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1.
Int J Nanomedicine ; 16: 2569-2584, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33833512

RESUMEN

Background: Multidrug resistance (MDR) has emerged to be a major hindrance in cancer therapy, which contributes to the reduced sensitivity of cancer cells toward chemotherapeutic drugs mainly owing to the over-expression of drug efflux transporters. The combination of gene therapy and chemotherapy has been considered as a potential approach to improve the anti-cancer efficacy by reversing the MDR effect. Materials and Methods: The AS1411 aptamer-functionalized micelles were constructed through an emulsion/solvent evaporation strategy for the simultaneous co-delivery of doxorubicin and miR-519c. The therapeutic efficacy and related mechanism of micelles were explored based on the in vitro and in vivo active targeting ability and the suppression of MDR, using hepatocellular carcinoma cell line HepG2 as a model. Results: The micelle was demonstrated to possess favorable cellular uptake and tumor penetration ability by specifically recognizing the nucleolin in an AS1411 aptamer-dependent manner. Further, the intracellular accumulation of doxorubicin was significantly improved due to the suppression of ABCG2-mediated drug efflux by miR-519c, resulting in the efficient inhibition of tumor growth. Conclusion: The micelle-mediated co-delivery of doxorubicin and miR-519c provided a promising strategy to obtain ideal anti-cancer efficacy through the active targeting function and the reversion of MDR.


Asunto(s)
Aptámeros de Nucleótidos/administración & dosificación , Carcinoma Hepatocelular/terapia , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos/métodos , Micelas , MicroARNs/administración & dosificación , Oligodesoxirribonucleótidos/administración & dosificación , Fosfoproteínas/antagonistas & inhibidores , Proteínas de Unión al ARN/antagonistas & inhibidores , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacología , Apoptosis , Aptámeros de Nucleótidos/química , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Ciclo Celular , Movimiento Celular , Proliferación Celular , Doxorrubicina/administración & dosificación , Resistencia a Múltiples Medicamentos , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Oligodesoxirribonucleótidos/química , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
2.
AAPS PharmSciTech ; 22(3): 130, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33835327

RESUMEN

Skin cancer is an alarming concern due to increased radiation and chemical exposure. Doxorubicin is a drug prescribed for various cancers by parenteral route. Apart from the pharmaceutical challenge of being a biopharmaceutical classification system (BCS) Class III drug, the side effects of doxorubicin are also a great concern. With an aim to enhance its safety and bioavailability, a phospholipid-based micellar system was developed. The developed nanometric and symmetric carriers not only offered substantial drug loading, but also offered a temporal drug release for longer durations. The pH-dependent drug release assured the spatial delivery at the target site, without loss of drug in the systemic circulation. The cancer cell toxicity studies along with the in vivo anti-tumor studies established the superior efficacy of the developed system. The blood profile studies and the biochemical estimations confirmed the safety of the developed nanocarriers. Lesser amount of drug was available for the microsomal degradation, as inferred by the biodistribution studies. The findings provide a proof of concept for the safer and effective doxorubicin delivery employing simple excipients like phospholipids for the management of skin cancer.


Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/uso terapéutico , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Antracenos , Antibióticos Antineoplásicos/farmacocinética , Carcinógenos , Línea Celular Tumoral , Doxorrubicina/farmacocinética , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Micelas , Nanoestructuras , Tamaño de la Partícula , Fosfolípidos , Piperidinas , Neoplasias Cutáneas/inducido químicamente , Distribución Tisular
3.
Lancet Haematol ; 8(4): e278-e288, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33770483

RESUMEN

BACKGROUND: To improve the long-term tumour control in early, unfavourable Hodgkin Lymphoma, the German Hodgkin Study Group (GHSG) HD14 trial compared four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with an intensified chemotherapy regimen consisting of two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated BEACOPP) plus two cycles of ABVD. The final analysis of the trial showed a significant advantage in terms of freedom from treatment failure (difference 7·2% [95% CI 3·8-10·5] at 5 years) for patients who received two cycles of escalated BEACOPP and two cycles of ABVD. However, there was no difference in overall survival between the two groups. To evaluate long-term efficacy and toxicity of this strategy, we did a follow-up analysis. METHODS: Patients aged 18-60 years with performance status of 2 or less and primary diagnosis of early, unfavourable Hodgkin lymphoma (all histologies) were included in an international, randomised, open-label, phase 3 trial. Patients were randomly assigned to receive four cycles of ABVD (ABVD group) or two cycles of escalated BEACOPP and two cycles of ABVD (2 + 2 group), both groups also received 30 Gy involved field radiotherapy. The ABVD dosing regimen was doxorubicin 25 mg/m2 (days 1 and 15), bleomycin 10 mg/m2 (days 1 and 15), vinblastine 6 mg/m2 (days 1 and 15), and dacarbazine 375 mg/m2 (days 1 and 15), repeated on day 29. The escalated BEACOPP dosing regimen was cyclophosphamide 1250 mg/m2 (day 1), doxorubicin 35 mg/m2 (day 1), etoposide 200 mg/m2 (days 1-3), procarbazine 100 mg/m2 (days 1-7), prednisone 40 mg/m2 (days 1-14), vincristine 1·4 mg/m2 (day 8; maximum 2 mg), and bleomycin 10 mg/m2 (day 8), repeated on day 22. After closure of the ABVD group according to prespecified rules, patients were assigned to receive two cycles of escalated BEACOPP and two cycles of ABVD (non-randomised 2 + 2 group), which continued until the end of the predefined 5-year recruitment period. In this prespecified long-term follow-up analysis, we aimed to evaluate the secondary endpoints progression-free survival, overall survival, and long-term toxicity. To this end, we did a descriptive intention-to-treat analysis of all qualified HD14 patients and on the predefined subsets of randomised qualified HD14 patients and patients in the non-randomised 2 + 2 group. The trial was registered on the International Standard Randomised Controlled Trial database, 04761296. FINDINGS: Between Jan 28, 2003, and Dec 29, 2009, 1686 patients were randomly assigned to the ABVD group (847 [50·2%] patients) and the 2 + 2 group (839 [49·8%] patients). 370 additional patients were recruited to the non-randomised 2 + 2 group. 1550 (92%) randomly assigned patients (median observation time 112 months [IQR 80-132]) and 339 (92%) patients in the non-randomised 2 + 2 group (median observation time 74 months [58-100]) were included in the qualified analysis set. 10-year overall survival in the randomly assigned patients was 94·1% (95% CI 92·0-95·7) for the ABVD group and 94·1% (91·8-95·7) for the 2 + 2 group (HR 1·0 [95% CI 0·6-1·5]; p=0·88). 8-year overall survival in the non-randomised 2 + 2 group was 95·1% (95% CI 91·6-97·2). 10-year progression-free survival in the randomly assigned patients was 85·6% (95% CI 82·6-88·1) for the ABVD group and 91·2% (88·4-93·3) for the 2 + 2 group (HR 0·5% [95% CI 0·4-0·7]; p=0·0001), accounting for a significant difference of 5·6% (95% CI 1·9-9·2) favouring the 2 + 2 group (p=0·0001). In the non-randomised 2 + 2 group, 8-year progression-free survival was 94·5% (95% CI 91·1-96·6). Standardised incidence ratios of second primary malignancies were similar between the ABVD group (2·3 [95% CI 1·6-3·1]) and the 2 + 2 group (2·5 [1·8-3·4]; Gray's p=0·80). Standardised incidence ratio of second primary malignancies was 3·1 (95% CI 1·7-5·0) in the non-randomised 2 + 2 group. INTERPRETATION: This long-term analysis confirms superior tumour control in the 2 + 2 group compared with the ABVD group without translating into an overall survival difference. At longer follow-up, there is no difference regarding second primary malignancies between groups. In conclusion, the 2 + 2 regimen spares a significant number of patients from the burden of relapse and additional treatment without increased long-term toxicity. FUNDING: Deutsche Krebshilfe eV and Swiss Federal Government.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Adulto , Bleomicina/administración & dosificación , Bleomicina/uso terapéutico , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Dacarbazina/administración & dosificación , Dacarbazina/uso terapéutico , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Etopósido/administración & dosificación , Etopósido/uso terapéutico , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Enfermedad de Hodgkin/patología , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Neoplasias Primarias Secundarias/epidemiología , Prednisona/administración & dosificación , Prednisona/uso terapéutico , Procarbazina/administración & dosificación , Procarbazina/uso terapéutico , Supervivencia sin Progresión , Resultado del Tratamiento , Vinblastina/administración & dosificación , Vinblastina/uso terapéutico , Vincristina/administración & dosificación , Vincristina/uso terapéutico
4.
Int J Mol Sci ; 22(4)2021 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-33671292

RESUMEN

Anticancer drugs, such as fluorouracil (5-FU), oxaliplatin, and doxorubicin (Dox) are commonly used to treat colorectal cancer (CRC); however, owing to their low response rate and adverse effects, the development of efficient drug delivery systems (DDSs) is required. The cellular prion protein PrPC, which is a cell surface glycoprotein, has been demonstrated to be overexpressed in CRC, however, there has been no research on the development of PrPC-targeting DDSs for targeted drug delivery to CRC. In this study, PrPC aptamer (Apt)-conjugated gold nanoparticles (AuNPs) were synthesized for targeted delivery of Dox to CRC. Thiol-terminated PrPC-Apt was conjugated to AuNPs, followed by hybridization of its complementary DNA for drug loading. Finally, Dox was loaded onto the AuNPs to synthesize PrPC-Apt-functionalized doxorubicin-oligomer-AuNPs (PrPC-Apt DOA). The PrPC-Apt DOA were spherical nanoparticles with an average diameter of 20 nm. Treatment of CRC cells with PrPC-Apt DOA induced reactive oxygen species generation by decreasing catalase and superoxide dismutase activities. In addition, treatment with PrPC-Apt DOA inhibited mitochondrial functions by decreasing the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, complex 4 activity, and oxygen consumption rates. Compared to free Dox, PrPC-Apt DOA decreased proliferation and increased apoptosis of CRC cells to a greater degree. In this study, we demonstrated that PrPC-Apt DOA targeting could effectively deliver Dox to CRC cells. PrPC-Apt DOA can be used as a treatment for CRC, and have the potential to replace existing anticancer drugs, such as 5-FU, oxaliplatin, and Dox.


Asunto(s)
Aptámeros de Nucleótidos/química , Neoplasias Colorrectales/tratamiento farmacológico , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Sistemas de Liberación de Medicamentos , Oro/química , Nanopartículas del Metal/química , Proteínas Priónicas/química , Apoptosis/efectos de los fármacos , Catalasa/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/farmacología , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/metabolismo , Superóxido Dismutasa/metabolismo
5.
Int J Nanomedicine ; 16: 1617-1630, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33688182

RESUMEN

Introduction: The clinical use of the antitumoral drug doxorubicin (Dox) is reduced by its dose-limiting toxicity, related to cardiotoxic side effects and myelosuppression. In order to overcome these drawbacks, here we describe the synthesis, the structural characterization and the in vitro cytotoxicity assays of hydrogels (HGs) and nanogels (NGs) based on short peptide sequences loaded with Dox or with its liposomal formulation, Doxil. Methods: Fmoc-FF alone or in combination with (FY)3 or PEG8-(FY)3 peptides, at two different ratios (1/1 and 2/1 v/v), were used for HGs and NGs formulations. HGs were prepared according to the "solvent-switch" method, whereas NGs were obtained through HG submicronition by the top-down methodology in presence of TWEEN®60 and SPAN®60 as stabilizing agents. HGs gelation kinetics were assessed by Circular Dichroism (CD). Stability and size of NGs were studied using Dynamic Light Scattering (DLS) measurements. Cell viability of empty and filled Dox HGs and NGs was evaluated on MDA-MB-231 breast cancer cells. Moreover, cell internalization of the drug was evaluated using immunofluorescence assays. Results: Dox filled hydrogels exhibit a high drug loading content (DLC=0.440), without syneresis after 10 days. Gelation kinetics (20-40 min) and the drug release (16-28%) over time of HGs were found dependent on relative peptide composition. Dox filled NGs exhibit a DLC of 0.137 and a low drug release (20-40%) after 72 h. Empty HGs and NGs show a high cell viability (>95%), whereas Dox loaded ones significantly reduce cell viability after 24 h (49-57%) and 72 h (7-25%) of incubation, respectively. Immunofluorescence assays evidenced a different cell localization for Dox delivered through HGs and NGs with respect to the free drug. Discussion: A modulation of the Dox release can be obtained by changing the ratios of the peptide components. The different cellular localization of the drug loaded into HGs and NGs suggests an alternative internalization mechanism. The high DLC, the low drug release and preliminary in vitro results suggest a potential employment of peptide-based HGs and NGs as drug delivery tools.


Asunto(s)
Doxorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos , Hidrogeles/química , Nanogeles/química , Péptidos/química , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/farmacología , Portadores de Fármacos/química , Liberación de Fármacos , Dispersión Dinámica de Luz , Endocitosis/efectos de los fármacos , Humanos
6.
Medicine (Baltimore) ; 100(11): e25188, 2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33726009

RESUMEN

RATIONALE: The HLH-94 protocol is a standard induction treatment for hemophagocytic lymphohistiocytosis. However, about 30% of patients may not respond. Ruxolitinib has been clinically proven to be an effective treatment for hemophagocytic lymphohistiocytosis (HLH). PATIENT CONCERNS: A previously healthy 14-year-old girl presented to the local hospital with a 4-day history of persistent fever and sore throat. DIAGNOSIS: Clinical and laboratory tests revealed fever >38.5°C, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, and an elevated interleukin-2 receptor level. INTERVENTION: This patient was treated with ruxolitinib and the HLH-94 protocol. OUTCOMES: The patient's clinical and some laboratory indices improved. Unfortunately, vital signs such as respiratory function and consciousness did not improve. LESSONS: This case report highlights the effect of using ruxolitinib in conjunction with the HLH-94 protocol. However, safety evaluation of this regimen was not performed because critically ill patient died too fast.


Asunto(s)
Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Herpesvirus Humano 4 , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Pirazoles/administración & dosificación , Adolescente , Protocolos Clínicos , Dexametasona/administración & dosificación , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Quimioterapia Combinada , Infecciones por Virus de Epstein-Barr/complicaciones , Etopósido/administración & dosificación , Resultado Fatal , Femenino , Humanos , Quimioterapia de Inducción , Unidades de Cuidados Intensivos , Linfohistiocitosis Hemofagocítica/virología , Metilprednisolona/administración & dosificación , Polietilenglicoles/administración & dosificación , Resultado del Tratamiento
7.
Life Sci ; 276: 119392, 2021 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-33774021

RESUMEN

AIMS: Exploring the genetic polymorphisms involved in the metabolism of anthracyclines can explain the causes of individual differences in myelosuppression during anthracycline-based chemotherapy. MAIN METHODS: By PCR and Sanger sequencing, SNP of candidate genes participating into the pharmacokinetics of anthracycline, including chemotherapeutic drug intake (SLC22A16 rs6907567), metabolism (AKR1A1 rs2088102, CBR1 rs20572) and transfer (ABCG2 rs2231142) are detected in 194 breast cancer patients undergoing anthracycline-based postoperative adjuvant chemotherapy. KEY FINDINGS: The CBR1 rs20572 (C>T) polymorphic allele, the ABCG2 rs2231142 (G>T) polymorphic allele, or the two polymorphic allele in combination significantly reduced the risk of leukopenia (OR 0.412, 95% CI 0.187-0.905, p = 0.025) and neutropenia (OR 0.354, 95% CI 0.148-0.846, p = 0.018). Either polymorphic allele T of CBR1 rs20572, or polymorphic allele C of AKR1A1 rs2088102 combined with the presence of both ABCG2 rs2231142(G>T) and SLC22A16 rs6907567(A>G) mutations were at extremely low risk of severe anemia of grades 3 and 4 (OR 0.058, 95% CI 0.006-0.554, p = 0.008, OR 0.065, 95% CI 0.006-0.689, p = 0.022, OR 0.037, 95% CI 0.004-0.36, p = 0.015, respectively). SIGNIFICANCE: These results suggested CBR1 rs20572, ABCG2 rs2231142, SLC22A16 rs6907567 and AKR1A1 rs2088102 might be potential protective factors for the reduction of hematologic toxicity incidence during anthracycline-based chemotherapy in breast cancer patients.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Biomarcadores de Tumor/genética , Enfermedades de la Médula Ósea/epidemiología , Neoplasias de la Mama/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Polimorfismo de Nucleótido Simple , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Adulto , Oxidorreductasas de Alcohol/genética , Aldehído Reductasa/genética , Enfermedades de la Médula Ósea/inducido químicamente , Enfermedades de la Médula Ósea/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , China/epidemiología , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Proteínas de Transporte de Catión Orgánico/genética , Pronóstico , Receptor ErbB-2/metabolismo , Receptores Estrogénicos/metabolismo , Receptores de Progesterona/metabolismo , Tasa de Supervivencia , Distribución Tisular
8.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652606

RESUMEN

Bladder cancer (BC) is the tenth most frequently detected cancer in both sexes. Type-I luteinizing hormone-releasing hormone (LHRH) receptor (LHRH-R-I) is expressed not only in the pituitary, but also in several types of cancer disease. There are few data about LHRH-R-I expression in human BC. This study aimed to investigate the expression of LHRH and LHRH-R-I in the transitional cell carcinoma (TCC) type of human BC. RNA was extracted from 24 human bladder tumor specimens and three BC cell lines. RT-PCR was performed to detect mRNA for LHRH and LHRH-R-I. The protein of LHRH-R-I was further studied by immunohistochemistry (IHC), ligand competition assay, and Western Blot. PCR products of LHRH were found in 19 of 24 (79%) specimens and mRNA of LHRH-R-I was detected in 20 of 24 specimens (83%). Positive immunostaining for LHRH-R-I with different expression intensity was found in all samples examined, showing negative correlation with TCC grade. Radioligand binding studies also showed the presence of specific LHRH-R-I and high affinity binding of LHRH analogs. The high incidence of LHRH-R in BC suggests that it could serve as a molecular target for therapy of human BC with cytotoxic LHRH analogs or modern powerful antagonistic analogs of LHRH.


Asunto(s)
Carcinoma de Células Transicionales/genética , Hormona Liberadora de Gonadotropina/genética , Receptores LHRH/genética , Neoplasias de la Vejiga Urinaria/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/epidemiología , Carcinoma de Células Transicionales/patología , Línea Celular Tumoral , Doxorrubicina/administración & dosificación , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/epidemiología , Neoplasias de la Vejiga Urinaria/patología
9.
Lancet Oncol ; 22(2): 267-276, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33539744

RESUMEN

BACKGROUND: Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. METHODS: In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB-IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0-2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin-carboplatin, or 15 mg/kg every 21 days combined with gemcitabine-carboplatin or paclitaxel-carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. FINDINGS: Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4-9·3) in the standard chemotherapy group and 11·8 months (10·8-12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41-0·65; log-rank p<0·0001). Most common grade 3-4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related. INTERPRETATION: Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice. FUNDING: Hoffmann-La Roche and Associazione Italiana per la Ricerca sul Cancro.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bevacizumab/administración & dosificación , Carboplatino/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Carboplatino/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Resistencia a Antineoplásicos , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Polietilenglicoles/administración & dosificación
10.
Lancet Oncol ; 22(2): 223-234, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33539742

RESUMEN

BACKGROUND: Combined-modality treatment consisting of chemotherapy and consolidation radiotherapy is standard of care for patients with early-stage unfavourable Hodgkin lymphoma. However, the use of radiotherapy can have long-term sequelae, which is of particular concern, as Hodgkin lymphoma is frequently diagnosed in young adults with a median age of approximately 30 years. In the German Hodgkin Study Group HD17 trial, we investigated whether radiotherapy can be omitted without loss of efficacy in patients who have a complete metabolic response after receiving two cycles of escalated doses of etoposide, cyclophosphamide, and doxorubicin, and regular doses of bleomycin, vincristine, procarbazine, and prednisone (eBEACOPP) plus two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy (2 + 2). METHODS: In this multicentre, open-label, randomised, phase 3 trial, patients (aged 18-60 years) with newly diagnosed early-stage unfavourable Hodgkin lymphoma (all histologies) and an Eastern Cooperative Oncology Group performance status of 2 or less were enrolled at 224 hospitals and private practices in Germany, Switzerland, Austria, and the Netherlands. Patients were randomly assigned (1:1) to receive either standard combined-modality treatment, consisting of the 2 + 2 regimen (eBEACOPP consisted of 1250 mg/m2 intravenous cyclophosphamide on day 1, 35 mg/m2 intravenous doxorubicin on day 1, 200 mg/m2 intravenous etoposide on days 1-3, 100 mg/m2 oral procarbazine on days 1-7, 40 mg/m2 oral prednisone on days 1-14, 1·4 mg/m2 intravenous vincristine on day 8 [maximum dose of 2 mg per cycle], and 10 mg/m2 intravenous bleomycin on day 8; ABVD consisted of 25 mg/m2 intravenous doxorubicin, 10 mg/m2 intravenous bleomycin, 6 mg/m2 intravenous vinblastine, and 375 mg/m2 intravenous dacarbazine, all given on days 1 and 15) followed by 30 Gy involved-field radiotherapy (standard combined-modality treatment group) or PET4-guided treatment, consisting of the 2 + 2 regimen followed by 30 Gy of involved-node radiotherapy only in patients with positive PET at the end of four cycles of chemotherapy (PET4; PET4-guided treatment group). Randomisation was done centrally and used the minimisation method and seven stratification factors (centre, age, sex, clinical symptoms, disease localisation, albumin concentration, and bulky disease), and patients and investigators were masked to treatment allocation until central review of the PET4 examination had been completed. With the final analysis presented here, the primary objective was to show non-inferiority of the PET4-guided strategy in a per-protocol analysis of the primary endpoint of progression-free survival. We defined non-inferiority as an absolute difference of 8% in the 5-year progression-free survival estimates between the two groups. Safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01356680. FINDINGS: Between Jan 13, 2012, and March 21, 2017, we enrolled and randomly assigned 1100 patients to the standard combined-modality treatment group (n=548) or to the PET4-guided treatment group (n=552); two patients in each group were found ineligible after randomisation. At a median follow-up of 46·2 months (IQR 32·7-61·2), 5-year progression-free survival was 97·3% (95% CI 94·5-98·7) in the standard combined-modality treatment group and 95·1% (92·0-97·0) in the PET4-guided treatment group (hazard ratio 0·523 [95% CI 0·226-1·211]). The between-group difference was 2·2% (95% CI -0·9 to 5·3) and excluded the non-inferiority margin of 8%. The most common grade 3 or 4 acute haematological adverse events were leucopenia (436 [83%] of 528 patients in the standard combined-modality treatment group vs 443 [84%] of 529 patients in the PET4-guided treatment group) and thrombocytopenia (139 [26%] vs 176 [33%]), and the most frequent acute non-haematological toxic effects were infection (32 [6%] vs 40 [8%]) and nausea or vomiting (38 [7%] vs 29 [6%]). The most common acute radiotherapy-associated adverse events were dysphagia (26 [6%] in the standard combined-modality treatment group vs three [2%] in the PET4-guided treatment group) and mucositis (nine [2%] vs none). 229 serious adverse events were reported by 161 (29%) of 546 patients in the combined-modality treatment group, and 235 serious adverse events were reported by 164 (30%) of 550 patients in the PET4-guided treatment group. One suspected unexpected serious adverse reaction (infection) leading to death was reported in the PET4-guided treatment group. INTERPRETATION: PET4-negativity after treatment with 2 + 2 chemotherapy in patients with newly diagnosed early-stage unfavourable Hodgkin lymphoma allows omission of consolidation radiotherapy without a clinically relevant loss of efficacy. PET4-guided therapy could thereby reduce the proportion of patients at risk of the late effects of radiotherapy. FUNDING: Deutsche Krebshilfe.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/radioterapia , Tomografía de Emisión de Positrones , Adolescente , Adulto , Bleomicina/administración & dosificación , Terapia Combinada , Ciclofosfamida/administración & dosificación , Dacarbazina/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/patología , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Prednisona/administración & dosificación , Procarbazina/administración & dosificación , Modelos de Riesgos Proporcionales , Rituximab/administración & dosificación , Resultado del Tratamiento , Vinblastina/administración & dosificación , Vincristina/administración & dosificación , Adulto Joven
11.
Medicine (Baltimore) ; 100(7): e24806, 2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33607843

RESUMEN

RATIONALE: Oral cancer often causes secondary primary cancers in the upper gastrointestinal tract. However, there are no reports of secondary primary cancers in patients with oral squamous cell carcinoma and malignant lymphoma of the small intestine. This report describes a case of metachronous multiple primary cancers of the tongue and small intestine malignant lymphoma. PATIENTS CONCERNS: The patient was admitted to our department with the chief complaint of pain in the right tongue. Partial tongue resection and supraomohyoid neck dissection were performed. One year after surgery, the patient experienced abdominal pain and bloody stools. DIAGNOSIS: Diffuse large B-cell lymphoma (DLBCL) was diagnosed via histological examination. INTERVENTIONS: A terminal ileum resection was performed. Postoperatively, the patient received 6 courses of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP). OUTCOMES: Five years after his initial diagnosis, there is no evidence of recurrence, metastasis, or other primary cancer. LESSONS: Oral cancer patients should always be followed up owing to a possibility of malignant tumors in other areas.


Asunto(s)
Carcinoma de Células Escamosas/complicaciones , Intestino Delgado/patología , Linfoma de Células B Grandes Difuso/patología , Neoplasias de la Lengua/patología , Cuidados Posteriores , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/cirugía , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Neoplasias Primarias Secundarias/patología , Prednisona/administración & dosificación , Prednisona/uso terapéutico , Rituximab/administración & dosificación , Rituximab/uso terapéutico , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/uso terapéutico
12.
Ann Hematol ; 100(4): 979-986, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33608849

RESUMEN

High-dose methotrexate (HD-MTX) at 3 g/m2 is one of the strategies for central nervous system (CNS) prophylaxis in the first-line treatment of aggressive lymphomas, especially in diffuse large B cell lymphoma patients with high-risk CNS-International Prognostic Index. The objective of our study was to retrospectively analyze the safety of 2 cycles of systemic HD-MTX administered as an ambulatory regimen. Between January 2013 and December 2016, 103 patients were carefully selected on 6 criteria, including age < 60, albumin > 34, performance status 0 or 1, normal renal and hepatic functions, good understanding of practical medical guidance, and no loss of weight. Strict procedures of HD-MTX infusion were observed including alkalinization, urine pH monitoring, and leucovorin rescue. Renal and hepatic functions were monitored at days 2 and 7. MTX clearance was not monitored. Toxicities and grades of toxicity were collected according to the NCI-CTCAE (version 4.0). Among the 103 selected patients, 92 (89%) patients successfully completed the planned 2 cycles of HD-MTX on an outpatient basis. Eleven patients completed only 1 cycle, 3 because of lymphoma progression and 8 because of toxicity including 3 grade II hepatotoxicity, 2 grade I/II renal toxicity, 1 grade III neutropenia, 1 active herpetic infection, and 1 grade III ileus reflex. Reported adverse events (AE) included 92 (84%) grade I/II and 18 (16%) grade III/IV. Grade III hepatotoxicity, mostly cytolysis, was the most frequent AE observed with 8 (8%) events. Grade III/IV hematologic toxicities concerned 9 patients with 8 grade III/IV neutropenia and 1 thrombocytopenia. Renal toxicity was rare, mild, and transient, observed with 4 (4%) grade I/II events. Ambulatory administration of HD-MTX at 3 g/m2 without MTX clearance monitoring is safe with strict medical guidance. It requires careful selection of patients before administration, and a renal and hepatic monitoring after the administration.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Sistema Nervioso Central/patología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , Metotrexato/uso terapéutico , Adolescente , Adulto , Atención Ambulatoria , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bleomicina/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Enfermedades Hematológicas/inducido químicamente , Humanos , Infusiones Intravenosas , Enfermedades Renales/inducido químicamente , Pruebas de Función Renal , Leucovorina/uso terapéutico , Pruebas de Función Hepática , Linfoma de Células B Grandes Difuso/patología , Linfoma no Hodgkin/patología , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Invasividad Neoplásica , Servicio Ambulatorio en Hospital , Prednisona/administración & dosificación , Estudios Retrospectivos , Rituximab/administración & dosificación , Vincristina/administración & dosificación , Vindesina/administración & dosificación , Adulto Joven
13.
Ann Hematol ; 100(4): 1013-1021, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33634349

RESUMEN

The prognosis of elderly patients diagnosed with diffuse large B cell lymphoma (DLBCL) is considered to be clearly inferior to that of younger patients. Besides tumor biology and comorbidities, treatment selection due to an assumed reduced tolerability may contribute to this difference. With increasingly more patients diagnosed at advanced age, current treatment selections need to be reviewed carefully. Hence, we analyzed the results of patients above the age of 70 in whom a diagnosis of DLBCL was made. Whereas patients up to 80 were frequently selected for and were able to tolerate standard treatment (86% intended use, 74% completion), patients above the age of 80 years were not only treated more cautiously (67 and 60%, respectively) but did show inferior response to treatment with standard treatment (CR rate for intended R-CHOP use 64% vs. 43%). However, on an individual level, patients receiving and completing standard treatment obtained results that resemble the results of younger patients, irrespective if aged more than 80 and impose superior to prior reports in this age cohort. Median PFS for the entire group of patients was 3.44 years, with 4.83 years for patients below 80 and only 1.09 years for patients above the age of 80. The corresponding figures for OS were 7.38 years (estimated); after 2 years, OS was 81% in the younger cohort in contrast to 68% in patients > 80 years. However, for patients not planned to receive or not tolerating R-CHOP, results remain poor; tailored approaches for these patients are required.


Asunto(s)
Linfoma de Células B Grandes Difuso/epidemiología , Factores de Edad , Anciano , Anciano de 80 o más Años , Antraciclinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/radioterapia , Masculino , Prednisona/administración & dosificación , Pronóstico , Supervivencia sin Progresión , Radioterapia Ayuvante , Rituximab/administración & dosificación , Resultado del Tratamiento , Vincristina/administración & dosificación
14.
Ann Hematol ; 100(4): 1049-1058, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33641019

RESUMEN

Treatment with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or escalated(e)-BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone) remains the international standard of care for advanced-stage classical Hodgkin lymphoma (HL). We performed a retrospective, multicentre analysis of 221 non-trial ("real-world") patients, aged 16-59 years, diagnosed with advanced-stage HL in the Anglia Cancer Network between 2004 and 2014, treated with ABVD or eBEACOPP, and compared outcomes with 1088 patients in the Response-Adjusted Therapy for Advanced Hodgkin Lymphoma (RATHL) trial, aged 18-59 years, with median follow-up of 87.0 and 69.5 months, respectively. Real-world ABVD patients (n=177) had highly similar 5-year progression-free survival (PFS) and overall survival (OS) compared with RATHL (PFS 79.2% vs 81.4%; OS 92.9% vs 95.2%), despite interim positron-emission tomography-computed tomography (PET/CT)-guided dose-escalation being predominantly restricted to trial patients. Real-world eBEACOPP patients (n=44) had superior PFS (95.5%) compared with real-world ABVD (HR 0.20, p=0.027) and RATHL (HR 0.21, p=0.015), and superior OS for higher-risk (international prognostic score ≥3 [IPS 3+]) patients compared with real-world IPS 3+ ABVD (100% vs 84.5%, p=0.045), but not IPS 3+ RATHL patients. Our data support a PFS, but not OS, advantage for patients with advanced-stage HL treated with eBEACOPP compared with ABVD and suggest higher-risk patients may benefit disproportionately from more intensive therapy. However, increased access to effective salvage therapies might minimise any OS benefit from reduced relapse rates after frontline therapy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bleomicina/administración & dosificación , Ensayos Clínicos como Asunto/estadística & datos numéricos , Terapia Combinada , Ciclofosfamida/administración & dosificación , Dacarbazina/administración & dosificación , Doxorrubicina/administración & dosificación , Inglaterra/epidemiología , Etopósido/administración & dosificación , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/terapia , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto/estadística & datos numéricos , Prednisona/administración & dosificación , Embarazo , Complicaciones Neoplásicas del Embarazo/tratamiento farmacológico , Complicaciones Neoplásicas del Embarazo/epidemiología , Procarbazina/administración & dosificación , Supervivencia sin Progresión , Estudios Retrospectivos , Resultado del Tratamiento , Vinblastina/administración & dosificación , Vincristina/administración & dosificación , Adulto Joven
15.
J Clin Neurosci ; 84: 38-41, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33485596

RESUMEN

Reversible cerebral vasoconstriction syndrome (RCVS) is an uncommon disorder characterised by thunderclap headache and self-resolving angiographic vasospasm in the presence or absence of neurological deficit. We present the first case of RCVS likely precipitated by a complex array of confounding factors including a hyperosmolar hyperglycaemic state (HHS), induction chemotherapy with cyclophosphamide, non-Hodgkin's lymphoma, pancytopenia and previous blood transfusions. However, the clinical presentation in this case of altered conscious state followed by thunderclap headache was highly suggestive of HHS being the crucial inciting factor. This report of RCVS associated with HHS lends unique insight into key underlying pathophysiological mechanisms, and warns of the need to maintain a high index of suspicion for this elusive condition given the dynamic and transient nature of its clinical and radiological features.


Asunto(s)
Coma Hiperglucémico Hiperosmolar no Cetósico/complicaciones , Vasoespasmo Intracraneal/etiología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Cefaleas Primarias/etiología , Enfermedad de Hodgkin/tratamiento farmacológico , Humanos , Quimioterapia de Inducción/métodos , Persona de Mediana Edad , Vincristina/administración & dosificación
16.
BMJ Case Rep ; 14(1)2021 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-33509853

RESUMEN

We present the first young paediatric patient with desmoplastic small round cell tumour (DSRCT) treated in UK with hyperthermic intraperitoneal chemotherapy (HIPEC). A 7-year-old girl was diagnosed with abdominal DSRCT with peritoneal and liver metastases. After six cycles of chemotherapy she obtained a partial response, including almost complete resolution of the two liver metastases. It was decided to pursue cytoreductive surgery (CRS) combined with HIPEC, a procedure commonly performed in adults, but seldom in a child. The surgery was macroscopically complete and the HIPEC uncomplicated. She continued treatment without delays, including whole abdomino-pelvic radiotherapy and maintenance chemotherapy (cyclophosphamide/vinorelbine for 12 months). She is currently in complete remission 4 months after end of treatment and 26 months after diagnosis. HIPEC was made possible by successful collaboration between multiple teams. CRS-HIPEC proved to be safe and feasible and could be offered to other children with diagnoses of peritoneal malignancies across the UK.


Asunto(s)
Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Procedimientos Quirúrgicos de Citorreducción/métodos , Tumor Desmoplásico de Células Pequeñas Redondas/terapia , Neoplasias Hepáticas/terapia , Neoplasias Pélvicas/terapia , Neoplasias Peritoneales/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Ciclofosfamida/administración & dosificación , Tumor Desmoplásico de Células Pequeñas Redondas/diagnóstico por imagen , Tumor Desmoplásico de Células Pequeñas Redondas/secundario , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Ifosfamida/administración & dosificación , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/secundario , Quimioterapia de Mantención , Terapia Neoadyuvante , Neoplasias Pélvicas/diagnóstico por imagen , Neoplasias Pélvicas/patología , Neoplasias Peritoneales/diagnóstico por imagen , Neoplasias Peritoneales/secundario , Radioterapia/métodos , Inducción de Remisión , Reino Unido , Vincristina/administración & dosificación , Vinorelbina/administración & dosificación
17.
ACS Appl Mater Interfaces ; 13(2): 2256-2268, 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33423468

RESUMEN

The aggressive progression of breast cancer is impacted significantly by the tumor microenvironment (TME). The current chemotherapy normally causes cytotoxicity to tumor cells, while does not effectively modulate the TME. Thus, the chemotherapy effect of breast cancer is usually dissatisfactory. In this study, a kind of hierarchically releasing bio-responsive nanoparticles (R(D)/H(S) NPs), constructed by ß-cyclodextrin-grafted heparin and pH-sensitive pseudorotaxane, were investigated to enhance the breast cancer chemotherapeutic efficacy through TME modulation. Doxorubicin (DOX) and transforming growth factor-ß (TGF-ß) receptor inhibitor (SB431542) loaded onto R(D)/H(S) NPs were released rapidly for the respective response to low pH in endosomes/lysosomes and heparanase (HPSE) in TME. Our results showed that R(D)/H(S) NPs effectively inhibited the formation of tumor-associated fibroblasts (TAFs) and reduced TGF-ß and collagen I secretion. Besides, the immunosuppressive microenvironment was effectively reversed into immunogenic, characterized by increased CD8+ and CD4+ T cell infiltration, which distinctly inhibited breast cancer metastasis. Therefore, R(D)/H(S) NPs remodeled the TME by downregulating TAFs, TGF-ß, and collagen I; activating the immune microenvironment; and then amplifying the chemotherapeutic efficacy of DOX.


Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Benzamidas/administración & dosificación , Preparaciones de Acción Retardada/química , Dioxoles/administración & dosificación , Doxorrubicina/administración & dosificación , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Microambiente Tumoral/efectos de los fármacos , Células 3T3 , Animales , Antibióticos Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Línea Celular Tumoral , Dioxoles/uso terapéutico , Doxorrubicina/uso terapéutico , Femenino , Concentración de Iones de Hidrógeno , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Rotaxanos/química , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo
18.
Int J Mol Sci ; 22(2)2021 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-33451063

RESUMEN

The development of multifunctional drug delivery systems combining two or more nanoparticle-mediated therapies for efficient cancer treatment is highly desired. To face this challenge, a photothermally active polydopamine (PDA) nanoparticle-based platform was designed for the loading of chemotherapeutic drug and targeting of cancer cells. PDA spheres were first functionalized with polyamidoamine (PAMAM) dendrimers followed by the conjugation with polyethylene glycol (PEG) moieties and folic acid (FA) targeting ligand. The anticancer drug doxorubicin (DOX) was then absorbed on the particle surface. We performed the physico-chemical characterization of this versatile material and we assessed further its possible application in chemo- and photothermal therapy using liver cancer cell model. These nanoparticles exhibited high near-infrared photothermal conversion efficacy and allowed for loading of the drug, which upon release in specifically targeted cancer cells suppressed their growth. Using cell proliferation, membrane damage, apoptosis, and oxidative stress assays we demonstrated high performance of this nanosystem in cancer cell death induction, providing a novel promising approach for cancer therapy.


Asunto(s)
Antineoplásicos/administración & dosificación , Dendrímeros/química , Portadores de Fármacos/química , Indoles/administración & dosificación , Nanopartículas/química , Poliaminas/química , Polímeros/administración & dosificación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Terapia Combinada , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Estrés Oxidativo/efectos de los fármacos , /métodos
19.
Life Sci ; 268: 118990, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33412214

RESUMEN

INTRODUCTION: One of the most used regimens to treat breast cancer is the dose-dense ACT protocol, a combination of anthracycline doxorubicin (DOX) with cyclophosphamide and paclitaxel (PCTX). However, many tumors show resistance to the protocols applied. It is known that the nucleotide excision repair (NER) pathway acts by removing the DOX-generated lesions, and this, together with other DNA repair pathways, can modulate the response to treatment. AIMS: To evaluate the in vitro growth profile of breast cancer cells (MCF7), and the modulation of DNA repair genes, submitted to a protocol using DOX and PCTX in a similar regimen to what is used in clinical practice. MAIN METHODS: MCF7 cells were treated with repeated cycles of DOX and PCTX and followed-up during and after each of the treatments. The population doubling of the remaining cells was calculated during the complete protocol and DNA repair gene expression was evaluated at different time-points. KEY FINDINGS: An increase in all NER genes analyzed after the DOX treatment was observed, but not after the PCTX treatment. MRE11was overexpressed at all evaluated time-points. There was a resumption of NER genes overexpression profile when cells were maintained for follow-up and retook their growth pattern, indicating that DNA repair pathways can modulate their expression during the chemotherapy exposure.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Reparación del ADN/efectos de los fármacos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Paclitaxel/administración & dosificación
20.
ACS Appl Mater Interfaces ; 13(3): 3605-3621, 2021 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-33449625

RESUMEN

Breast cancer is a major threat to health and lives of females. Biomimetic nanotechnology brought brighter hope for early diagnosis and treatment of breast cancer. Here, we proposed a platelet (PLT) membrane-derived strategy for enhanced photoacoustic (PA)/ultrasonic (US)/fluorescence (FL) multimodal imaging and augmented synergistic photothermal/chemotherapeutic efficacy in tumor cells. A PA imaging contrast and photothermal agent, nanocarbons (CNs), a chemotherapeutic and FL material, doxorubicin (DOX), and perfluoropentane (PFP) were coencapsulated into the poly(lactic-co-glycolic) acid (PLGA) skeletons. Then, the PLT membranes were coated onto the PLGA NPs, which were named as "nanoplatelets" (DOX-PFP-CNs@PLGA/PM NPs). The "nanoplatelets", which conserved the structural advantages and inherent properties of PLTs, could not only escape from phagocytosis of macrophages but also actively targeted tumor cells by the way of antigen-antibody interactions between P-selectin on the PM and CD44 receptors of the tumor cells. With CNs and DOX loaded in, these "nanoplatelets" could serve as an excellent contrast agent for PA/FL imaging. Under laser irradiation, the "nanoplatelets" could turn light energy into heat energy. The laser-triggered photothermal effect, on the one hand, could ablate the tumor cells immediately, and on the other hand, could initiate the optical droplet vaporization of PFP, which subsequently enhanced US imaging and promoted the discharge of encapsulated DOX from the "nanoplatelets" for remarkably strengthening photothermal therapeutic power in turn. In this work, as compared with the bare drug-loaded nanoparticles, the "nanoplatelets" exhibited much more accumulation in the tumor cells, demonstrating superior multimodal imaging capability and preferable synergistic therapeutic performance. In conclusion, the "nanoplatelets" could serve as contrast agents for US imaging and PA imaging to guide the therapy. What is more, the bioinspired PLT-derived, targeted, and nontoxic "nanoplatelets", which were exploited for multimodal PA/US/FL imaging-guided synergistic photothermal/chemo therapy, will be of great value to breast cancer theranostics in the days to come.


Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/terapia , Sistemas de Liberación de Medicamentos/métodos , Nanoestructuras/química , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/uso terapéutico , Materiales Biomiméticos/química , Biomimética , Neoplasias de la Mama/patología , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Femenino , Fluorocarburos/administración & dosificación , Fluorocarburos/uso terapéutico , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Ratones Endogámicos BALB C , Imagen Óptica/métodos , Técnicas Fotoacústicas/métodos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Nanomedicina Teranóstica/métodos
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