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1.
Cancer Res Treat ; 55(4): 1355-1362, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36996864

RESUMO

PURPOSE: This phase II, open-label, multicenter study aimed to investigate the efficacy and safety of a rituximab intensification for the 1st cycle with every 21-day of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP-21) among patients with previously untreated advanced-stage or bulky diffuse large B-cell lymphoma (DLBCL). MATERIALS AND METHODS: Ninety-two patients with stage III/IV or bulky DLBCL from 21 institutions were administered 8 cycles of R-CHOP-21 with an additional one dose of rituximab intensification on day 0 of the 1st cycle (RR-CHOP). The primary endpoint was a complete response (CR) rate after 3 cycles of chemotherapy. RESULTS: Among the 92 DLBCL patients assessed herein, the response rate after 3 cycles of chemotherapy was 88.0% (38.0% CR+50.0% partial response [PR]). After the completion of 8 cycles of chemotherapy, the overall response rate was observed for 68.4% (58.7% CR+9.8% PR). The 3-year progression-free survival rate was 64.0%, and the 3-year overall survival rate was 70.4%. Febrile neutropenia was one of the most frequent grade 3 adverse events (40.0%) and 5 treatment-related deaths occurred. Compared with the clinical outcomes of patients who received R-CHOP chemotherapy as a historical control, the interim CR rate was higher in male patients with RR-CHOP (20.5% vs. 48.8%, p=0.016). CONCLUSION: Rituximab intensification on days 0 to the 1st cycle of the standard 8 cycles R-CHOP-21 for advanced DLBCL yielded favorable response rates after the 3 cycles of chemotherapy and acceptable toxicities, especially for male patients. ClinicalTrials.gov ID: NCT01054781.


Assuntos
Linfoma Difuso de Grandes Células B , Prednisolona , Humanos , Masculino , Rituximab/uso terapêutico , Vincristina , Prednisolona/efeitos adversos , Ciclofosfamida , Doxorrubicina , Linfoma Difuso de Grandes Células B/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resultado do Tratamento
2.
J Inflamm Res ; 15: 4623-4636, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35991005

RESUMO

Background: Dunnione has anti-inflammatory properties arising from its ability to alter the ratio of NAD+/NADH through NAD(P)H quinone oxidoreductase 1 (NQO1) enzymatic action, followed by subsequent inhibition of NF-κB and inflammatory cytokines. Psoriasis is a chronic, inflammatory skin disorder in which the IL-23/Th17 axis plays an important role in inflammation. However, it is unclear whether modulation of NAD+ levels affects psoriasis, such as skin inflammation. Therefore, in this study, we investigated the effect of NAD+/NADH ratio modulation on imiquimod (IMQ)-induced, psoriasis-like skin inflammation in mice. Methods: Psoriasis-like skin inflammation was generated by daily topical application of IMQ cream. The severity of dermatitis was assessed using the Psoriasis Area Severity Index (PASI) and histochemistry. Expression of inflammatory cytokines was detected by enzyme-linked immunosorbent assay and quantitative PCR. Acetylation of NF-κB p65 and STAT3 was determined by Western blotting. Results: Dunnione improved IMQ-induced epidermal hyperplasia and inflammation, consistent with decreased levels of inflammatory cytokines (IL-17, IL-22, and IL-23) in skin lesions. Moreover, we found that an increase in the NAD+/NADH ratio by dunnione restored SIRT1 activity, thereby reduced imiquimod-induced STAT3 acetylation, which modulates the expression of psoriasis-promoting inflammatory cytokines, such as IL-17, IL-22, and IL-23. Conclusion: Pharmacological modulation of cellular NAD+ levels could be a promising therapeutic approach for psoriasis-like skin disease.

3.
Int J Mol Sci ; 22(21)2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34769515

RESUMO

Cancer-associated thrombosis is the second-leading cause of mortality in patients with cancer and presents a poor prognosis, with a lack of effective treatment strategies. NAD(P)H quinone oxidoreductase 1 (NQO1) increases the cellular nicotinamide adenine dinucleotide (NAD+) levels by accelerating the oxidation of NADH to NAD+, thus playing important roles in cellular homeostasis, energy metabolism, and inflammatory responses. Using a murine orthotopic 4T1 breast cancer model, in which multiple thrombi are generated in the lungs at the late stage of cancer development, we investigated the effects of regulating the cellular NAD+ levels on cancer-associated thrombosis. In this study, we show that dunnione (a strong substrate of NQO1) attenuates the prothrombotic state and lung thrombosis in tumor-bearing mice by inhibiting the expression of tissue factor and formation of neutrophil extracellular traps (NETs). Dunnione increases the cellular NAD+ levels in lung tissues of tumor-bearing mice to restore the declining sirtuin 1 (SIRT1) activity, thus deacetylating nuclear factor-kappa B (NF-κB) and preventing the overexpression of tissue factor in bronchial epithelial and vascular endothelial cells. In addition, we demonstrated that dunnione abolishes the ability of neutrophils to generate NETs by suppressing histone acetylation and NADPH oxidase (NOX) activity. Overall, our results reveal that the regulation of cellular NAD+ levels by pharmacological agents may inhibit pulmonary embolism in tumor-bearing mice, which may potentially be used as a viable therapeutic approach for the treatment of cancer-associated thrombosis.


Assuntos
Neoplasias da Mama/complicações , Armadilhas Extracelulares/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/metabolismo , NAD/metabolismo , Naftoquinonas/farmacologia , Trombofilia/tratamento farmacológico , Tromboplastina/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Sirtuína 1/metabolismo , Trombofilia/etiologia , Trombofilia/prevenção & controle , Tromboplastina/antagonistas & inibidores , Trombose/tratamento farmacológico , Trombose/etiologia , Trombose/prevenção & controle
4.
Int J Hematol ; 114(3): 355-362, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34302593

RESUMO

Cutaneous T-cell lymphomas (CTCLs) are a group of T-cell lymphomas with low incidence. Due to their indolent characteristics, treatment strategies have not yet been established for advanced CTCLs. In this study, relative incidence of CTCLs in Asia was estimated and the therapeutic outcomes presented based on various treatments currently used in clinics for advanced CTCLs. As part of a prospective registry study of peripheral T-cell lymphoma (PTCL) conducted across Asia, including Korea, China, Taiwan, Singapore, Malaysia, and Indonesia, subgroup analysis was performed for patients with CTCLs. Among 486 patients with PTCL, 37 with CTCL (7.6%) were identified between April 2016 and February 2019. Primary cutaneous ALK-negative anaplastic large cell lymphoma (ALCL, 35.1%) was the most common subtype. With a median follow-up period of 32.1 months, median progression-free survival (PFS) was 53.5 months (95% CI 0.0-122.5), and overall survival was not reached. 14 patients (48.2%) underwent subsequent treatment after the first relapse, but the response rate was 20% with a PFS of 2.2 months (95% CI 0.3-4.0). Six patients received autologous stem cell transplantation (auto-SCT). However, auto-SCT did not result in better outcomes. Additional studies are needed on standard care treatment of advanced or refractory and relapsed CTCLs.


Assuntos
Linfoma Cutâneo de Células T/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ásia/epidemiologia , Terapia Combinada , Diagnóstico Diferencial , Gerenciamento Clínico , Feminino , Humanos , Incidência , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/etiologia , Linfoma Cutâneo de Células T/terapia , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/epidemiologia , Linfoma de Células T Periférico/etiologia , Linfoma de Células T Periférico/terapia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Vigilância em Saúde Pública , Sistema de Registros , Adulto Jovem
5.
Lancet Reg Health West Pac ; 10: 100126, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34327343

RESUMO

BACKGROUND: Peripheral T-cell lymphomas (PTCLs) are uncommon and their frequency is regionally heterogeneous. Several studies have been conducted to evaluate the clinical features and treatment outcomes of this disease entity, but the majority of these were conducted in limited areas, making it difficult to comprehensively analyze their relative frequency and clinical features. Furthermore, no consensus treatment for PTCLs has been established. Therefore, we conducted an Asia-specific study to understand the relative frequency of PTCLs and assess treatments and their outcomes in Asian patients. METHODS: We performed a multinational, multicenter, prospective registry of adult patients with PTCLs that was named as the International Cooperative non-Hodgkin T-cell lymphoma prospective registry study where thirty-two institutes from six Asian countries and territories (Korea, China, Taiwan, Singapore, Malaysia, and Indonesia) participated. FINDINGS: A total of 486 patients were registered between April 2016 and February 2019, and more than a half of patients (57%) had stage III or IV. Extranodal natural killer (NK)/T- cell lymphoma was the most common subtype (n = 139,28.6%), followed by angioimmunoblastic T-cell lymphoma (AITL, n = 120,24.7%), PTCL-not otherwise specified (PTCL-NOS, n = 101,20.8%), ALK-positive anaplastic large cell lymphoma (ALCL, n = 34,6.9%), and ALK-negative ALCL (n = 30,6.2%). The median progression-free survival (PFS) and overall survival (OS) were 21.1 months (95% CI,10.6-31.6) and 83.6 months (95% CI, 56.7-110.5), respectively. Upfront use of combined treatment with chemotherapy and radiotherapy showed better PFS than chemotherapy alone in localized ENKTL whereas consolidation with upfront autologous stem cell transplantation (SCT) provided longer PFS in advance stage ENKTL. In patients with PTCLs other than ENKTL, anthracycline-containing chemotherapies were widely used, but the outcome of those regimens was not satisfactory, and upfront autologous SCT was not significantly associated with survival benefit, either. The treatment outcome of salvage chemotherapy was disappointing, and none of the salvage strategies showed superiority to one another. INTERPRETATION: This multinational, multicenter study identified the relative frequency of each subtype of PTCLs across Asian countries, and the survival outcomes according to the therapeutic strategies currently used. FUNDING: Samsung Biomedical Research Institute.

6.
Ann Hematol ; 100(8): 2051-2059, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33447888

RESUMO

Carfilzomib, lenalidomide, and dexamethasone (KRd) effectively improve survival in patients with relapsed and refractory multiple myeloma (RRMM). However, the outcome of KRd treatment in Asian patients reflecting a general RRMM population outside of a clinical trial has not been reported. Fifty-five RRMM patients who were treated with carfilzomib in combination with Rd from the time of the first approval of KRd in the Republic of Korea were analyzed. The median age was 61 years. The percentage of patients with an ECOG performance status ≥ 3, creatinine clearance < 50 mL/min, high-risk cytogenetics, and ≥ 4 lines of prior treatment were 9%, 22%, 31%, and 27%, respectively. Forty-one patients started treatment with KRd, whereas the remaining 14 patients (25%) were added carfilzomib during the Rd treatment. In the whole cohort, the overall response rate was 73% and progression-free survival was 8.8 months. The addition of carfilzomib in patients who were refractory or had disease progression during Rd treatment reattained a response in half of the patients. The advantage of carfilzomib with Rd was significant in patients in the first relapse. Toxicity profile was acceptable, excluding severe infections. Carfilzomib in combination with Rd is effective and has a reasonable adverse event rate in Asian patients with RRMM.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/uso terapêutico , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/epidemiologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/epidemiologia , Oligopeptídeos/efeitos adversos , Intervalo Livre de Progressão , República da Coreia/epidemiologia
7.
Cancer Res Treat ; 51(1): 90-97, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29510613

RESUMO

PURPOSE: Data on the efficacy of olanzapine in patients receiving moderately emetogenic chemotherapy (MEC) are limited. This study aimed to evaluate and compare the efficacy of olanzapine versus placebo in controlling nausea and vomiting in patients receiving MEC. MATERIALS AND METHODS: We conducted a randomized, double-blind, placebo-controlled study to determine whether olanzapine can reduce the frequency of chemotherapy-induced nausea and vomiting (CINV) and improve the quality of life (QOL) in patients receiving palonosetron and dexamethasone as prophylaxis for MEC-induced nausea and vomiting. The primary end point was complete response for the acute phase (0-24 hours after chemotherapy). The secondary end points were complete response for the delayed (24-120 hours) and overall phase (0-120 hours), proportion of significant nausea (visual analogue scale ≥ 25 mm), use ofrescue medications, and effect on QOL. RESULTS: Fifty-six patients were randomized to the olanzapine (n=29) and placebo (n=27) groups. Complete response rates were not significantly different between the olanzapine and placebo groups in the acute (96.5% vs. 88.0%, p=0.326), delayed (69.0% vs. 48.0%, p=0.118), and overall phases (69.0% vs. 48.0%, p=0.118). However, the percentage of patients with significant nausea (17.2% vs. 44.0%, p=0.032) and the use of rescue medications (0.03±0.19 vs. 1.88±2.88, p=0.002) were lower in the olanzapine group than in the placebo. Furthermore, the olanzapine group demonstrated better QOL (p=0.015). CONCLUSION: Olanzapine combined with palonosetron and dexamethasone significantly improved QOL and vomiting control among previously untreated patients receiving MEC, although the efficacy was limited to the reduction of the frequency of CINV.


Assuntos
Antineoplásicos/efeitos adversos , Dexametasona/administração & dosagem , Náusea/prevenção & controle , Olanzapina/administração & dosagem , Palonossetrom/administração & dosagem , Administração Intravenosa , Adulto , Idoso , Dexametasona/uso terapêutico , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Olanzapina/uso terapêutico , Palonossetrom/uso terapêutico , Qualidade de Vida , Resultado do Tratamento
8.
Acta Haematol ; 140(3): 146-156, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30253397

RESUMO

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is an independent prognostic marker in solid and hematological cancers. While the derived NLR (dNLR) was shown to be non-inferior to the NLR in large cohorts of patients with different cancer types, it has not been validated as a prognostic marker for multiple myeloma (MM) to date. METHODS: Between May 22, 2011 and May 29, 2014, 176 patients with MM from 38 centers who were ineligible for autologous stem cell transplantation were analyzed. The dNLR was calculated using complete blood count differential data. The optimal dNLR cut-off value according to receiver operating characteristic analysis of overall survival (OS) was 1.51. All patients were treated with melphalan and prednisone combined with bortezomib. RESULTS: The complete response rate was lower in the high dNLR group compared to the low dNLR group (7 vs. 26.1%, respectively; p = 0.0148); the corresponding 2-year OS rates were 72.2 and 84.7%, respectively (p = 0.0354). A high dNLR was an independent poor prognostic factor for OS (hazard ratio 2.217, 95% CI 1.015-4.842; p = 0.0458). CONCLUSION: The dNLR is a readily available and cheaply obtained parameter in clinical studies, and shows considerable potential as a new prognostic marker for transplantation-ineligible patients with MM.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfócitos/citologia , Mieloma Múltiplo/terapia , Neutrófilos/citologia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Área Sob a Curva , Intervalo Livre de Doença , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Transplante Autólogo
9.
Medicine (Baltimore) ; 97(21): e10778, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29794758

RESUMO

Standard treatment for locally advanced (stage III-IV) head and neck squamous cell cancer (LA-HNSCC) is concurrent chemoradiation therapy (CCRT) with cisplatin 100 mg/m every 3 weeks. For medically unfit patients susceptible to treatment-related adverse events, low-dose weekly cisplatin (30-40 mg/m) can be used as an alternative. In this study, we retrospectively compared the therapeutic outcomes of low-dose weekly cisplatin regimen and standard regimen in CCRT for LA-HNSCC.The medical records of histologically confirmed LA-HNSCC patients were retrospectively reviewed from January 1, 2007 to December 31, 2012. Patients who were treated with CCRT as initial treatment were included.Among 220 patients eligible, 65 (29.5%) were treated with cisplatin dosing schedule of 100 mg/m every 3 weeks and 155 (70.5%) with 30 to 40 mg/m weekly. The overall response rate in 3-weekly group was 92.3% and did not differ from that in weekly group (91.0%). The median progression-free survival of the weekly group was not attained but was not significantly different from that of 3-weekly group (50.7 months, 95% confidence interval [CI] 42.2-59.1 months) (P = .81). Also, the median overcall survival did not differ significantly between 2 groups (P = .34).In the present study, low-dose weekly cisplatin showed therapeutic outcomes comparable to standard-dose cisplatin in CCRT for LA-HNSCC. Prospective comparison of standard-dose three-weekly and low-dose weekly cisplatin is warranted.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/administração & dosagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Quimiorradioterapia/métodos , Terapia Combinada , Esquema de Medicação , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
10.
Support Care Cancer ; 26(11): 3721-3728, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29732483

RESUMO

PURPOSE: There is growing interest in integrating electronic patient-reported outcome (PRO) measures into routine oncology practice for symptom monitoring. Here, we evaluated the feasibility and accessibility of electronic PRO measures using a smartphone (PRO-SMART) for cancer patients receiving routine chemotherapy. METHODS: The proposed PRO-SMART application obtains daily personal health record (PHR) data from cancer patients via a smartphone. An analysis report of cumulative PHR data is provided to the clinician in a format suitable for upload to electronic medical records (EMRs). Cancer outpatients who had received at least two cycles of chemotherapy and who were scheduled for two more cycles were enrolled. RESULTS: Between February 2015 and December 2016, 111 patients were screened and 101 of these were included. One-hundred patients used PRO-SMART at least once and were included in the final analysis (90.1% overall accessibility among all screened patients). The number of symptomatic adverse events (AEs) related to chemotherapy recorded in EMRs (mean ± standard deviation [SD]) increased from 0.92 ± 0.80 to 2.26 ± 1.80 (P < 0.001), and grading of AEs increased from 0.81 ± 0.69 to 1.00 ± 0.62 (P = 0.029). After using PRO-SMART, the numeric rating scale for pain (mean ± SD) increased from 0.20 ± 0.72 to 0.99 ± 1.55 (P < 0.001). A patient-reported questionnaire revealed that 64.2% of patients found it useful and 83% found it easy to use. CONCLUSIONS: This study suggests that the proposed PRO-SMART is feasible and accessible for assessment of symptomatic AEs in cancer patients receiving chemotherapy for a prospective randomized trial.


Assuntos
Acesso à Informação , Antineoplásicos/uso terapêutico , Registros Eletrônicos de Saúde , Monitorização Fisiológica/métodos , Neoplasias/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Smartphone , Adulto , Idoso , Registros Eletrônicos de Saúde/estatística & dados numéricos , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aplicativos Móveis , Monitorização Fisiológica/normas , Dor , Projetos Piloto , Smartphone/estatística & dados numéricos , Inquéritos e Questionários
11.
Cancer Res Treat ; 50(2): 590-598, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28602052

RESUMO

PURPOSE: The treatment strategy for elderly patients older than 80 years with diffuse large B-cell lymphoma (DLBCL) has not been established because of poor treatment tolerability and lack of data. MATERIALS AND METHODS: This multicenter retrospective study was conducted to investigate clinical characteristics, treatment patterns and outcomes of patients older than 80 years who were diagnosed with DLBCL at 19 institutions in Korea between 2005 and 2016. RESULTS: A total of 194 patients were identified (median age, 83.3 years). Of these, 114 patients had an age-adjusted International Prognostic Index (aaIPI) score of 2-3 and 48 had a Charlson index score of 4 or more. R-CHOP was given in 124 cases, R-CVP in 13 cases, other chemotherapy in 17 cases, radiation alone in nine cases, and surgery alone in two cases. Twenty-nine patients did not undergo any treatment. The median number of chemotherapy cycles was three. Only 37 patients completed the planned treatment cycles. The overall response rate from 105 evaluable patientswas 90.5% (complete response, 41.9%). Twentynine patients died due to treatment-related toxicities (TRT). Thirteen patients died due to TRT after the first cycle. Median overall survival was 14.0 months. The main causes of death were disease progression (30.8%) and TRT (27.1%). In multivariate analysis, overall survival was affected by aaIPI, hypoalbuminemia, elevated creatinine, and treatment. CONCLUSION: Age itself should not be a contraindication to treatment. However, since elderly patients show higher rates of TRT due to infection, careful monitoring and dose modification of chemotherapeutic agents is needed.


Assuntos
Linfoma Difuso de Grandes Células B/terapia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , República da Coreia , Estudos Retrospectivos , Resultado do Tratamento
12.
Biomed Res Int ; 2016: 4048390, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26881219

RESUMO

Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors. In addition to its antitumor activity, cisplatin affects normal cells and may induce adverse effects such as ototoxicity, nephrotoxicity, and peripheral neuropathy. Various mechanisms such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and inflammatory responses are closely associated with cisplatin-induced nephrotoxicity; however, the precise mechanism remains unclear. The cofactor nicotinamide adenine dinucleotide (NAD(+)) has emerged as a key regulator of cellular energy metabolism and homeostasis. Recent studies have demonstrated associations between disturbance in intracellular NAD(+) levels and clinical progression of various diseases through the production of reactive oxygen species and inflammation. Furthermore, we demonstrated that reduction of the intracellular NAD(+)/NADH ratio is critically involved in cisplatin-induced kidney damage through inflammation and oxidative stress and that increase of the cellular NAD(+)/NADH ratio suppresses cisplatin-induced kidney damage by modulation of potential damage mediators such as oxidative stress and inflammatory responses. In this review, we describe the role of NAD(+) metabolism in cisplatin-induced nephrotoxicity and discuss a potential strategy for the prevention or treatment of cisplatin-induced adverse effects with a particular focus on NAD(+)-dependent cellular pathways.


Assuntos
Cisplatino/efeitos adversos , Neoplasias/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal/patologia , Apoptose/efeitos dos fármacos , Cisplatino/uso terapêutico , Dano ao DNA/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , NAD/metabolismo , Neoplasias/complicações , Neoplasias/patologia , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal/induzido quimicamente
13.
Hear Res ; 333: 235-246, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26341473

RESUMO

Ototoxicity is an important issue in patients receiving cisplatin chemotherapy. Numerous studies have demonstrated that cisplatin-induced ototoxicity is related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD(+)) has emerged as an important regulator of energy metabolism and cellular homeostasis. Here, we demonstrate that the levels and activities of sirtuin-1 (SIRT1) are suppressed by the reduction of intracellular NAD(+) levels in cisplatin-mediated ototoxicity. We provide evidence that the decreases in SIRT1 activity and expression facilitated by increasing poly(ADP-ribose) polymerase-1 (PARP-1) activation and microRNA-34a levels through cisplatin-mediated p53 activation aggravate the associated ototoxicity. Furthermore, we show that the induction of cellular NAD(+) levels using dunnione, which targets intracellular NQO1, prevents the toxic effects of cisplatin through the regulation of PARP-1 and SIRT1 activity. These results suggest that direct modulation of cellular NAD(+) levels by pharmacological agents could be a promising therapeutic approach for protection from cisplatin-induced ototoxicity.


Assuntos
Cisplatino , Cóclea/efeitos dos fármacos , Perda Auditiva/prevenção & controle , Audição/efeitos dos fármacos , NAD/metabolismo , Naftoquinonas/farmacologia , Substâncias Protetoras/farmacologia , Acetilação , Animais , Cóclea/metabolismo , Cóclea/fisiopatologia , Citoproteção , Modelos Animais de Doenças , Perda Auditiva/induzido quimicamente , Perda Auditiva/metabolismo , Perda Auditiva/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/metabolismo , NAD(P)H Desidrogenase (Quinona)/deficiência , NAD(P)H Desidrogenase (Quinona)/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína Supressora de Tumor p53/metabolismo
14.
J Immunol Res ; 2015: 602154, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26634217

RESUMO

Gamma-aminobutyric acid receptor subunit pi (GABRP) is involved in inhibitory synaptic transmission in the central nervous system. This gene encodes multisubunit chloride channels and is also expressed in numerous nonneuronal tissues such as the uterus and the ovaries. This study was aimed to validate whether the polymorphisms in the GABRP gene are associated with the susceptibility to systematic lupus erythematosus (SLE). The genotype frequencies of the rs929763, rs732157, and rs3805455 of the GABRP gene in SLE patients were significantly different from those of the control group (P < 0.0001, P = 0.05 and 0.002, resp.). Additional analysis showed that the genotype of the rs929763 and rs3805455 of the GABRP gene were also significantly associated with female SLE patients (P < 0.0001, P = 0.005, resp.). Two haplotype frequencies including a major haplotype of GABRP SNPs were more significantly different between the SLE patients and the healthy controls (P = 0.038 and 4.2E - 24, resp.). These results suggest that the polymorphisms in the GABRP gene might be associated with the susceptibility to SLE and the haplotype of GABRP SNPs is useful genetic marker for SLE.


Assuntos
Marcadores Genéticos/genética , Lúpus Eritematoso Sistêmico/genética , Receptores de GABA-A/genética , Adulto , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Coreia (Geográfico) , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Polimorfismo Genético , Fatores Sexuais , Transmissão Sináptica/genética
15.
Biochem Biophys Res Commun ; 467(4): 697-703, 2015 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-26498527

RESUMO

Although cisplatin is a widely used anticancer drug for the treatment of a variety of tumors, its use is critically limited because of adverse effects such as ototoxicity, nephrotoxicity, neuropathy, and gastrointestinal damage. Cisplatin treatment increases oxidative stress biomarkers in the small intestine, which may induce apoptosis of epithelial cells and thereby elicit damage to the small intestine. Nicotinamide adenine dinucleotide (NAD(+)) is a cofactor for various enzymes associated with cellular homeostasis. In the present study, we demonstrated that the hyper-activation of poly(ADP-ribose) polymerase-1 (PARP-1) is closely associated with the depletion of NAD(+) in the small intestine after cisplatin treatment, which results in downregulation of sirtuin1 (SIRT1) activity. Furthermore, a decrease in SIRT1 activity was found to play an important role in cisplatin-mediated small intestinal damage through nuclear factor (NF)-κB p65 activation, facilitated by its acetylation increase. However, use of dunnione as a strong substrate for the NADH:quinone oxidoreductase 1 (NQO1) enzyme led to an increase in intracellular NAD(+) levels and prevented the cisplatin-induced small intestinal damage correlating with the modulation of PARP-1, SIRT1, and NF-κB. These results suggest that direct modulation of cellular NAD(+) levels by pharmacological NQO1 substrates could be a promising therapeutic approach for protecting against cisplatin-induced small intestinal damage.


Assuntos
Antineoplásicos/toxicidade , Cisplatino/toxicidade , Intestino Delgado/efeitos dos fármacos , NAD/metabolismo , Naftoquinonas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/metabolismo , Sirtuína 1/metabolismo , Fator de Transcrição RelA/metabolismo
16.
Blood Res ; 50(3): 160-6, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26457283

RESUMO

BACKGROUND: Among the currently available prognostic models for diffuse large B-cell lymphoma (DLBCL), we investigated to determine which is most adoptable for DLBCL patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) followed by upfront autologous stem cell transplantation (auto-SCT). METHODS: We retrospectively evaluated survival differences among risk groups based on the International Prognostic Index (IPI), the age-adjusted IPI (aaIPI), the revised IPI (R-IPI), and the National Comprehensive Cancer Network IPI (NCCN-IPI) at diagnosis in 63 CD20-positive DLBCL patients treated with R-CHOP followed by upfront auto-SCT. RESULTS: At the time of auto-SCT, 74.6% and 25.4% of patients had achieved complete remission and partial remission after R-CHOP, respectively. As a whole, the 5-year overall (OS) and progression-free survival (PFS) rates were 78.8% and 74.2%, respectively. The 5-year OS and PFS rates according to the IPI, aaIPI, R-IPI, and NCCN-IPI did not significantly differ among the risk groups for each prognostic model (P-values for OS: 0.255, 0.337, 0.881, and 0.803, respectively; P-values for PFS: 0.177, 0.904, 0.295, and 0.609, respectively). CONCLUSION: There was no ideal prognostic model among those currently available for CD20-positive DLBCL patients treated with R-CHOP followed by upfront auto-SCT.

17.
Oncologist ; 20(12): 1432-9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26463869

RESUMO

BACKGROUND: In a previous pilot study, adrenal suppression was found to be common after antiemetic dexamethasone therapy in cancer patients. The objective of this large prospective multicenter study was to confirm the incidence and factors associated with secondary adrenal suppression related to antiemetic dexamethasone therapy in cancer patients receiving chemotherapy. METHODS: Chemotherapy-naïve patients who were scheduled to receive at least three cycles of highly or moderately emetogenic chemotherapy with dexamethasone as an antiemetic were enrolled. Patients with a suppressed adrenal response before chemotherapy or those administered corticosteroids within 6 months of enrollment in the study were excluded. RESULTS: Between October 2010 and August 2014, 481 patients receiving chemotherapy underwent the rapid adrenocorticotropic hormone (ACTH) stimulation test to assess eligibility; 350 of these patients were included in the final analysis. Fifty-six patients (16.0%) showed a suppressed adrenal response in the rapid ACTH stimulation test at 3 or 6 months after the start of the first chemotherapy. The incidence of adrenal suppression was affected by age, performance status, stage, and use of megestrol acetate in univariate analysis. Multivariate analysis revealed that secondary adrenal suppression associated with antiemetic dexamethasone therapy was significantly associated with megestrol acetate treatment (odds ratio: 3.06; 95% confidence interval: 1.60 to 5.86; p < .001). CONCLUSION: This large prospective study indicates that approximately 15% of cancer patients receiving chemotherapy with a normal adrenal response show suppressed adrenal responses after antiemetic dexamethasone therapy. This result was particularly significant for patients cotreated with megestrol acetate.


Assuntos
Insuficiência Adrenal/induzido quimicamente , Antieméticos/efeitos adversos , Dexametasona/efeitos adversos , Neoplasias/tratamento farmacológico , Insuficiência Adrenal/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Acetato de Megestrol/administração & dosagem , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
18.
Hear Res ; 326: 30-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25891352

RESUMO

Ototoxicity is an important issue in patients receiving cisplatin chemotherapy. Numerous studies have demonstrated that several mechanisms, including oxidative stress, DNA damage, and inflammatory responses, are closely associated with cisplatin-induced ototoxicity. Although much attention has been directed at identifying ways to protect the inner ear from cisplatin-induced damage, the precise underlying mechanisms have not yet been elucidated. The cofactor nicotinamide adenine dinucleotide (NAD(+)) has emerged as an important regulator of cellular energy metabolism and homeostasis. NAD(+) acts as a cofactor for various enzymes including sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs), and therefore, maintaining adequate NAD(+) levels has therapeutic benefits because of its effect on NAD(+)-dependent enzymes. Recent studies demonstrated that disturbance in intracellular NAD(+) levels is critically involved in cisplatin-induced cochlear damage associated with oxidative stress, DNA damage, and inflammatory responses. In this review, we describe the importance of NAD(+) in cisplatin-induced ototoxicity and discuss potential strategies for the prevention or treatment of cisplatin-induced ototoxicity with a particular focus on NAD(+)-dependent cellular pathways.


Assuntos
Cisplatino/efeitos adversos , Perda Auditiva/induzido quimicamente , Perda Auditiva/prevenção & controle , NAD/metabolismo , Animais , Antineoplásicos/efeitos adversos , Dano ao DNA , Audição/efeitos dos fármacos , Audição/fisiologia , Perda Auditiva/metabolismo , Humanos , Inflamação/induzido quimicamente , Redes e Vias Metabólicas , Modelos Biológicos , Espécies Reativas de Oxigênio/metabolismo
19.
Leuk Res ; 38(10): 1252-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25176346

RESUMO

We investigated three splicing factor proteins (SFPs; NSRP70, SRSF1, and HNRNPA1) in 187 adults with and without acute leukemia (AL). We showed that NSRP70 is a novel lymphoblastic AL (ALL) surrogate marker, which presented excellent diagnostic accuracy (92%) and disappeared during remission. Its highest molecular weight form, but not total amount, was associated with adverse genetic abnormalities in myeloid AL (AML). Furthermore, we identified that these SFPs were more prevalent in ALL than in AML; were not correlated with their mRNA levels; and their formations in AL may occur without coding mutations and relate to post-translational modifications.


Assuntos
Biomarcadores Tumorais/análise , Proteínas Nucleares/biossíntese , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Processamento Alternativo , Feminino , Imunofluorescência , Humanos , Immunoblotting , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteômica , Transcrição Gênica , Adulto Jovem
20.
Blood Res ; 49(2): 107-14, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25025012

RESUMO

BACKGROUND: We investigated factors that influence outcomes in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab combined with the CHOP regimen (R-CHOP) followed by upfront autologous stem cell transplantation (Auto-SCT). METHODS: We retrospectively evaluated survival differences between subgroups based on the age-adjusted International Prognostic Index (aaIPI) and revised-IPI (R-IPI) at diagnosis, disease status, and positron emission tomographic/computerized tomographic (PET/CT) status at transplantation in 51 CD20-positive DLBCL patients treated with R-CHOP followed by upfront Auto-SCT. RESULTS: Patients had either stage I/II bulky disease (5.9%) or stage III/IV disease (94.1%). The median patient age at diagnosis was 47 years (range, 22-66 years); 53.3% and 26.7% had high-intermediate and high risks according to aaIPI, respectively. At the time of Auto-SCT, 72.5% and 27.5% experienced complete (CR) and partial remission (PR) after R-CHOP, respectively. The median time from diagnosis to Auto-SCT was 7.27 months (range, 3.4-13.4 months). The 5-year overall (OS) and progression-free survival (PFS) were 77.3% and 72.4%, respectively. The 5-year OS and PFS rates according to aaIPI, R-IPI, and PET/CT status did not differ between the subgroups. More importantly, the 5-year OS and PFS rates of the patients who achieved PR at the time of Auto-SCT were not inferior to those of the patients who achieved CR (P=0.223 and 0.292, respectively). CONCLUSION: Survival was not influenced by the aaIPI and R-IPI at diagnosis, disease status, or PET/CT status at transplantation, suggesting that upfront Auto-SCT might overcome unfavorable outcomes attributed to PR after induction chemoimmunotherapy.

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