidence of secondary CNS involvement. Further research is necessary to enable a deeper understanding of the pathophysiology of the disease and further improve the clinical outcomes.


Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma Difuso de Grandes Células B , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Vincristina/uso terapêutico
3.
Rinsho Ketsueki ; 62(6): 641-648, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34219092

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, and nearly 70% of patients may be cured by administering R-CHOP therapy. However, R-CHOP is found to be inadequate in approximately one-third of the DLBCL cases, and refractory disease to R-CHOP is usually associated with a major cause of mortality. Therefore, it is essential to improve the efficacy of initial treatment in order to avoid unfavorable outcomes in patients with refractory DLBCL. In general, R-CHOP comprises of CHOP regimen that is repeated every 3 weeks and adding one-dose rituximab in each cycle. Although this combination method of rituximab with CHOP is effective and convenient, it does not contain enough scientific rationale and the schedule of rituximab administration has not been optimized. The pharmacokinetics of rituximab differs substantially among individuals and its serum half-life is approximately more than 500 hours; therefore, the peak concentration increases cumulatively by weekly infusion. A previous study revealed that patients with high blood concentration of rituximab showed higher response rate and longer progression-free survival. These findings suggest that the retention of higher levels of rituximab concentration and combination with chemotherapy during an early treatment period may bring about improvement of treatment effect. The HOVON group and Japan Clinical Oncology Group conducted randomized phase III studies to evaluate the efficacy of the dose-dense rituximab strategy for untreated DLBCL.


Assuntos
Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Japão , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Resultado do Tratamento , Vincristina/uso terapêutico
4.
Int J Mol Sci ; 22(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063119

RESUMO

One of the promising strategies for improvement of cancer treatment is application of a combination therapy. The aim of this study was to investigate the anticancer activity of nanoformulations containing doxorubicin and iron oxide particles covered with polymeric shells bearing cholesterol moieties. It was postulated that due to high affinity to cell membranes, particles comprising poly(cholesteryl acrylate) can sensitize cancer cells to doxorubicin chemotherapy. The performed analyses revealed that the developed systems are effective against the human breast cancer cell lines MCF-7 and MDA-MB-231 even at low doses of the active compound applied (0.5 µM). Additionally, high compatibility and lack of toxicity of the tested materials against human red blood cells, immune (monocytic THP-1) cells, and cardiomyocyte H9C2(2-1) cells was demonstrated. Synergistic effects observed upon administration of doxorubicin with polymer-iron oxide hybrids comprising poly(cholesteryl acrylate) may provide an opportunity to limit toxicity of the drug and to improve its therapeutic efficiency at the same time.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Colesterol/química , Doxorrubicina/uso terapêutico , Fenômenos Magnéticos , Polímeros/química , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Doxorrubicina/toxicidade , Difusão Dinâmica da Luz , Feminino , Humanos , Teste de Materiais , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Termogravimetria
5.
Medicine (Baltimore) ; 100(25): e26214, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160385

RESUMO

ABSTRACT: To investigate the relationship between the changes in circulating CD45RO+T lymphocyte subsets following neoadjuvant therapy for rectal cancer in patients with locally advanced rectal cancer.The clinicopathological data of 185 patients with rectal cancer who received neoadjuvant therapy in the General Surgery Department of Beijing Chaoyang Hospital affiliated to Capital Medical University from June 2015 to June 2017 were analyzed. Venous blood samples were collected 1 week before neoadjuvant therapy and 1 week before surgery, and the expression of CD45RO+T was detected by flow cytometry. The receiver operating characteristic curve analysis was used to determine the optimal cut-off point of CD45RO+ratio. Log-rank test and multivariate Cox regression were used to analyze the overall survival rate (OS) and disease-free survival rate (DFS) associated with CD45RO+ratio.Circulating CD45RO+ratio of 1.07 was determined as the optimal cut-off point and CD45RO+ratio-high was associated with lower tumor regression grade grading (P = .031), T stage (P = .001), and tumor node metastasis (TNM) stage (P = .012). The 3-year DFS and OS rate in the CD45RO+ratio-high group was significantly higher than that in the CD45RO+ratio-low group (89.2% vs 60.1%, P<.001; 94.4% vs 73.2%, P<.001). The multivariate Cox analysis revealed that elevated CD45RO+ratio was an independent factor for better DFS (OR, 0.339; 95% CI, 0.153-0.752; P = .008) and OS (OR, 0.244; 95% CI,0.082-0.726; P = .011).Circulating CD45RO+ratio could predict the tumor regression grade of neoadjuvant therapy for rectal cancer, as well as long-term prognosis. These findings could be used to stratify patients and develop alternative strategies for adjuvant therapy.


Assuntos
Quimiorradioterapia Adjuvante/métodos , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Retais/terapia , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Separação Celular , Colonoscopia , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Citometria de Fluxo , Seguimentos , Humanos , Antígenos Comuns de Leucócito/metabolismo , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/imunologia , Estadiamento de Neoplasias , Oxaliplatina/uso terapêutico , Prednisona/uso terapêutico , Período Pré-Operatório , Protectomia , Prognóstico , Radioterapia de Intensidade Modulada , Neoplasias Retais/sangue , Neoplasias Retais/imunologia , Neoplasias Retais/mortalidade , Reto/diagnóstico por imagem , Reto/patologia , Reto/cirurgia , Estudos Retrospectivos , Taxa de Sobrevida , Subpopulações de Linfócitos T/metabolismo , Vindesina/uso terapêutico
6.
Langmuir ; 37(24): 7356-7363, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34111931

RESUMO

Diblock copolymer-based prodrugs have been widely designed for tumor treatment after self-assembly; however, premature drug leakage could not be ignored because their hydrophobic prodrug cores were directly exposed to the media. Here, an amphiphilic triblock copolymer prodrug with a hydrophilic PEG block, a pH-sensitive poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) block, and a hydrophobic reduction-cleavable prodrug block was synthesized for tumor-specific pH/reduction dual-triggered drug delivery, via the successive RAFT polymerization of DPA and a DOX-based monomer (MAL-DOX) with a PEG-based macro-CTA. The core-shell and core-shell-corona nanoparticles could be obtained by one-step and two-step self-assembly. With the pH-sensitive gatekeeper formed by the PDPA block, the core-shell-corona nanoparticles possessed a smaller diameter with narrow distribution and better drug release with lower drug leakage. MTT assays demonstrated the selective cytotoxicity of the core-shell-corona nanoparticles to the cancer cells was dose-dependent because of the reduction-cleavable prodrug. The negligible drug leakage and selective cytotoxicity to cancer cells endow the proposed core-shell-corona prodrug nanoparticles with promising potential for tumor treatment without toxic side effects on the normal cells.


Assuntos
Nanopartículas , Neoplasias , Pró-Fármacos , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Micelas , Neoplasias/tratamento farmacológico
7.
Lancet Oncol ; 22(7): 1034-1046, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34143970

RESUMO

BACKGROUND: Most patients with ovarian cancer will relapse after receiving frontline platinum-based chemotherapy and eventually develop platinum-resistant or platinum-refractory disease. We report results of avelumab alone or avelumab plus pegylated liposomal doxorubicin (PLD) compared with PLD alone in patients with platinum-resistant or platinum-refractory ovarian cancer. METHODS: JAVELIN Ovarian 200 was an open-label, parallel-group, three-arm, randomised, phase 3 trial, done at 149 hospitals and cancer treatment centres in 24 countries. Eligible patients were aged 18 years or older with epithelial ovarian, fallopian tube, or peritoneal cancer (maximum of three previous lines for platinum-sensitive disease, none for platinum-resistant disease) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to avelumab (10 mg/kg intravenously every 2 weeks), avelumab plus PLD (40 mg/m2 intravenously every 4 weeks), or PLD and stratified by disease platinum status, number of previous anticancer regimens, and bulky disease. Primary endpoints were progression-free survival by blinded independent central review and overall survival in all randomly assigned patients, with the objective to show whether avelumab alone or avelumab plus PLD is superior to PLD. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02580058. The trial is no longer enrolling patients and this is the final analysis of both primary endpoints. FINDINGS: Between Jan 5, 2016, and May 16, 2017, 566 patients were enrolled and randomly assigned (combination n=188; PLD n=190, avelumab n=188). At data cutoff (Sept 19, 2018), median duration of follow-up for overall survival was 18·4 months (IQR 15·6-21·9) for the combination group, 17·4 months (15·2-21·3) for the PLD group, and 18·2 months (15·8-21·2) for the avelumab group. Median progression-free survival by blinded independent central review was 3·7 months (95% CI 3·3-5·1) in the combination group, 3·5 months (2·1-4·0) in the PLD group, and 1·9 months (1·8-1·9) in the avelumab group (combination vs PLD: stratified HR 0·78 [repeated 93·1% CI 0·59-1·24], one-sided p=0·030; avelumab vs PLD: 1·68 [1·32-2·60], one-sided p>0·99). Median overall survival was 15·7 months (95% CI 12·7-18·7) in the combination group, 13·1 months (11·8-15·5) in the PLD group, and 11·8 months (8·9-14·1) in the avelumab group (combination vs PLD: stratified HR 0·89 [repeated 88·85% CI 0·74-1·24], one-sided p=0·21; avelumab vs PLD: 1·14 [0·95-1·58], one-sided p=0·83]). The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysesthesia syndrome (18 [10%] in the combination group vs nine [5%] in the PLD group vs none in the avelumab group), rash (11 [6%] vs three [2%] vs none), fatigue (ten [5%] vs three [2%] vs none), stomatitis (ten [5%] vs five [3%] vs none), anaemia (six [3%] vs nine [5%] vs three [2%]), neutropenia (nine [5%] vs nine [5%] vs none), and neutrophil count decreased (eight [5%] vs seven [4%] vs none). Serious treatment-related adverse events occurred in 32 (18%) patients in the combination group, 19 (11%) in the PLD group, and 14 (7%) in the avelumab group. Treatment-related adverse events resulted in death in one patient each in the PLD group (sepsis) and avelumab group (intestinal obstruction). INTERPRETATION: Neither avelumab plus PLD nor avelumab alone significantly improved progression-free survival or overall survival versus PLD. These results provide insights for patient selection in future studies of immune checkpoint inhibitors in platinum-resistant or platinum-refractory ovarian cancer. FUNDING: Pfizer and Merck KGaA, Darmstadt, Germany.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Compostos de Platina/uso terapêutico , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Pessoa de Meia-Idade , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/mortalidade , Compostos de Platina/efeitos adversos , Polietilenoglicóis/uso terapêutico , Fatores de Tempo
8.
BMJ Case Rep ; 14(6)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162604

RESUMO

Intravascular large B-cell lymphoma (IVLBCL) is an aggressive and rare type of diffuse extranodal B-cell lymphoma. Diagnosis and treatment are challenging and clinical presentation is variable. Physicians should be aware of this rare but life-threatening lymphoma without adenopathy and treatment should be promptly started. We describe the case of a 70-year-old woman who presented with general malaise, acute dyspnoea, platypnoea and lactic acidosis. Echocardiography revealed an extracardiac shunt, the cause of her orthodeoxia. The patient developed rapid liver failure and underwent liver biopsy. Anatomopathological findings suggested IVLBCL, non-germinal center type. She achieved complete remission after rituximab, cyclophosphamide, doxorubicin, vincristine, methylprednisolone chemotherapy but relapsed 1 year after initial presentation with multiple organ involvement. The patient's relapsed disease was treated with rituximab, iphosphamide, carboplatin, etoposide and she is still in complete remission 2 years later.


Assuntos
Acidose Láctica , Linfoma Difuso de Grandes Células B , Acidose Láctica/diagnóstico , Acidose Láctica/tratamento farmacológico , Acidose Láctica/etiologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Dispneia , Feminino , Humanos , Hipóxia , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Vincristina/uso terapêutico
9.
J Int Med Res ; 49(6): 3000605211017037, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34082600

RESUMO

Primary colonic lymphoma is a very rare malignant tumor with no standard treatment. We report two cases of primary colonic lymphoma successfully treated with surgery and chemotherapy, and chemotherapy alone, respectively. The first case was a 61-year-old woman who presented with abdominal pain of more than 1 month. The patient was diagnosed with a colonic tumor, and immunohistochemical examinations confirmed the initial diagnosis of colonic lymphoma. The patient underwent laparoscopic-assisted right hemicolectomy followed by postoperative adjuvant chemotherapy with the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen, combined with targeted therapy with rituximab (R-CHOP). The second case was a 78-year-old man who presented with a complaint of abdominal distention for more than 1 year. Diffuse large B-cell lymphoma was definitively diagnosed by immunohistochemical examinations, and the patient underwent systemic chemotherapy with the R-CHOP regimen. Primary colonic lymphoma is a rare type of non-Hodgkin's lymphoma (NHL), and the clinical treatment is not standardized, unlike for many other types of lymphoma. Therefore, treatment is mainly based on the patient's symptoms to determine whether surgery or systemic chemotherapy is appropriate. Rituximab is effective in some patients and may play an important role in the treatment of unresectable or asymptomatic colonic lymphoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Colo , Idoso , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Vincristina/uso terapêutico
10.
Int J Nanomedicine ; 16: 4073-4085, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34163160

RESUMO

Background: The efficacy of systemic chemotherapy for hepatocellular carcinoma (HCC) is predominantly hampered by low accumulation in tumor tissue and the high systemic toxicity of anticancer drugs. In this study, we designed an in situ drug-loaded injectable thermosensitive hydrogel system for the simultaneous delivery of norcantharidin-loaded nanoparticles (NCTD-NPs) and doxorubicin (Dox) via intratumoral administration to HCC tumors. Methods: NCTD-NPs were prepared by the thin film dispersion method using PCEC polymers as the carrier. Then, NCTD-NPs and Dox were co-encapsulated in a thermosensitive hydrogel based on Pluronic F127 (PF127) to construct a dual drug-loaded hydrogel system. The rheological properties of the drug-loaded hydrogel were studied using a rheometer. Drug release of the drug-loaded hydrogel and cytotoxicity in HepG2 cells were evaluated in vitro. An H22 tumor-bearing mice model was used to assess the in vivo antitumor activity of the drug-loaded hydrogel via intratumoral administration. Results: The prepared drug-loaded hydrogel exhibited good thermal-sensitive properties, which remained liquid at room temperature and rapidly transformed into a non-flowing gel at body temperature, and released the drugs in a sustained manner. In vitro studies revealed that the drug-loaded hydrogel exhibited remarkable antiproliferative activity in HepG2 cells compared to free drugs. In vivo antitumor efficacy experiments showed that the drug-loaded hydrogel significantly suppressed tumor growth, alleviated side effects, and prolonged the survival time of mice bearing H22 tumors compared to the other groups. Moreover, immunohistochemical staining revealed that the expression of Ki-67 and CD31 in the drug-loaded hydrogel group was significantly lower than that in the other groups (P < 0.05), indicating that the drug-loaded hydrogel effectively inhibited tumor proliferation and angiogenesis. Conclusion: The formulated hybrid thermosensitive hydrogel system with sustained drug release and enhanced therapeutic efficacy was demonstrated to be a promising strategy for the local-regional treatment of HCC via intratumoral administration.


Assuntos
Antineoplásicos/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Doxorrubicina/administração & dosagem , Hidrogéis/química , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/química , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Temperatura Corporal , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Preparações de Ação Retardada , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Poloxâmero/química
11.
In Vivo ; 35(4): 1951-1957, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34182468

RESUMO

BACKGROUND: Hepatic dysfunction in patients with classical Hodgkin lymphoma (cHL) is of multifactorial aetiology. Prompt evaluation with laboratory tests and imaging methods is sufficient for diagnosis in most cases. Intrahepatic cholestasis and vanishing bile duct syndrome (VBDS) may complicate cHL as rare paraneoplastic phenomena. Liver biopsy provides crucial evidence of cholestasis, and ductopenia, if present, confirms the diagnosis of VBDS. CASE REPORT: We report on a cHL patient that presented with jaundice and bulky mediastinal disease and unfold the therapeutic dilemmas we confronted. Marked hyperbilirubinemia was successfully reversed with brentuximab vedotin (BV) at a dose of 1.2 mg/kg and the patient was subsequently treated with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) at full doses, achieving complete metabolic response. A literature review of intrahepatic cholestasis in cHL is also presented based on currently available data with focus on treatment options and clinicopathologic associations. CONCLUSION: VBDS and intrahepatic cholestasis are rare and potentially fatal complications of cHL. Their prompt recognition and appropriate treatment can dramatically affect cHL patients' outcome. BV, used at a reduced dose as a bridging therapy, should be considered as a high-priority treatment plan in these challenging cases.


Assuntos
Colestase Intra-Hepática , Doença de Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina , Brentuximab Vedotin , Dacarbazina/uso terapêutico , Doxorrubicina/uso terapêutico , Doença de Hodgkin/complicações , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/tratamento farmacológico , Humanos , Vimblastina/uso terapêutico
12.
Res Vet Sci ; 137: 208-216, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34020336

RESUMO

The present study aimed to verify the changes in the expression levels of 13 candidate genes associated with chemotherapy resistance and to construct a scoring system to predict resistance to these drugs. The expression levels of the 13 candidate genes were compared between 20 dogs with lymphoma that were sensitive to drugs used in CHOP-based protocol and 16 dogs with lymphoma that were resistant to these drugs. The expression levels of six genes; ASNS, CCR3, CALCA, FCER1A, LOC448801, and EDNRB were significantly different between the two groups. A scoring system to predict resistance to cyclophosphamide, doxorubicin and vincristine, which are used in CHOP-based protocol, was constructed based on expression levels of the six genes in these 36 dogs using logistic regression models. After internal validation, sensitivity and specificity of the scoring system were 0.759 and 0.853, respectively. External validation was conducted in another cohort of 33 dogs with lymphoma, and sensitivity and specificity of the scoring system were 0.800 and 0.696, respectively. In conclusion, this study identified six genes associated with resistance to drugs used in CHOP-based protocol in canine lymphoma and proposed a novel scoring system to predict resistance to these drugs. This system might be beneficial in selecting the most appropriate chemotherapy protocol for individual dogs with lymphoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças do Cão/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Linfoma/veterinária , Transcriptoma , Animais , Estudos de Coortes , Ciclofosfamida/uso terapêutico , Cães , Doxorrubicina/uso terapêutico , Feminino , Linfoma/tratamento farmacológico , Masculino , Prednisona/uso terapêutico , Projetos de Pesquisa , Vincristina/uso terapêutico
13.
Biomater Sci ; 9(9): 3348-3361, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33949362

RESUMO

The in vivo delivery of nanomedicine is severely hampered by the limited enhanced permeability and retention effect (EPR) in tumors. Aiming at overcoming this limitation and achieving high anti-tumor effect of chemotherapeutics, we specially addressed an available strategy from a viewpoint of increasing the drug loading of nano-carriers. Here, we constructed a novel pH-responsive polymersome based on the drug-driven self-assembly of amphiphilic polyphosphazenes PAP containing the ortho ester group ABD and mPEG2000. Due to the non-covalent attractive forces between PAP and doxorubicin hydrochloride (DOX·HCl), DOX·HCl can induce the self-assembly of PAP via embedding itself in the lamella to form vesicles and the subsequent location in the center aqueous chamber of the resultant nano-vesicles, which resulted in the high drug loading content of 35.77 wt%. In addition, with the incorporation of cholesteryl hemisuccinate (CholHS), the premature leakage of DOX·HCl was significantly inhibited under physiological conditions. Meanwhile, the pH-sensitive drug release occurred at pH 5.5 by the advantage of the pH-sensitive biodegradation of ABD in PAP. Consequently, this CholHS-incorporated DOX·HCl-driven PAP vesicle achieved excellent anti-tumor effect with tumor growth inhibition up to 82.4% in S180 tumor-bearing mice. Taken together, our newly developed drug-driven vesicles may promote the development of efficient drug delivery systems for application in cancer therapy.


Assuntos
Neoplasias , Preparações Farmacêuticas , Animais , Linhagem Celular Tumoral , Doxorrubicina/uso terapêutico , Portadores de Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Camundongos , Neoplasias/tratamento farmacológico
14.
Orv Hetil ; 162(22): 884-888, 2021 05 30.
Artigo em Húngaro | MEDLINE | ID: mdl-34052798

RESUMO

Összefoglaló. Az eltunoepeút-szindróma ritka, rossz prognózisú kórkép. Az epeutak progresszív destrukciójával, az intrahepaticus epeutak eltunésével jár, epepangáshoz, biliaris cirrhosishoz, végül májelégtelenséghez vezet. A háttérben álló kiváltó okok között infekciók, ischaemia, gyógyszermellékhatások, illetve daganatos megbetegedések szerepelhetnek. A malignitások közül a leggyakrabban a Hodgkin-lymphomához társult formájával találkozhatunk. Cikkünkben egy fiatal, Hodgkin-lymphomás betegünk esetét szeretnénk bemutatni, akinél az icterus hátterében eltunoepeút-szindróma igazolódott, melyet egyéb okok kizárását követoen szövettani mintavétellel igazoltunk. A két ciklus ABVD-protokoll szerinti kezelést követo PET/CT az alapbetegség tekintetében komplett metabolikus remissziót igazolt. A klinikai javuláshoz azonban hosszú hónapokra volt szükség. Végül az epeúteltunés esetünkben reverzibilis folyamatnak bizonyult, az alapbetegség tekintetében a komplett metabolikus remisszió elérésével az epeút-károsodás megállítható volt. Orv Hetil. 2021; 162(22): 884-888. Summary. destruction and loss of the intrahepatic bile ducts leading to cholestatis, biliar chirrosis and finally liver failure. It has been described in different pathologic conditions including infections, ischemia, adverse drug reactions and malignancies. The Hodgkin's lymphoma-associated type occurs most frequently among the forms of the disease of malignant origin. In this report, we introduce the case of a 32-year-old male patient with Hodgkin's lymphoma, diagnosed with vanishing bile duct syndrome upon liver biopsy as a root cause behind his icterus. The PET/CT has proven complete metabolic remission after 2 cycles of ABVD chemoterapy. Clinical improvement, however, occurred only after several months. Finally the loss of bile ducts proved to be a reversible process, the complete metabolic remission of Hodgkin's lymphoma resulted in the regeneration of the bile ducts. Orv Hetil. 2021; 162(22): 884-888.


Assuntos
Doença de Hodgkin , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Ductos Biliares , Bleomicina , Dacarbazina/uso terapêutico , Doxorrubicina/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Humanos , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Vimblastina/uso terapêutico
15.
Int J Nanomedicine ; 16: 3457-3472, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34045853

RESUMO

Purpose: Malignant melanoma is one of the most devastating types of cancer with rapid relapse and low survival rate. Novel strategies for melanoma treatment are currently needed to enhance therapeutic efficiency for this disease. In this study, we fabricated a multifunctional drug delivery system that incorporates dacarbazine (DTIC) and indocyanine green (ICG) into manganese-doped mesoporous silica nanoparticles (MSN(Mn)) coupled with magnetic resonance imaging (MRI) and photothermal imaging (PI), for achieving the superior antitumor effect of combined chemo-photothermal therapy. Materials and Methods: MSN(Mn) were characterized in terms of size and structural properties, and drug loading and release efficiency MSN(Mn)-ICG/DTIC were analyzed by UV spectra. Photothermal imaging effect and MR imaging effect of MSN(Mn)-ICG/DTIC were detected by thermal imaging system and 3.0 T MRI scanner, respectively. Then, the combined chemo-phototherapy was verified in vitro and in vivo by morphological evaluation, ultrasonic and pathological evaluation. Results: The as-synthesized MSN(Mn) were characterized as mesoporous spherical nanoparticles with 125.57±5.96 nm. MSN(Mn)-ICG/DTIC have the function of drug loading-release which loading ratio of ICG and DTIC could reach to 34.25±2.20% and 50.00±3.24%, and 32.68±2.10% of DTIC was released, respectively. Manganese doping content could reach up to 65.09±2.55 wt%, providing excellent imaging capability in vivo which the corresponding relaxation efficiency was 14.33 mM-1s-1. And outstanding photothermal heating ability and stability highlighted the potential biomedical applicability of MSN(Mn)-ICG/DTIC to kill cancer cells. Experiments by A375 melanoma cells and tumor-bearing mice demonstrated that the compound MSN(Mn)-ICG/DTIC have excellent biocompatibility and our combined therapy platform delivered a superior antitumor effect compared to standalone treatment in vivo and in vitro. Conclusion: Our findings demonstrate that composite MSN(Mn)-ICG/DTIC could serve as a multifunctional platform to achieve a highly effective chemo-photothermal combined therapy for melanoma treatment.


Assuntos
Imageamento por Ressonância Magnética , Melanoma/diagnóstico por imagem , Melanoma/terapia , Terapia Fototérmica , Animais , Linhagem Celular Tumoral , Terapia Combinada , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Verde de Indocianina/química , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos , Nanopartículas/química , Dióxido de Silício/química
16.
Int J Pharm ; 602: 120661, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33933638

RESUMO

The sufficient accumulation of drugs is crucial for efficient treatment in a complex tumor microenvironment. Drug delivery systems (DDS) with high surface area and selective cytotoxicity present a novel approach to mitigate insufficient drug loading for improved therapeutic response. Herein, a doxorubicin-conjugated bimetallic gold-core palladium-shell nanocarrier with multiple dense arrays of branches (Au@PdNDs.PEG/DOX) was characterized and its efficacy against breast adenocarcinoma (MCF-7) and lung adenocarcinoma (A549) cells were evaluated. Enhanced darkfield and hyperspectral imaging (HSI) microscopy were used to study the intracellular uptake and accumulation of the DOX-loaded nanodendrites A fascinating data from a 3D-CytoViva fluorescence imaging technique provided information about the dynamics of localization and distribution of the nanocarrier. In vitro cytotoxicity assays indicated that Au@PdNDs.PEG/DOX inhibited the proliferative effects of MCF-7 cells at equivalent IC50 dosage compared to DOX alone. The nanocarrier triggered higher induction of apoptosis proved by a time-dependent phosphatidylserine V release, cell cycle arrest, and flow cytometry analysis. Moreover, the cell cycle phase proportion increase suggests that the enhanced apoptotic effect induced by Au@PdNDs.PEG/DOX was via a G2/M phase arrest. Thus, this study demonstrated the potential of dendritic nanoparticles to improve DOX therapeutic efficiency and plasmonic-mediated intracellular imaging as a suitable theranostic platform for deployment in nanomedicine.


Assuntos
Neoplasias da Mama , Sistemas de Liberação de Medicamentos , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Doxorrubicina/uso terapêutico , Feminino , Ouro/uso terapêutico , Humanos , Células MCF-7 , Microambiente Tumoral
17.
Int J Nanomedicine ; 16: 3185-3199, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34007173

RESUMO

Background: The acidic microenvironment of cancer can promote tumor metastasis and drug resistance. Acidic tumor microenvironment-targeted therapy is currently an important means for treating tumors, inhibiting metastasis, and overcoming drug resistance. In this study, a dual pH-responsive DOX-encapsulated liposome (DOPE-DVar7-lip@DOX) was designed and fabricated for targeting the acidic tumor microenvironment. On the one hand, the response of acid-sensitive peptide (DVar7) to the acidic tumor microenvironment increased the uptake of liposomes in tumors and prolonged the retention time; on the other hand, the response of acid-sensitive phospholipid (DOPE) to the acidic tumor microenvironment improved the controlled release of DOX in tumors. Methods: The acid-sensitive peptide DVar7 modified liposomes can be obtained by simple incubation of DSPE-DVar7 with DOX-loaded DOPE liposomes (DOPE-lip@DOX). The tumor targeting of the dual pH-responsive liposome was investigated in vitro and in vivo by near-infrared fluorescence imaging. The tumor therapeutic efficacy of DOPE-DVar7-lip@DOX was evaluated in breast cancer mouse model using the traditional liposome as a control. Moreover, we regulated the tumor microenvironment acidity by injecting glucose to further enhance the therapeutic efficacy of cancer. Results: DVar7 can allosterically insert into the tumor cell membrane in the acidic tumor microenvironment to enhance the tumor uptake of liposomes and prolong the retention time of liposomes in tumor. In addition, the therapeutic efficacy of pH-responsive liposomes can be further enhanced by glucose injection regulating the acidity of tumor microenvironment. Discussion: DVar7 modified acid-sensitive nanocarriers combined with acidity regulation have great potential to improve drug resistance in clinical practice, thus improving the response rate and therapeutic effect of chemotherapy.


Assuntos
Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos , Glucose/administração & dosagem , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Lipossomos , Camundongos Endogâmicos BALB C , Neoplasias/patologia , Imagem Óptica , Tamanho da Partícula , Fosfatidiletanolaminas/química
18.
Int J Nanomedicine ; 16: 3217-3240, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34007175

RESUMO

Background: GD2 is a mainstream biomarker for neuroblastoma (NB)-targeted therapy. Current anti-GD2 therapeutics exhibit several side effects since GD2 is also expressed at low levels on normal cells. Thus, current anti-GD2 therapeutics can be compromised by the coexistence of the target receptor on both cancer cells and normal cells. Propose: Aptamers are promising and invaluable molecular tools. Because of the pH difference between tumor and normal cells, in this study, we constructed a pH-sensitive aptamer-mediated drug delivery system (IGD-Targeted). Methods: In vivo Systematic Evolution of Ligands by Exponential Enrichment (SELEX) was used to generate a novel GD2 aptamer. Flow cytometry and molecular docking were applied to assess the binding specificities, affinities abilities of the aptamers. Confocal microscope, CCK8 assay, and BrdU assay were utilized to evaluate whether IGD-Targeted could only bind with GD2 at acidic environment. To evaluate whether IGD-Targeted could inhibit GD2-positive tumor and protect normal cells, in vivo living imaging, histomorphological staining, blood test, and RNA-sequencing were observed in animal model. Results: GD2 aptamer termed as DB67 could bind with GD2-positive cells with high specificity, while has minimal cross-reactivities to other negative cells. It has been validated that the i-motif in IGD-Targeted facilitates the binding specificity and affinity of the GD2 aptamer to GD2-positive NB tumor cells but does not interfere with GD2-positive normal cells at the pH of the cellular microenvironment. In addition, IGD-Targeted is capable of delivering Dox to only GD2-positive NB tumor cells and not to normal cells in vivo and in vitro, resulting in precise inhibition of tumor cells and protection of normal cells. Conclusion: This study suggests that IGD-Targeted as a promising platform for NB therapy which could show greater tumor inhibition and fewer side effects to normal cells, regardless of the existence of the same receptor on the target and nontarget cells.


Assuntos
Antineoplásicos/uso terapêutico , Aptâmeros de Nucleotídeos/química , DNA/química , Nanomedicina , Neuroblastoma/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Neuroblastoma/genética , Neuroblastoma/patologia , Técnica de Seleção de Aptâmeros , Transcriptoma/genética , Microambiente Tumoral/efeitos dos fármacos
19.
Blood Adv ; 5(9): 2426-2437, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33961018

RESUMO

The dilemma of whether to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) with a full or reduced dose intensity (DI) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone+rituximab) is often faced by clinicians. We conducted a systematic review assessing the impact of R-CHOP DI on DLBCL survival outcomes, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines. We searched MEDLINE, EMBASE, and Cochrane CENTRAL for studies with ≥100 patients treated with R-CHOP/R-CHOP-like therapies published from January 2002 through November 2020. Studies were included if they reported the impact of R-CHOP DI on survival outcomes. We screened records, extracted data, and reviewed all the studies for quality and statistical appraisal. Of 380 screened records, 13 studies including 5188 patients were reviewed. DI was often calculated as the ratio of the cumulative delivered dose of prespecified drug(s) to the cumulative planned dose multiplied by a time-correction factor. Lower DI (intended or relative) was associated with inferior survival in 7 of 9 studies reporting crude survival analyses. Multivariable analysis using DI as a covariate was performed in 10 studies. Six showed an association (P < .05) with adjustment for other covariates, and 4 did not. Most studies and those larger studies of higher quality showed poorer outcomes associated with reduced DI. In subgroups aged ≥80 years, survival was not consistently affected by reduced DI. DI-specific randomized trials are warranted, but these data support full-dose R-CHOP in elderly and fit patients aged <80 years with DLBCL, but not in those aged ≥80 years, where dose-reduced R-CHOP does not appear to compromise survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Difuso de Grandes Células B , Idoso , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Rituximab/uso terapêutico , Vincristina/uso terapêutico
20.
Clin Adv Hematol Oncol ; 19(5): 320-325, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33989279

RESUMO

Single-agent lenalidomide has modest activity in diffuse large B-cell lymphoma (DLBCL) and is thought to be more potent in activated B-cell (ABC) lymphomas, which are more treatment-resistant. However, the addition of lenalidomide to rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in randomized clinical trials has shown equivocal benefit, despite phase 2 studies that suggested otherwise. These equivocal results suggest that either the cell of origin (COO) has limited importance for prescribing lenalidomide, or that lenalidomide is not the optimal agent for exploiting the vulnerability of ABC lymphomas. As more recent analyses have shown that the genetic landscape of DLBCL is considerably more complex than the binary COO paradigm, the disappointing impact of lenalidomide is less surprising. In contrast to the marginal benefit from the addition of lenalidomide to R-CHOP, recent studies suggest that lenalidomide in combination with novel agents has potent activity. Lenalidomide was recently approved in combination with the anti-monoclonal B-cell antibody tafasitamab for patients with relapsed DLBCL after 1 to 3 previous treatments. This combination has led to surprisingly prolonged progression-free survival rates, along with possible cure in a subset of patients. In addition, early-phase single-arm trials are also showing deep and durable responses in relapsed patients when lenalidomide is combined with the novel agents ibrutinib and venetoclax. Although these drugs have limited single-agent activity in DLBCL, their pronounced activity in combination suggests a possible unique synergistic effect. Overall, recent studies suggest that lenalidomide will continue to be an active player in the treatment for DLBCL but likely in combination with other novel agents rather than in combination with chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Lenalidomida/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Resultado do Tratamento , Vincristina/uso terapêutico
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