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1.
Asian Pac J Cancer Prev ; 21(3): 799-807, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32212810

RESUMO

PURPOSE: The aim of this prospective randomized study is to compare cisplatin at 2 dose levels given concurrently with intensity modulated radiation therapy (IMRT) in the treatment of locally advanced HNSCC. The main objectives were to evaluate treatment toxicities, loco-regional control, tumor response and patients compliance. METHODS: Patients were randomized into two groups that either received 30 mg/m2 cisplatin weekly (arm A) or 100 mg/m2 once every 3 weeks (arm B). Radiotherapy prescribed dose was 70Gy in 33 fractions. Treatment adverse events were documented. RESULTS: Sixty patients with locally advanced HNSCC were included in this study. Recruitment started at the beginning of July 2016 and ended in July 2019. The Median follow-up was 24 months. Acute non-hematological toxicities of grade 3 or higher during the treatment course were significantly more observed in Arm B patients (76.6%) compared to Arm A patients (56.6%) with a P-value of 0.007. Hematological toxicities in the form of anemia, leucopenia and neutropenia were also significantly higher in Arm B patients with a p-value of 0.435, 0.002 & 0,002, respectively. The median 2 year loco-regional control rate in Arm B was 72.8% versus 57.6% in Arm A with a p-value of 0.015. Complete responses were similar between both groups (77%). Compliance to treatment was better in Arm A with 70% of the patients received at least 6 weekly doses where as 60% of the patients in Arm B completed the three cycles of treatment and 40 % received only 2 cycles. CONCLUSION: Once weekly low dose cisplatin treatment showed lower acute toxicity and a better compliance compared to once every 3 weeks high dose cisplatin treatment at the expense of a lower loco-regional control.


Assuntos
Cisplatino/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Idoso , Cisplatino/efeitos adversos , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Doses de Radiação
2.
Bratisl Lek Listy ; 121(2): 143-150, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115968

RESUMO

OBJECTIVES: This study was aimed to explore the effects of follistatin on cisplatin-induced renal dysfunction, histopathological changes, apoptosis, inflammation and oxidative damage in rats. BACKGROUND: Follistatin plays an important role in the developmental and regeneration processes of kidney by blocking the actions of activin, which is a member of transforming growth factor-ß superfamily. METHODS: Twenty seven rats were separated into 4 equal groups: Control, Cp (cisplatin, 6 mg/kg, intrapertoneally (ip)), F1 (cisplatin + 1 µg/day follistatin ip for 4 consecutive days) and F4 (cisplatin + 4 µg/day follistatin ip single dose) groups. Renal health was monitored by blood urea nitrogen, serum creatinine and histological analysis. Apoptosis, inflammation and oxidative stress was investigated in kidney tissue. Activin A levels in serum and kidney were evaluated as well. RESULTS: Follistatin administration showed a considerable nephroprotective effect against cisplatin-induced nephrotoxicity by preventing renal functional and structural abnormalities, apoptosis and inflammation. The activin A levels in both serum and kidney were also suppressed by follistatin administration. CONCLUSION: Exogenous follistatin ameliorates acute kidney injury, by blocking activin A. The renoprotective effect of follistatin against cisplatin-induced nephrotoxicity appears to be associated with its anti-inflammatory, antiapoptotic and direct nephroprotective actions (Tab. 1, Fig. 7, Ref. 23).


Assuntos
Lesão Renal Aguda , Cisplatino , Folistatina , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Cisplatino/efeitos adversos , Folistatina/farmacologia , Folistatina/uso terapêutico , Inflamação , Rim , Estresse Oxidativo , Ratos
3.
Artigo em Chinês | MEDLINE | ID: mdl-32086932

RESUMO

Cisplatin is an anti-tumor drug which is widely used for the treatment of various solid tumors. Unfortunately, seriousside-effects have affected patients, such as hearing loss. Up to now, there is no clear and effective measure to protect the cisplatin-induced ototoxicity in the clinical use of cisplatin studies indicated that autophagy may be involved in the whole process of cisplatin-induced hearing loss. In this review, the relationship between cisplatin ototoxicity and autophagy was reviewed. It is hoped that this study can provide reference for further study of cisplatin ototoxicity and intervention of autophagy with autophagy activator or inhibitor.


Assuntos
Antineoplásicos/efeitos adversos , Autofagia , Cisplatino/efeitos adversos , Perda Auditiva/induzido quimicamente , Humanos
4.
Dis Colon Rectum ; 63(2): 242-255, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31914116

RESUMO

BACKGROUND: Peritoneal metastases arise in patients with a variety of primary cancers, and are associated with a poor prognosis. Systemic chemotherapy is the mainstay of treatment; however, the morbidity is considerable and the survival benefit is modest. Cytoreductive surgery and heated intraperitoneal chemotherapy is a potentially curative treatment available to a minority of patients; however, most develop recurrent disease. A novel palliative treatment for peritoneal metastases, pressurized intraperitoneal aerosol chemotherapy, has recently been introduced. Pressurized intraperitoneal aerosol chemotherapy utilizes an aerosol of chemotherapy in carbon dioxide gas. It is instilled into the abdomen under pressure via laparoscopic ports. No cytoreduction is performed. Pressurized intraperitoneal aerosol chemotherapy can be repeated at 6-week intervals. Oxaliplatin or cis-platinum and doxorubicin have been used to date. OBJECTIVE: This study aims to systematically review and evaluate the method, and the preclinical and early clinical results of pressurized intraperitoneal aerosol chemotherapy. DATA SOURCES: Medline and the Cochrane Library were the data sources for the study. STUDY SELECTION: Peer-reviewed series of greater than 10 patients, with sufficient patient data, through April 2019, were selected. INTERVENTION: Patients with peritoneal metastases underwent pressurized intraperitoneal aerosol chemotherapy. MAIN OUTCOME MEASURES: Patient dropout, histologic tumor response, adverse events, and 30-day mortality were the primary outcomes measured. RESULTS: A total of 921 patients with peritoneal metastases were brought to the operating room for pressurized intraperitoneal aerosol chemotherapy. The number of pressurized intraperitoneal aerosol chemotherapy treatments administered was as follows: 1 treatment, 862 (94%); 2 treatments, 645 (70%); and 3 treatments, 390 patients (42%). Initial laparoscopic access was not possible in 59 patients (6.4%). Common Terminology Criteria for Adverse Events grade 3 or higher were noted in 13.7% of the patients who, collectively, underwent a total of 2116 treatments. The 30-day mortality was 2.4% (22/921). LIMITATIONS: This study was limited by the heterogeneity of reported data and primary tumor types and by the lack of long-term survival data. CONCLUSIONS: Early clinical results are encouraging, but tumor-specific, prospective, randomized trials are needed to compare pressurized intraperitoneal aerosol chemotherapy to systemic chemotherapy. This method has yet to be introduced to the United States. It is another therapeutic option for patients with peritoneal metastases and will broaden the patient base for future clinical trials.


Assuntos
Aerossóis/administração & dosagem , Cuidados Paliativos/métodos , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/secundário , Aerossóis/efeitos adversos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dióxido de Carbono/administração & dosagem , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Procedimentos Cirúrgicos de Citorredução/métodos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Humanos , Hipertermia Induzida/métodos , Instilação de Medicamentos , Laparoscopia/métodos , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Oxaliplatina/uso terapêutico , Neoplasias Peritoneais/mortalidade , Pressão , Resultado do Tratamento
5.
Gynecol Oncol ; 156(1): 13-22, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31708167

RESUMO

BACKGROUND: Improvements in disease free survival for epithelial ovarian, peritoneal or fallopian tube cancer (EOC) will only come with improved primary therapy. Incorporation of poly-ADP-ribose inhibitors (PARPi) in the frontline setting may represent one strategy. This study sought to determine the maximum tolerated and feasible doses of the PARPi veliparib in combination with chemotherapy for EOC. METHODS: A phase I, 3 + 3 dose escalation evaluated dose-limiting toxicities (DLTs) in cycles 1-2. Once <2/6 patients experienced a DLT, that dose level expanded to evaluate feasibility over 4 cycles. This study opened 10/2009 and closed 8/2016. Eligible patients had untreated, stage II-IV EOC. Veliparib was added either continuous (day 1-21) or intermittent (day - 2 to 5) during 6 cycles of chemotherapy. Three chemotherapy backbones were evaluated (2 intravenous (q3week and weekly) and 1 intraperitoneal (IP)) all inclusive of bevacizumab with and as maintenance to 22 cycles. FINDINGS: Dose evaluations for 424 treated patients were available. Regimen 1 (q3 week), continuous (Reg1c) the maximum tolerated dose (MTD) was 250 mg veliparib BID and feasible dose was 150 mg BID. For regimen 1, intermittent (Reg1i) the MTD and feasible dose were 400 and 250 mg BID. For Reg2c (weekly paclitaxel) the MTD and feasible dose were 150 mg BID. For Reg2i the MTD and feasible dose were 250 and 150 mg BID. For Reg3c (IP) the MTD and feasible dose were 150 mg BID and for Reg3i (IP), the MTD and feasible dose were 400 mg and 300 mg BID. INTERPRETATION: The feasible dose for Reg1c, 2c, 2i and 3c was 150 mg po BID. For Reg1i and 3i the dose was pushed to 250 and 300 mg po BID respectively. There is no apparent difference in efficacy between continuous and intermittent dosing indicating that the higher doses achieved in intermittent dosing may not be needed. (NCT00989651). FUNDING: National Cancer Institute.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Epitelial do Ovário/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Estudos de Coortes , Relação Dose-Resposta a Droga , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Injeções Intraperitoneais , Injeções Intravenosas , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Neoplasias Peritoneais/patologia , Intervalo Livre de Progressão
6.
J Biochem Mol Toxicol ; 34(2): e22431, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31833131

RESUMO

Cisplatin-induced nephrotoxicity persists as a clinical problem despite several supportive measures to alleviate renal damage. Daidzein (DZ), a dietary isoflavone having antioxidant and anti-inflammatory activity, is investigated in this study for protective effects against cisplatin-induced renal injury in rats. DZ (25, 50, or 100 mg/kg; intraperitoneally; 10 days) was administered along with Cisplatin, single dose, on the 7th day of the experiment. On the 11th day, the rats were euthanized, and different samples were collected for analysis. Biochemical, histopathological, and molecular parameters were assessed to evaluate the effect of daidzein. Cisplatin injection resulted in renal dysfunction, lipid peroxidation that led to consumption of antioxidants, exaggerated apoptosis, and inflammation. These changes were associated with increase in the signaling proteins. DZ attenuated the toxic effects of cisplatin on the kidney at 100 mg/kg dose. The study concludes with the finding that daidzein imparts protection against the nephrotoxic effect of Cisplatin and can be considered as a novel, potential therapy.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/dietoterapia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Isoflavonas/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Nefrite/dietoterapia , Estresse Oxidativo/efeitos dos fármacos , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Cisplatino/efeitos adversos , Citocinas/sangue , Isoflavonas/administração & dosagem , Isoflavonas/farmacologia , Rim/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Ratos , Resultado do Tratamento
7.
Int J Cancer ; 146(2): 413-423, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31246277

RESUMO

In the OS2006 study, patients younger than 18 years were treated with a methotrexate-based regimen (MTX), patients older than 25 years with a doxorubicin-cisplatin-ifosfamide-based regimen (API-AI), whereas patients aged 18-25 years received either API-AI or MTX. We herein report the prespecified subgroup analysis of the outcome of 106 patients treated with API-AI. Preoperative chemotherapy combined three doxorubicin-ifosfamide-cisplatin (API) and two doxorubicin-ifosfamide (AI) courses. Postoperative chemotherapy was assigned by risk group: localised patients with a good histological response (<10% viable cells) received two AI and two cisplatin-ifosfamide (PI) courses; patients with synchronous metastases, poor histological response or unresectable primary received five cycles of etoposide-ifosfamide (EI). Of the 106 patients, 61 were randomised to receive or not zoledronate. Median age was 30 years (range 18-67), 66 (62%) patients were >25 years. The primary tumours were axial in 28 patients (26%), and 28 (26%) presented with metastases. Ninety-six patients (91%) had surgery, conservative in 82 (85%); 36 patients (38%, 95% CI 28-48%) were good responders. Toxicity was manageable, with no significant difference in severe acute toxicity between patients aged >25 years and those younger. With a median follow-up of 4.8 years, the 5-year event-free survival and overall survival rates were 46% (95% CI 36-56) and 57% (95% CI 47-67), respectively. The primary tumour size and initial metastases correlated with a higher risk of event. In these 106 osteosarcoma adult patients, API-AI proved feasible with no excess of toxicity, and favourable activity despite poor-prognosis factors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Ósseas/terapia , Osteossarcoma/terapia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Estudos de Viabilidade , Feminino , Seguimentos , França/epidemiologia , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Prognóstico , Taxa de Sobrevida , Adulto Jovem , Ácido Zoledrônico/administração & dosagem , Ácido Zoledrônico/efeitos adversos
8.
Talanta ; 207: 120343, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31594623

RESUMO

The aim of this work is to clarify the effect of curcumin and beta-carotene on cisplatin-induced tissue damage and to demonstrate the potential of Raman spectroscopy to detect tissue changes consistent with liver and kidney histopathology as a potential diagnostic adjunct. In the study, 56 Wistar albino female rats were used and randomly divided into 7 groups (n:8). Sham group received only sesame oil; Cisplatin group, received a single dose injection of cisplatin; Beta-carotene group, treated with beta-carotene orally; Cisplatin + Beta-carotene group, pretreated with beta-carotene 30 min prior to the cisplatin injection, then received cisplatin; Curcumin group, orally treated with curcumin; Cisplatin + Curcumin group, pretreated with curcumin 30min prior to the cisplatin injection, then received cisplatin. The second application was performed 1 week after the first application. One of the liver and kidney tissues was taken to 10% form for histopathological examinations and the others were taken to -80 °C for raman spectroscopy. Received sections were hematoxylin-eosin stained. The avidin-biotin peroxidase method was used for to investigate anti-TNF-α and IL1-ß activities. TUNEL method was applied to determine apoptotic cells. According to our histopathological findings, beta-carotene and especially curcumin have been found to possess hepatorenal protective activities. These datas were supported by the microscopic damage scores. Although some of these findings were observed in both the cisplatin + curcumin and cisplatin + beta-carotene groups, the incidence and severity of histopathological lesions were less than the cisplatin group. Both immunohistochemical studies and Raman spectroscopy results consistent with histopathological examination of hematoxylen-eosin stained sections. Raman spectroscopy represents a suitable tool to provide insights into structural factors involved in the mechanisms underlying antitumor effects of platinum drug.


Assuntos
Cisplatino/efeitos adversos , Análise Espectral Raman , Animais , Feminino , Inflamação , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Ratos , Ratos Wistar
9.
J Ethnopharmacol ; 247: 112269, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31610261

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Cisplatin (CP) is the classical chemotherapeutic drug for various cancer, but it also accompanies reproductive toxicity and genotoxicity. Liuwei Dihuang Pill (LW) is the traditional Chinese medicine prescription for treating Kidney-Yin deficiency syndrome, which has been reported to prevent and treat various diseases. However, the protective effect of LW on CP-induced reproductive toxicity and genotoxicity has not been reported. AIM OF THE STUDY: To investigate the potential protective effect and mechanism of LW on CP-induced reproductive toxicity and genotoxicity in male mice. MATERIALS AND METHODS: Mice were given LW (0.4, 1.2 and 3.6 g/kg) or Vitamin C (0.1 g/kg) once daily by oral gavage for thirteen consecutive days. Then, CP (3.00 mg/kg) was given intraperitoneal injection once daily for five consecutive days starting on the ninth day. The protective effects of LW against CP-induced reproductive toxicity and genotoxicity were evaluated by body weight, testis ratio, sperm count, sperm viability, sperm abnormal morphology type, micronuclei test, testicular histopathology, serum malondialdehyde (MDA), total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) level. RESULTS: The results demonstrated that LW could significantly increase CP-induced the reduction of sperm count and sperm viability, then decrease abnormal sperm type rate and micronucleus rate. Moreover, LW also could improve testicular abnormal histopathologic morphology induced by CP exposure. Meanwhile, LW decreased serum MDA level and increased T-SOD, GSH-Px and CAT level compared to CP group. CONCLUSION: our findings show that LW has protective effects on CP-induced reproductive toxicity and genotoxicity. LW decreases serum MDA level and increases T-SOD, GSH-Px and CAT level, which indicates that antioxidant activity may be the potential mechanism of LW to resist reproductive toxicity and genotoxicity.


Assuntos
Antioxidantes/farmacologia , Cisplatino/efeitos adversos , Medicamentos de Ervas Chinesas/farmacologia , Substâncias Protetoras/farmacologia , Animais , Dano ao DNA/efeitos dos fármacos , Humanos , Infertilidade/induzido quimicamente , Infertilidade/prevenção & controle , Masculino , Camundongos , Testes para Micronúcleos , Modelos Animais , Estresse Oxidativo/efeitos dos fármacos , Contagem de Espermatozoides , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia , Testículo/efeitos dos fármacos , Testículo/patologia
10.
Medicine (Baltimore) ; 98(51): e18210, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31860968

RESUMO

BACKGROUND: Cisplatin is often used for the treatment of oral cancer (OC). However, there are inconsistent results. Thus, this study plans to systematically assess the clinical efficacy and safety of cisplatin for adult patients with OC. METHODS: We will search for PUBMED, EMBASE, Cochrane Library, AMED, Cumulative Index to Nursing and Allied Health Literature, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. All of them will be searched from the construction of each database up to the present with no restrictions of language and publication status. The data analysis will be conducted using RevMan 5.3 software to assess the efficacy and safety of cisplatin for adult patients with OC. RESULTS: This study will summarize the most recent high-quality evidence and will provide helpful information about the efficacy and safety of cisplatin for adult patients with OC. CONCLUSION: The findings of this study will provide convinced evidence of cisplatin for adult patients with OC, and provide recommendations for clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019156558.


Assuntos
Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias Bucais/tratamento farmacológico , Adulto , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Humanos , Resultado do Tratamento
11.
Biochemistry (Mosc) ; 84(12): 1502-1512, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31870254

RESUMO

Autophagy plays an important role in the pathogenesis of acute kidney injury (AKI). Although autophagy activation was shown to be associated with an increased lifespan and beneficial effects in various pathologies, the impact of autophagy activators, particularly, rapamycin and its analogues on AKI remains obscure. In our study, we explored the effects of rapamycin treatment in in vivo and in vitro models of ischemic and cisplatin-induced AKI. The impact of rapamycin on the kidney function after renal ischemia/reperfusion (I/R) or exposure to the nephrotoxic agent cisplatin was assessed by quantifying blood urea nitrogen and serum creatinine and evaluating the content of neutrophil gelatinase-associated lipocalin, a novel biomarker of AKI. In vitro experiments were performed on the primary culture of renal tubular cells (RTCs) that were subjected to oxygen-glucose deprivation (OGD) or incubated with cisplatin under various rapamycin treatment protocols. Cell viability and proliferation were estimated by the MTT assay and real-time cell analysis using an RTCA iCELLigence system. Although rapamycin inhibited mTOR (mammalian target of rapamycin) signaling, it failed to enhance the autophagy and to ameliorate the severity of AKI caused by ischemia or cisplatin-induced nephrotoxicity. Experiments with RTCs demonstrated that rapamycin exhibited the anti-proliferative effect in primary RTCs cultures but did not protect renal cells exposed to OGD or cisplatin. Our study revealed for the first time that the mTOR inhibitor rapamycin did not prevent AKI caused by renal I/R or cisplatin-induced nephrotoxicity and, therefore, cannot be considered as an ideal mimetic of the autophagy-associated nephroprotective mechanisms (e.g., those induced by caloric restriction), as it had been suggested earlier. The protective action of such approaches like caloric restriction might not be limited to mTOR inhibition and can proceed through more complex mechanisms involving alternative autophagy-related targets. Thus, the use of rapamycin and its analogues for the treatment of various AKI forms requires further studies in order to understand potential protective or adverse effects of these compounds in different contexts.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/prevenção & controle , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Isquemia/prevenção & controle , Sirolimo/farmacologia , Lesão Renal Aguda/metabolismo , Animais , Células Cultivadas , Glucose/metabolismo , Isquemia/metabolismo , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Masculino , Oxigênio/metabolismo , Substâncias Protetoras/farmacologia , Ratos , Serina-Treonina Quinases TOR/metabolismo
12.
PLoS One ; 14(12): e0226769, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31877176

RESUMO

The production of reactive oxygen species (ROS) by cisplatin is one of the major mechanisms of cisplatin-induced cytotoxicity. We examined the preventive effect of α-lipoic acid (LA) on cisplatin-induced toxicity via its antioxidant effects on in vitro and ex vivo culture systems. To elucidate the mechanism of the antioxidant activity of LA, NRF2 was inhibited using NRF2 siRNA, and the change in antioxidant activity of LA was characterized. MTT assays showed that LA was safe at concentrations up to 0.5 mM in HEI-OC1 cells and had a protective effect against cisplatin-induced cytotoxicity. Intracellular ROS production in HEI-OC1 cells was rapidly increased by cisplatin for up to 48 h. However, treatment with LA significantly reduced the production of ROS and increased the expression of the antioxidant proteins HO-1 and SOD1. Ex vivo, the organs of Corti of the group pretreated with LA exhibited better preservation than the group that received cisplatin alone. We also confirmed the nuclear translocation of NRF2 after LA administration, and that NRF2 inhibition decreased the antioxidant activity of LA. Together, these results indicate that the antioxidant activity of LA was through the activation of the NRF2/HO-1 antioxidant pathway.


Assuntos
Antineoplásicos/efeitos adversos , Antioxidantes/farmacologia , Cisplatino/efeitos adversos , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ácido Tióctico/farmacologia , Animais , Linhagem Celular , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
Adv Clin Exp Med ; 28(11): 1537-1543, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31766081

RESUMO

BACKGROUND: Cisplatin, used in cancer treatment, has toxic and apoptotic effects on the peripheral nervous system. Rutin, also known as vitamin P, has antioxidant and antiapoptotic activity. OBJECTIVES: The purpose of this study was to investigate the biochemical and histopathologic efficacy of rutin on neurotoxic and apoptotic effects caused by cisplatin in the peripheral nervous system. MATERIAL AND METHODS: Twenty-four albino Wistar male rats were divided into the following 4 groups: control group (CG), only cisplatin-injected group (CIS), cisplatin and rutin 50 mg/kg (RG-50)-injected group, and cisplatin and rutin 100 mg/kg (RG-100)-injected group. Analyses were performed on sciatic nerve tissue of experimental animals. Analyses of malondialdehyde (MDA), total glutathione (tGSH), glutathione reductase (GSHRd), glutathione-s-transferase (GST), and superoxide dismutase (SOD) were performed. Caspase-3 expression in nerve tissue was also investigated. The analyzed groups were compared with CG. RESULTS: Biochemical investigation shows that there is a statistically significant difference between CG and only CIS and RG-50. Control group and RG-100 were found to be similar. Cisplatin-induced changes were observed in histopathological analysis of the nerve tissue. The RG-100 and CG were found to be similar. The caspase-3 expression in the neural tissue was compared between groups. Control group and CIS were found to be different. Control group and RG-100 were found to be similar. CONCLUSIONS: Antioxidant and antiapoptotic effectiveness of rutin was detected against the toxic effects caused by cisplatin in the peripheral nerve tissue.


Assuntos
Antineoplásicos/efeitos adversos , Antioxidantes/farmacologia , Cisplatino/efeitos adversos , Tecido Nervoso/efeitos dos fármacos , Rutina/farmacologia , Animais , Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Glutationa/metabolismo , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Rutina/uso terapêutico , Superóxido Dismutase/metabolismo
14.
Lancet ; 394(10212): 1929-1939, 2019 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-31590988

RESUMO

BACKGROUND: Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum-etoposide) in treatment-naive patients with ES-SCLC. METHODS: This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum-etoposide; durvalumab plus tremelimumab plus platinum-etoposide; or platinum-etoposide alone. All drugs were administered intravenously. Platinum-etoposide consisted of etoposide 80-100 mg/m2 on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL per min or cisplatin 75-80 mg/m2 (administered on day 1 of each cycle). Patients received up to four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum-etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum-etoposide group. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum-etoposide group versus the platinum-etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing. FINDINGS: Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum-etoposide group and 269 to the platinum-etoposide group. Durvalumab plus platinum-etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59-0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5-14·8) in the durvalumab plus platinum-etoposide group versus 10·3 months (9·3-11·2) in the platinum-etoposide group, with 34% (26·9-41·0) versus 25% (18·4-31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum-etoposide group and 166 (62%) of 266 in the platinum-etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients. INTERPRETATION: First-line durvalumab plus platinum-etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received. FUNDING: AstraZeneca.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Etoposídeo/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Esquema de Medicação , Etoposídeo/efeitos adversos , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Carcinoma de Pequenas Células do Pulmão/mortalidade
15.
BMC Cancer ; 19(1): 954, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615466

RESUMO

BACKGROUND: The efficacy of hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC) remains unclear. We conducted a multi-center randomized phase II study comparing a sequential HAIC-sorafenib regimen versus sorafenib alone as an initial therapy for HCC. METHODS: Patients were randomly assigned (ratio, 1:1) to receive sequential HAIC with cisplatin followed by sorafenib (HAIC group, n = 35) or sorafenib alone (sorafenib group, n = 33) as an initial therapy. The primary endpoint was the one-year survival rate. Secondary endpoint included overall survival (OS), the 2-year survival rate, the time-to-progression (TTP), the objective response rate (ORR), the disease control rate (DCR), and safety. RESULTS: For the primary endpoint, the one-year survival rates were 46% in the HAIC group and 58% in the sorafenib group. The median OS period was 10.0 months (95% CI, 7.0-18.8) in the HAIC group and 15.2 months (95% CI, 8.2-19.7) in the sorafenib group (hazard ratio [HR], 1.08; 95% CI, 0.63 to 1.86, P = 0.78). The median TTP, ORR and DCR in the HAIC group were 2.8 months (95% CI, 1.7-5.5), 14.3, and 45.7%, respectively, while those in the sorafenib group were 3.9 months (95% CI, 2.3-6.8), 9.1, and 45.5%, respectively. No unexpected adverse events related to HAIC or sorafenib were observed in either group. CONCLUSIONS: Sequential HAIC with cisplatin and sorafenib does not improve the survival benefit, compared with sorafenib alone, when used as an initial therapy for advanced HCC. However, this study was underpowered in regard to its primary and secondary endpoints, so the results should be interpreted with caution. TRIAL REGISTRATION: UMIN ID 000006147 , registration data: August 11, 2011.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Cisplatino/uso terapêutico , Infusões Intra-Arteriais , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/mortalidade , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Feminino , Seguimentos , Artéria Hepática , Humanos , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Sorafenibe/administração & dosagem , Sorafenibe/efeitos adversos , Taxa de Sobrevida , Resultado do Tratamento
16.
Jpn J Clin Oncol ; 49(11): 1009-1015, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31665358

RESUMO

OBJECTIVES: To explore the risk factors of laryngo-esophageal dysfunction-free survival and nutritional support dependence over 12 months in patients with unresectable locally advanced head and neck carcinomas who received chemoradiotherapy in a phase II trial of JCOG0706 (UMIN000001272). METHODS: Forty-five patients received radiation therapy for a total of 70 Gy/35fr concurrently with S-1 and cisplatin. Risk factors of laryngo-esophageal dysfunction-free survival and nutritional support dependence over 12 months were analyzed using Cox regression models and logistic regression models, respectively, with consideration to patient laboratory data just before chemoradiotherapy. Radiation fields were reviewed to analyze the relationship between the extent of the irradiated field and functional outcome. RESULTS: With a median follow-up period of 3.5 years, 3-year laryngo-esophageal dysfunction-free survival was 48.9%. For laryngo-esophageal dysfunction-free survival, hazards ratio of 2.35 in patients with nutritional support at registration (vs. without nutritional support; 95% confidence interval 0.96-5.76). For nutritional support dependence over 12 months, odds ratio was 6.77 in patients with hemoglobin less than the median of 13.4 g/dl (vs. higher than or equal to the median; 95% confidence interval 1.24-36.85) and was 6.00 in patients with albumin less than the median of 3.9 g/dl (vs. higher than or equal to the median; 95% confidence interval 1.11-32.54). Primary sites in disease-free patients with nutritional support dependence over 12 months were the oropharynx (N = 2) or hypopharynx (N = 1), and all pharyngeal constrictor muscles were included in irradiated fields with a curative dose. CONCLUSIONS: This supplementary analysis showed that pretreatment severe dysphagia requiring nutritional support, anemia and hypoalbuminemia might have a negative prognostic impact on long-term functional outcomes after curative chemoradiotherapy in head and neck cancer.


Assuntos
Quimiorradioterapia/efeitos adversos , Transtornos de Deglutição/terapia , Apoio Nutricional/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Adulto , Idoso , Anemia/dietoterapia , Quimiorradioterapia/métodos , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Hipoalbuminemia/dietoterapia , Masculino , Pessoa de Meia-Idade , Ácido Oxônico/efeitos adversos , Ácido Oxônico/uso terapêutico , Prognóstico , Tegafur/efeitos adversos , Tegafur/uso terapêutico
17.
Nat Commun ; 10(1): 4150, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31515474

RESUMO

Cisplatin is one of the most widely used chemotherapeutic drugs for the treatment of cancer. Unfortunately, one of its major side effects is permanent hearing loss. Here, we show that glutathione transferase α4 (GSTA4), a member of the Phase II detoxifying enzyme superfamily, mediates reduction of cisplatin ototoxicity by removing 4-hydroxynonenal (4-HNE) in the inner ears of female mice. Under cisplatin treatment, loss of Gsta4 results in more profound hearing loss in female mice compared to male mice. Cisplatin stimulates GSTA4 activity in the inner ear of female wild-type, but not male wild-type mice. In female Gsta4-/- mice, cisplatin treatment results in increased levels of 4-HNE in cochlear neurons compared to male Gsta4-/- mice. In CBA/CaJ mice, ovariectomy decreases mRNA expression of Gsta4, and the levels of GSTA4 protein in the inner ears. Thus, our findings suggest that GSTA4-dependent detoxification may play a role in estrogen-mediated neuroprotection.


Assuntos
Cisplatino/efeitos adversos , Glutationa Transferase/metabolismo , /enzimologia , Animais , Limiar Auditivo/efeitos dos fármacos , Capilares/patologia , Cóclea/enzimologia , Cóclea/patologia , Cóclea/fisiopatologia , Cruzamentos Genéticos , Dano ao DNA/genética , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa Transferase/deficiência , Perda Auditiva/complicações , Perda Auditiva/enzimologia , Perda Auditiva/fisiopatologia , Masculino , Camundongos Endogâmicos CBA , /patologia , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Gânglio Espiral da Cóclea/efeitos dos fármacos , Gânglio Espiral da Cóclea/patologia
18.
Oncology ; 97(6): 319-326, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31553989

RESUMO

BACKGROUND: Magnesium premedication is reported to have a significant effect on reducing cisplatin-induced nephrotoxicity in several types of cancer. However, the effectiveness of magnesium administration in reducing nephrotoxicity remains unknown in esophageal cancer, especially regarding neoadjuvant therapy. METHODS: Between January 2017 and January 2019, 105 patients who underwent neoadjuvant chemotherapy followed by surgery were included in this study. Of these patients, 40 received intravenous magnesium premedication (magnesium group), whereas the remaining 65 did not (control group). We investigated the -association between magnesium premedication and chemotherapy-related nephrotoxicity. RESULTS: Baseline characteristics, such as age, body mass index, clinical stage, comorbidity, and pretreatment renal function, were not significantly different -between the magnesium and control groups. Clinical and -pathological responses were similar between the 2 groups. Regarding chemotherapy-related toxicity, there were no significant differences in hematological side effects, such as anemia, thrombopenia, and neutropenia, between both groups. However, nephrotoxicity of grade 2 and higher was significantly less frequent in the magnesium group than in the control group (2.5 vs. 21.5%, p = 0.0026), although there was no significant difference in the incidence of other nonhematological adverse events, such as nausea and diarrhea. Multivariate analysis indicated magnesium premedication and heart disease as independent factors associated with cisplatin-induced nephrotoxicity (p = 0.0026 and p = 0.0424, respectively). CONCLUSION: We showed that intravenous magnesium premedication exerts a protective effect against renal dysfunction in esophageal cancer patients undergoing neoadjuvant chemotherapy including high-dose cisplatin. Large-scale prospective studies are needed to confirm the effect of magnesium premedication on reducing nephrotoxicity in esophageal cancer patients undergoing neoadjuvant therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/efeitos adversos , Neoplasias Esofágicas/tratamento farmacológico , Rim/efeitos dos fármacos , Magnésio/administração & dosagem , Pré-Medicação , Administração Intravenosa , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
Int. arch. otorhinolaryngol. (Impr.) ; 23(3): 267-275, July-Sept. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1040018

RESUMO

Abstract Introduction Riluzole (2-amino-6-trifluoromethoxy benzothiazole) is known as a neuroprotective, antioxidant, antiapoptotic agent. It may have beneficial effects on neuronal cell death due to cisplatin-induced ototoxicity. Objective To evaluate the effect of riluzole on cisplatin-induced ototoxicity in guinea pigs. Methods Twenty-four guinea pigs, studied in three groups, underwent auditory brainstem response evaluation using click and 8 kHz tone burst stimuli. Subsequently, 5 mg/kg of cisplatin were administered to all animals for 3 days intraperitoneally (i.p.) to induce ototoxicity. Half an hour prior to cisplatin, groups 1, 2 and 3 received 2 ml of saline i.p., 6 mg/kg of riluzole hydrochloride i.p., and 8 mg/kg of riluzole hydrochloride i.p., respectively, for 3 days. The auditory brainstem responses were repeated 24 hours after the last drug administration. The cochleae were analyzed by transmission electron microscopy (TEM). Results After drug administiration, for 8,000 Hz stimulus, group 1 had significantly higher threshold shifts when compared with groups 2 (p < 0.05) and 3 (p < 0.05), and there was no significant difference in threshold shifts between groups 2 and 3 (p > 0.05). Transmission electron microscopy findings demonstrated the protective effect of riluzole on the hair cells and the stria vascularis, especially in the group treated with 8 mg/kg of riluzole hydrochloride. Conclusion We can say that riluzolemay have a protective effect on cisplatin- induced ototoxicity. However, additional studies are needed to confirm these results and the mechanisms of action of riluzole.


Assuntos
Animais , Masculino , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Cisplatino/efeitos adversos , Riluzol/farmacologia , Perda Auditiva Neurossensorial/induzido quimicamente , Limiar Auditivo/efeitos dos fármacos , Estria Vascular/efeitos dos fármacos , Estria Vascular/patologia , Nervo Coclear/efeitos dos fármacos , Nervo Coclear/patologia , Riluzol/uso terapêutico , Modelos Animais , Microscopia Eletrônica de Transmissão , Cobaias , Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Auditivas/patologia , Degeneração Neural/induzido quimicamente
20.
BMC Cancer ; 19(1): 770, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31382912

RESUMO

BACKGROUND: Etoposide (E) at 100 mg/m2 combined with Cisplatin (P) at 20 mg/m2 represents an induction 2-day regimen embedded in our clinical practice for patients with advanced GCT or TN at high risk of early death. We evaluated 24/7 Em-EP administration to a combined GCT-TN cohort at our Emergency Cancer Treatment Centre (ECTC) to determine its efficacy within the acute setting. METHODS: Patients who received Em-EP during a five-year interval were identified from electronic databases at Imperial College Healthcare NHS Trust. Data collected included demographics, treatment details and clinical outcome. RESULTS: Em-EP was administered in the emergency setting to 104 patients, predominantly young adults (median age 35, range 17-71). Half the cases were GCT (n = 52): 22 male (6 seminomas, 13 non-seminomas); 30 female (2 dysgerminomas, 28 non-dysgerminomas). The other 50% were treated for TN (n = 52): 45 gestational (GTN) and 7 non-gestational. Most patients received Em-EP for a new cancer diagnosis (n = 100, 96%), within 24 h (n = 93, 89%) and out-of-hours (n = 74, 70%). Indications for Em-EP included symptomatic disease (n = 66, 63%), high-burden disease, (n = 51, 49%) and organ failure requiring Intensive Care Unit support (n = 9, 9%). Neutropenic sepsis was observed in 5%. Four-week overall survival after Em-EP administration was 98%. CONCLUSIONS: Despite the potentially fatal complications encountered in the acute setting, early mortality with Em-EP is low at our ECTC. Specialist units that treat unwell patients with advanced GCT or TN should consider making Em-EP available 24/7 for emergency administration. Its efficacy within a prospective cohort and in other platinum-sensitive malignancies requires evaluation.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Cisplatino/uso terapêutico , Serviços Médicos de Emergência , Etoposídeo/uso terapêutico , Doença Trofoblástica Gestacional/tratamento farmacológico , Doença Aguda , Adolescente , Adulto , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Assistência à Saúde , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Febre/etiologia , Seguimentos , Doença Trofoblástica Gestacional/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Gravidez , Estudos Prospectivos , Estudos Retrospectivos , Sepse/etiologia , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
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