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1.
Lancet ; 398(10302): 759-771, 2021 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-34454674

RESUMO

BACKGROUND: First-line therapy for advanced oesophageal cancer is currently limited to fluoropyrimidine plus platinum-based chemotherapy. We aimed to evaluate the antitumour activity of pembrolizumab plus chemotherapy versus chemotherapy alone as first-line treatment in advanced oesophageal cancer and Siewert type 1 gastro-oesophageal junction cancer. METHODS: We did a randomised, placebo-controlled, double-blind, phase 3 study across 168 medical centres in 26 countries. Patients aged 18 years or older with previously untreated, histologically or cytologically confirmed, locally advanced, unresectable or metastatic oesophageal cancer or Siewert type 1 gastro-oesophageal junction cancer (regardless of PD-L1 status), measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, and Eastern Cooperative Oncology Group performance status of 0-1, were randomly assigned (1:1) to intravenous pembrolizumab 200 mg or placebo, plus 5-fluorouracil and cisplatin (chemotherapy), once every 3 weeks for up to 35 cycles. Randomisation was stratified by geographical region, histology, and performance status. Patients, investigators, and site staff were masked to group assignment and PD-L1 biomarker status. Primary endpoints were overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 combined positive score (CPS) of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients. This trial is registered with ClinicalTrials.gov, NCT03189719, and is closed to recruitment. FINDINGS: Between July 25, 2017, and June 3, 2019, 1020 patients were screened and 749 were enrolled and randomly assigned to pembrolizumab plus chemotherapy (n=373 [50%]) or placebo plus chemotherapy (n=376 [50%]). At the first interim analysis (median follow-up of 22·6 months), pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more (median 13·9 months vs 8·8 months; hazard ratio 0·57 [95% CI 0·43-0·75]; p<0·0001), oesophageal squamous cell carcinoma (12·6 months vs 9·8 months; 0·72 [0·60-0·88]; p=0·0006), PD-L1 CPS of 10 or more (13·5 months vs 9·4 months; 0·62 [0·49-0·78]; p<0·0001), and in all randomised patients (12·4 months vs 9·8 months; 0·73 [0·62-0·86]; p<0·0001). Pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for progression-free survival in patients with oesophageal squamous cell carcinoma (6·3 months vs 5·8 months; 0·65 [0·54-0·78]; p<0·0001), PD-L1 CPS of 10 or more (7·5 months vs 5·5 months; 0·51 [0·41-0·65]; p<0·0001), and in all randomised patients (6·3 months vs 5·8 months; 0·65 [0·55-0·76]; p<0·0001). Treatment-related adverse events of grade 3 or higher occurred in 266 (72%) patients in the pembrolizumab plus chemotherapy group versus 250 (68%) in the placebo plus chemotherapy group. INTERPRETATION: Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved overall survival in patients with previously untreated, advanced oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients regardless of histology, and had a manageable safety profile in the total as-treated population. FUNDING: Merck Sharp & Dohme.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Fluoruracila/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sobrevida
2.
Int J Clin Oncol ; 26(10): 1871-1880, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34453640

RESUMO

BACKGROUND: To compare irinotecan-alone, paclitaxel-alone, and each combination chemotherapy with S-1 in patients with advanced gastric cancer (AGC) that is refractory to S-1 or S-1 plus cisplatin (SP). METHODS: Patients with AGC after first-line chemotherapy with S-1 or SP, or patients during adjuvant chemotherapy or within 26 weeks after adjuvant chemotherapy completion with S-1 with confirmed disease progression were eligible. Patients were randomly divided into four groups based on treatment: irinotecan-alone (irinotecan; 150 mg/m2, day 1, q14 days), paclitaxel-alone (paclitaxel; 80 mg/m2, days 1, 8, 15, q28 days), S-1 plus irinotecan (irinotecan; 80 mg/m2, days 1, 15, S-1; 80 mg/m2, days 1-21, q35 days), and S-1 plus paclitaxel (paclitaxel; 50 mg/m2, day1, 8, S-1; 80 mg/m2, days 1-14, q21 days). The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS), response rate, and safety. RESULTS: From July 2008 to March 2012, 127 patients were enrolled. No difference in median OS was observed in the irinotecan vs. paclitaxel groups or in the monotherapy groups vs. the S-1 combination therapy groups. Median PFS was longer in the paclitaxel group compared with the irinotecan group (4.1 vs. 3.6 months, p = 0.035), although no difference was observed when comparing monotherapy vs. S-1 combination. The most common grade 3 to 4 hematological adverse events were neutropenia with no difference in incidence rate across the treatment groups. CONCLUSIONS: There was no difference in OS between irinotecan and paclitaxel no in OS prolongation of S-1 combination therapy in second-line chemotherapy.


Assuntos
Neoplasias Gástricas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Paclitaxel/efeitos adversos , Neoplasias Gástricas/tratamento farmacológico
3.
Medicine (Baltimore) ; 100(33): e26850, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34414935

RESUMO

BACKGROUND: Gastric cancer (GC) is a strong cause of global cancer mortality. Nucleotide excision repair (NER) can modulate platinum-based chemotherapeutic efficacy by removing drug-produced DNA damage. Some studies have found a link between excision repair cross complementation group 1 (ERCC1) rs2298881, one gene in NER pathway, and response to chemotherapy. However, the results have been disputed. METHODS: We conducted a meta-analysis to reevaluate the association between polymorphisms of NER gene (ERCC1 rs2298881) and the clinical outcomes in gastric cancer patients receiving platinum-based chemotherapy. Searching PubMed, Web of Science, EMBASE, Google Scholar, and China National Knowledge Infrastructure, 2 independent searchers found all pertinent literatures up to May 1, 2021. We enrolled studies according to consistent selection criteria, extracted and vitrified data. Crude odds ratios (ORs) and hazard ratios (HRs) with 95% confidence interval (CI) were applied to evaluate the effect of ERCC1 rs2298881 on patients treated by platinum-based chemotherapy. RESULTS: By the data gathered from 6 independent studies, 1940 cases diagnosed with gastric cancer and treated with chemotherapy were included, containing 1208 Good-Responders and 732 Poor-Responders. With a comprehensive meta-analysis, we found that the patients with ERCC1 rs2298881A allele had a worse response to chemotherapy than those who with rs2298881C allele under allelic model (A vs C), with the pooled OR of 0.780 (95% CI: 0.611-0.996, P = .046). And our analysis indicated that AA genotype was associated with unfavorable overall survival (HR = 1.540, 95% CI = 1.106-2.144, P = .011) compared with CC genotype. CONCLUSIONS: ERCC1 rs2298881 is suggested as a marker of clinical outcome in gastric cancer patients treated by platinum-based chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Oxaliplatina/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Humanos , Polimorfismo de Nucleotídeo Único , Prognóstico , Neoplasias Gástricas/mortalidade
4.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360968

RESUMO

Platinum-based chemotherapies, such as cisplatin, play a large role in cancer treatment. The development of resistance and treatment toxicity creates substantial barriers to disease control, yet. To enhance the therapeutic index of cisplatin-based chemotherapy, it is imperative to circumvent resistance and toxicity while optimizing tumor sensitization. One of the primary mechanisms by which cancer cells develop resistance to cisplatin is through upregulation of DNA repair pathways. In this review, we discuss the DNA damage response in the context of cisplatin-induced DNA damage. We describe the proteins involved in the pathways and their roles in resistance development. Common biomarkers for cisplatin resistance and their utilization to improve patient risk stratification and treatment personalization are addressed. Finally, we discuss some of the current treatments and future strategies to circumvent the development of cisplatin resistance.


Assuntos
Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Dano ao DNA , Reparo do DNA , Resistencia a Medicamentos Antineoplásicos , Neoplasias/genética , Animais , Antineoplásicos/toxicidade , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Cisplatino/toxicidade , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
5.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361047

RESUMO

Chemoresistance of germ cell tumors (GCTs) represents an intensively studied property of GCTs that is the result of a complicated multifactorial process. One of the driving factors in this process is the tumor microenvironment (TME). Intensive crosstalk between the DNA damage/DNA repair pathways and the TME has already been reported. This study aimed at evaluating the interplay between the immune TME and endogenous DNA damage levels in GCT patients. A cocultivation system consisting of peripheral blood mononuclear cells (PBMCs) from healthy donors and GCT cell lines was used in an in vitro study. The patient cohort included 74 chemotherapy-naïve GCT patients. Endogenous DNA damage levels were measured by comet assay. Immunophenotyping of leukocyte subpopulations was performed using flow cytometry. Statistical analysis included data assessing immunophenotypes, DNA damage levels and clinicopathological characteristics of enrolled patients. The DNA damage level in PBMCs cocultivated with cisplatin (CDDP)-resistant GCT cell lines was significantly higher than in PBMCs cocultivated with their sensitive counterparts. In GCT patients, endogenous DNA damage levels above the cutoff value were independently associated with increased percentages of natural killer cells, CD16-positive dendritic cells and regulatory T cells. The crosstalk between the endogenous DNA damage level and specific changes in the immune TME reflected in the blood of GCT patients was revealed. The obtained data contribute to a deeper understanding of ongoing interactions in the TME of GCTs.


Assuntos
Dano ao DNA , Leucócitos Mononucleares/imunologia , Neoplasias Testiculares/imunologia , Microambiente Tumoral/imunologia , Adulto , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/imunologia , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucócitos Mononucleares/classificação , Masculino , Pessoa de Meia-Idade , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia
6.
Head Face Med ; 17(1): 34, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34399796

RESUMO

OBJECTIVE: To investigate the predictability of ophthalmic artery involvement in maxillary sinus cancer using preprocedural contrast enhanced CT and MRI. METHODS: We analyzed advanced (T3, T4a, and T4b) primary maxillary sinus squamous cell carcinoma treated with super-selective intra-arterial cisplatin infusion and concomitant radiotherapy (RADPLAT) from Oct 2016 to Mar 2020. Two diagnostic radiologists evaluated the tumor invasion site around the maxillary sinus using preprocedural imaging. These results were compared with the angiographic involvement of the ophthalmic artery using statistical analyses. We also evaluated our RADPLAT quality using complication rate, response to treatment, local progressive free survival (LPFS), and overall survival (OS). RESULTS: Twenty patients were included in this study. There were ten cases of ophthalmic artery tumor stain and there was a correlation between ophthalmic artery involvement and invasion for ethmoid sinus with statistically significant differences. Other imaging findings were not associated with ophthalmic artery involvement. CONCLUSIONS: Ethmoid sinus invasion on preprocedural imaging could suggest ophthalmic artery involvement in maxillary sinus cancer. It may be useful in predicting prognosis and treatment selection.


Assuntos
Antineoplásicos , Carcinoma de Células Escamosas , Neoplasias do Seio Maxilar , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Cisplatino/uso terapêutico , Humanos , Seio Maxilar/diagnóstico por imagem , Neoplasias do Seio Maxilar/diagnóstico por imagem , Neoplasias do Seio Maxilar/terapia
7.
Anticancer Res ; 41(8): 4117-4126, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281882

RESUMO

BACKGROUND/AIM: Cancer stem cells (CSCs) contribute to resistance against neoadjuvant chemotherapy (NAC) in esophageal squamous cell carcinoma (ESCC). We conducted a retrospective observational study for the relationship between the expression levels of CSC markers in biopsy specimens prior to 5-fluorouracil plus cisplatin (FP)-NAC and the pathological responses. PATIENTS AND METHODS: We included 171 patients with ESCC who underwent the FP-NAC followed by radical resection. Biopsy specimens prior to the FP-NAC were obtained and immunochemically stained for CD44, CD133, and CD24. RESULTS: The biopsy specimens of the non-responders had the CD44high/CD24low expression at high levels, which was found as an independent predictor of not only FP-NAC resistance but also poor overall survival by multivariate analyses. CONCLUSION: CD44high/CD24low expression in the biopsy specimens prior to FP-NAC may be a predictor of FP-NAC resistance and poor prognosis of ESCC patients.


Assuntos
Antígenos CD/metabolismo , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Fluoruracila/uso terapêutico , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/cirurgia , Esofagectomia , Feminino , Humanos , Masculino , Terapia Neoadjuvante , Células-Tronco Neoplásicas/metabolismo , Estudos Retrospectivos
8.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34298999

RESUMO

The development of drug resistance in tumors is a major obstacle to effective cancer chemotherapy and represents one of the most significant complications to improving long-term patient outcomes. Despite early positive responsiveness to platinum-based chemotherapy, the majority of lung cancer patients develop resistance. The development of a new combination therapy targeting cisplatin-resistant (CR) tumors may mark a major improvement as salvage therapy in these patients. The recent resurgence in research into cellular metabolism has again confirmed that cancer cells utilize aerobic glycolysis ("the Warburg effect") to produce energy. Hence, this observation still remains a characteristic hallmark of altered metabolism in certain cancer cells. However, recent evidence promotes another concept wherein some tumors that acquire resistance to cisplatin undergo further metabolic alterations that increase tumor reliance on oxidative metabolism (OXMET) instead of glycolysis. Our review focuses on molecular changes that occur in tumors due to the relationship between metabolic demands and the importance of NAD+ in redox (ROS) metabolism and the crosstalk between PARP-1 (Poly (ADP ribose) polymerase-1) and SIRTs (sirtuins) in CR tumors. Finally, we discuss a role for the tumor metabolites of the kynurenine pathway (tryptophan catabolism) as effectors of immune cells in the tumor microenvironment during acquisition of resistance in CR cells. Understanding these concepts will form the basis for future targeting of CR cells by exploiting redox-metabolic changes and their consequences on immune cells in the tumor microenvironment as a new approach to improve overall therapeutic outcomes and survival in patients who fail cisplatin.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Cisplatino/uso terapêutico , Glicólise/efeitos dos fármacos , Humanos , Cinurenina/metabolismo , NAD/metabolismo , Oxirredução , Poli(ADP-Ribose) Polimerase-1/metabolismo , Sirtuínas/metabolismo
9.
Int J Pharm ; 606: 120899, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34324990

RESUMO

We successfully prepared and characterized a hyaluronic acid- and folic acid-based hydrogel for the delivery of cisplatin (GEL-CIS) with the aim to induce specific and efficient incorporation of CIS into ovarian cancer (OC) cells, improve its antineoplastic effect and avoid CIS-resistance. The slow and controlled release of the drug from the polymeric network and its swelling degree at physiologic pH suggested its suitability for CIS delivery in OC. We compared here the effects of pure CIS to that of GEL-CIS on human OC cell lines, either wild type or CIS-resistant, in basal conditions and in the presence of macrophage-derived conditioned medium, mimicking the action of tumor-associated macrophages in vivo. GEL-CIS inhibited OC cell growth and migration more efficiently than pure CIS and modulated the expression of proteins involved in the Epithelial Mesenchymal Transition, a process playing a key role in OC metastatic spread and resistance to CIS.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Ácido Fólico/farmacologia , Humanos , Ácido Hialurônico/farmacologia , Hidrogéis/farmacologia , Neoplasias Ovarianas/tratamento farmacológico
10.
Adv Clin Exp Med ; 30(8): 849-857, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34286518

RESUMO

BACKGROUND: Induction of acquired drug resistance occurs frequently with cisplatin-based therapy for non-small cell lung cancer (NSCLC). As recent studies have demonstrated that deregulation of microRNAs (miRNAs) is associated with drug resistance in cancers, correcting the deregulation of miRNAs represents a promising strategy to reverse acquired resistance in NSCLC. OBJECTIVES: This study investigated the functional role of miR-15b in cisplatin resistance in NSCLC. MATERIAL AND METHODS: Cisplatin-resistant PC9 and A549 NSCLC cell lines (PC9-R and A549-R) were established through long-term exposure to cisplatin. Differences in miR-15b expression between cisplatin-resistant NSCLC cell lines and their parental cell lines were identified through quantitative real-time polymerase chain reaction (qRT-PCR). The effect of anti-miR-15b on the sensitivity of PC9-R and A549-R to cisplatin-induced cytotoxicity was evaluated using Cell Counting Kit-8 (CCK-8) assays. Regulation of GSK-3ß by miR-15b was confirmed with luciferase reporter assays. Cell apoptosis and mitochondrial membrane potential (MMP) were measured using flow cytometry analysis. RESULTS: In PC9-R and A549-R cells, miR-15b was significantly overexpressed. However, knockdown of miR-15b clearly reduced cisplatin resistance in PC9-R and A549-R cells. Researching the mechanism, we proved that GSK-3ß was the target of miR-15b. Knockdown of miR-15b significantly increased the expression GSK-3ß and thus promoted the degradation of MCL-1, which is a key anti-apoptosis protein. As a result, anti-miR-15b expanded the cisplatin-induced apoptosis in cisplatin-resistant NSCLC cells. CONCLUSIONS: Knockdown of miR-15b partially reversed cisplatin resistance in NSCLC cells through the GSK-3ß/MCL-1 pathway.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Quinase 3 da Glicogênio Sintase/farmacologia , Quinase 3 da Glicogênio Sintase/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , MicroRNAs/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/uso terapêutico
11.
Oncoimmunology ; 10(1): 1950954, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34290910

RESUMO

Malignant cells adapt to the hostile tumor microenvironment by escaping from, or actively suppressing, anticancer immune responses. In the past, we reported that reduced synthesis of active vitamin B6 (due to downregulation of pyridoxal kinase) or overactivation of poly(ADP-ribose) polymerase confers resistance to chemotherapy with cisplatin. Recently, we found that these prognostically adverse alterations in oncometabolism also correlate with the rarefaction of immune effectors in the tumor bed.


Assuntos
Neoplasias , Poli Adenosina Difosfato Ribose , Microambiente Tumoral/imunologia , Cisplatino/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Poli(ADP-Ribose) Polimerases , Piridoxal Quinase
12.
J Med Case Rep ; 15(1): 417, 2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34325722

RESUMO

BACKGROUND: Metastatic choriocarcinoma in the third trimester of pregnancy is extremely rare. CASE PRESENTATION: A 25-year-old Chinese woman (gravida 3, para 0) who was 28 weeks pregnant was admitted for sudden convulsion, aconuresis, and unconsciousness. The decision was made to perform an emergency cesarean delivery and craniotomy, hematoma clearance, and decompression. Pathological examination confirmed choriocarcinoma with brain metastasis. The patient underwent chemotherapy with the etoposide, cisplatin (EP) and etoposide, methotrexate and dactinomycin alternating with cyclophosphamide and vincristine (EMACO) regimens. A satisfactory result was achieved. CONCLUSIONS: When encountering intracranial mass or bilateral pulmonary nodules in a pregnant woman, especially one in the third trimester, metastatic choriocarcinoma should be considered.


Assuntos
Neoplasias Encefálicas , Coriocarcinoma , Neoplasias Uterinas , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Coriocarcinoma/tratamento farmacológico , Coriocarcinoma/patologia , Cisplatino/uso terapêutico , Ciclofosfamida/uso terapêutico , Dactinomicina/uso terapêutico , Etoposídeo/uso terapêutico , Feminino , Humanos , Metotrexato/uso terapêutico , Gravidez , Terceiro Trimestre da Gravidez , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/patologia , Vincristina/uso terapêutico
13.
Nat Commun ; 12(1): 4230, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244494

RESUMO

Extracellular matrix protein-1 (ECM1) promotes tumorigenesis in multiple organs but the mechanisms associated to ECM1 isoform subtypes have yet to be clarified. We report in this study that the secretory ECM1a isoform induces tumorigenesis through the GPR motif binding to integrin αXß2 and the activation of AKT/FAK/Rho/cytoskeleton signaling. The ATP binding cassette subfamily G member 1 (ABCG1) transduces the ECM1a-integrin αXß2 interactive signaling to facilitate the phosphorylation of AKT/FAK/Rho/cytoskeletal molecules and to confer cancer cell cisplatin resistance through up-regulation of the CD326-mediated cell stemness. On the contrary, the non-secretory ECM1b isoform binds myosin and blocks its phosphorylation, impairing cytoskeleton-mediated signaling and tumorigenesis. Moreover, ECM1a induces the expression of the heterogeneous nuclear ribonucleoprotein L like (hnRNPLL) protein to favor the alternative mRNA splicing generating ECM1a. ECM1a, αXß2, ABCG1 and hnRNPLL higher expression associates with poor survival, while ECM1b higher expression associates with good survival. These results highlight ECM1a, integrin αXß2, hnRNPLL and ABCG1 as potential targets for treating cancers associated with ECM1-activated signaling.


Assuntos
Processamento Alternativo , Carcinoma Epitelial do Ovário/genética , Proteínas da Matriz Extracelular/metabolismo , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Ovarianas/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/terapia , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas da Matriz Extracelular/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas/genética , Humanos , Integrina alfaXbeta2/genética , Integrina alfaXbeta2/metabolismo , Estimativa de Kaplan-Meier , Camundongos , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Ovário/patologia , Ovário/cirurgia , Fosforilação/genética , Prognóstico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA-Seq , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Int J Mol Sci ; 22(13)2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34281219

RESUMO

The cure rate of germ cell tumours (GCTs) has significantly increased from the late 1970s since the introduction of cisplatin-based therapy, which to date remains the milestone for GCTs treatment. The exquisite cisplatin sensitivity has been mainly explained by the over-expression in GCTs of wild-type TP53 protein and the lack of TP53 somatic mutations; however, several other mechanisms seem to be involved, many of which remain still elusive. The findings about the role of TP53 in platinum-sensitivity and resistance, as well as the reported evidence of second cancers (SCs) in GCT patients treated only with surgery, suggesting a spectrum of cancer predisposing syndromes, highlight the need for a deepened understanding of the role of TP53 in GCTs. In the following report we explore the complex role of TP53 in GCTs cisplatin-sensitivity and resistance mechanisms, passing through several recent genomic studies, as well as its role in GCT patients with SCs, going through our experience of Center of reference for both GCTs and cancer predisposing syndromes.


Assuntos
Genes p53 , Neoplasias Embrionárias de Células Germinativas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/secundário , Proteína Supressora de Tumor p53/genética
15.
Int J Mol Sci ; 22(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204834

RESUMO

In head and neck cancers, the effectiveness of cisplatin (CisPt) treatment is limited by its toxicity, especially when higher doses are necessary, and the possible occurrence of cisplatin resistance. This study evaluated the effects of resveratrol (RSV) on the expression of different genes involved in the response of human tumor cells (FaDu, PE/CA-PJ49) to cisplatin therapy. Our results revealed that RSV induced apoptosis amplification in both FaDu and PE/CA-PJ49 cells and modulated the expression of specific genes differently than in normal HaCaT cells. In FaDu cells, combined CisPt + RSV treatment induced an increase in apoptosis, which was associated with an increase in c-MYC and TP53 and a decrease in BCL-2 expression. While CisPt + RSV treatment induced apoptosis in PE/CA-PJ49 cells by inhibition of BCL-2 associated with high levels of MDM-2 and subsequently led to inhibition of TP53 gene expression. Decreased c-MYC expression in PE/CA-PJ49 treated with CisPt + RSV was accompanied by cell cycle blockage in G0/G1 phase. In conclusion, RSV influences tumor cell response to CisPt by inducing apoptosis and modulating gene expression. In addition, in normal HaCaT cells, RSV was able to reduce the harmful effects of CisPt.


Assuntos
Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Cisplatino/uso terapêutico , Neoplasias de Cabeça e Pescoço/patologia , Resveratrol/farmacologia , Apoptose/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/genética , Humanos , Concentração Inibidora 50
16.
Aging (Albany NY) ; 13(13): 17407-17427, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34232919

RESUMO

Ovarian cancer is the third most common cancer and the second most common cause of gynecologic cancer death in women. Its routine clinical management includes surgical resection and systemic therapy with chemotherapeutics. While the first-line systemic therapy requires the combined use of platinum-based agents and paclitaxel, many ovarian cancer patients have recurrence and eventually succumb to chemoresistance. Thus, it is imperative to develop new strategies to overcome recurrence and chemoresistance of ovarian cancer. Repurposing previously-approved drugs is a cost-effective strategy for cancer drug discovery. The antiparasitic drug mebendazole (MBZ) is one of the most promising drugs with repurposing potential. Here, we investigate whether MBZ can overcome cisplatin resistance and sensitize chemoresistant ovarian cancer cells to cisplatin. We first established and characterized two stable and robust cisplatin-resistant (CR) human ovarian cancer lines and demonstrated that MBZ markedly inhibited cell proliferation, suppressed cell wounding healing/migration, and induced apoptosis in both parental and CR cells at low micromole range. Mechanistically, MBZ was revealed to inhibit multiple cancer-related signal pathways including ELK/SRF, NFKB, MYC/MAX, and E2F/DP1 in cisplatin-resistant ovarian cancer cells. We further showed that MBZ synergized with cisplatin to suppress cell proliferation, induce cell apoptosis, and blunt tumor growth in xenograft tumor model of human cisplatin-resistant ovarian cancer cells. Collectively, our findings suggest that MBZ may be repurposed as a synergistic sensitizer of cisplatin in treating chemoresistant human ovarian cancer, which warrants further clinical studies.


Assuntos
Antinematódeos/farmacologia , Antineoplásicos/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mebendazol/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Cisplatino/uso terapêutico , Reposicionamento de Medicamentos , Feminino , Humanos , Camundongos , Camundongos Nus , Ensaio Tumoral de Célula-Tronco , Cicatrização , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Clin Ter ; 172(4): 260-263, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34247206

RESUMO

Abstract: Nasopharyngeal carcinoma, one of the most common head and neck cancers in Southeast Asia, is uncommon in Western countries and it is frequently diagnosed in advanced stage. Chemotherapy given with radiation therapy, followed by more chemotherapy, is the standard of care of stage IV nasopharyngeal carcinoma but Cetuximab, an epidermal growth factor (EGFR) inhibitor, is now making its way in the treatment of locoregionally advanced nasopharyngeal carcinoma. We report a case of 58 years old patient with metastatic nasopharyngeal carcinoma with an astonishing response to Cetuximab. At the time of writing, the patient is still in treatment with Cetuximab with excellent disease control.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab/uso terapêutico , Cisplatino/uso terapêutico , Fluoruracila/uso terapêutico , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
18.
Biol Res ; 54(1): 22, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34321115

RESUMO

BACKGROUND: Accumulated evidence demonstrates cisplatin, a recommended chemotherapy, modulating pro-survival autophagic response that contributes to treatment failure in lung cancer patients. However, distinct mechanisms involved in cisplatin-induced autophagy in human lung cancer cells are still unclear. RESULTS: Herein, role of autophagy in cisplatin resistance was indicated by a decreased cell viability and increased apoptosis in lung cancer H460 cells pre-incubated with wortmannin, an autophagy inhibitor, prior to treatment with 50 µM cisplatin for 24 h. The elevated level of hydroxyl radicals detected via flow-cytometry corresponded to autophagic response, as evidenced by the formation of autophagosomes and autolysosomes in cisplatin-treated cells. Interestingly, apoptosis resistance, autophagosome formation, and the alteration of the autophagic markers, LC3-II/LC3-I and p62, as well as autophagy-regulating proteins Atg7 and Atg3, induced by cisplatin was abrogated by pretreatment of H460 cells with deferoxamine, a specific hydroxyl radical scavenger. The modulations in autophagic response were also indicated in the cells treated with hydroxyl radicals generated via Fenton reaction, and likewise inhibited by pretreatment with deferoxamine. CONCLUSIONS: In summary, the possible role of hydroxyl radicals as a key mediator in the autophagic response to cisplatin treatment, which was firstly revealed in this study would benefit for the further development of novel therapies for lung cancer.


Assuntos
Antineoplásicos , Neoplasias Pulmonares , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Autofagia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Radical Hidroxila/farmacologia , Radical Hidroxila/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico
19.
World J Surg Oncol ; 19(1): 217, 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34281546

RESUMO

BACKGROUND: Despite the established oncological benefits of neoadjuvant chemotherapy for esophageal squamous cell cancer, not all cases demonstrate benefit. Hence, predicting the response to chemotherapy before treatment is desirable. Some reports have shown that immune factors are related to the chemotherapy response. This study aimed to investigate the utility of serum IgG levels for predicting chemotherapy response. METHODS: Among the patients who underwent esophagectomy after neoadjuvant chemotherapy at Nagoya City University Hospital between December 2012 and June 2019, 130 cases were included in this study. Response to chemotherapy and pretreatment serum IgG levels were examined in 77 cases. FP (5-fluorouracil and cisplatin) therapy or DCF (docetaxel, cisplatin, and 5-FU) therapy was performed as neoadjuvant chemotherapy. DCF therapy was selected for patients aged <75 years, who could be safely administered chemotherapy based on their medical history. RESULTS: This study divided cases into two groups: the effective response group (PR) and ineffective response group (SD and PD). We classified 1, 37, and 39 cases as PD, PR, and SD, respectively. None of the cases were classified as CR. The effective response group had significantly lower serum IgG levels than the ineffective response group (p < 0.001). The cutoff serum IgG value was determined to be 1087 mg/dL. The low IgG group had significantly more cases who had effective response to chemotherapy compared with the high IgG group (odds ratio [OR] = 9.009; 95% confidence interval [CI] = 2.974-30.157; p < 0.001). Univariate and multivariate analyses revealed serum IgG level to be an independent predictor for response to chemotherapy (p = 0.001). Furthermore, cases with effective pathological response had significantly lower pretreatment serum IgG levels than those who did not (p = 0.006). CONCLUSIONS: Our finding showed that serum IgG levels can be an independent predictor of the response to neoadjuvant chemotherapy for esophageal squamous cell carcinoma. TRIAL REGISTRATION: This retrospective study was approved by the review board of Nagoya City University Graduate School of Medical Sciences (reception number: 60-18-0008 ).


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Neoplasias de Cabeça e Pescoço , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/cirurgia , Esofagectomia , Fluoruracila/uso terapêutico , Humanos , Imunoglobulina G , Terapia Neoadjuvante , Prognóstico , Estudos Retrospectivos
20.
Int J Mol Sci ; 22(13)2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34281253

RESUMO

Radical cystectomy is the primary treatment for muscle-invasive bladder cancer; however, approximately 50% of patients develop metastatic disease within 2 years of diagnosis, which results in dismal prognosis. Therefore, systemic treatment is important to improve the prognosis of muscle-invasive bladder cancer. Currently, several guidelines recommend cisplatin-based neoadjuvant chemotherapy before radical cystectomy, and adjuvant chemotherapy is recommended in patients who have not received neoadjuvant chemotherapy. Immune checkpoint inhibitors have recently become the standard treatment option for metastatic urothelial carcinoma. Owing to their clinical benefits, several immune checkpoint inhibitors, with or without other agents (including other immunotherapy, cytotoxic chemotherapy, and emerging agents such as antibody drug conjugates), are being extensively investigated in perioperative settings. Several studies for perioperative immunotherapy have shown that immune checkpoint inhibitors have promising efficacy with relatively low toxicity, and have explored the predictive molecular biomarkers. Herein, we review the current evidence and discuss the future perspectives of perioperative systemic treatment for muscle-invasive bladder cancer.


Assuntos
Neoplasias da Bexiga Urinária/terapia , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/tendências , Cisplatino/uso terapêutico , Cistectomia , Humanos , Imunoterapia/métodos , Imunoterapia/tendências , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/tendências , Invasividade Neoplásica/patologia , Assistência Perioperatória/métodos , Assistência Perioperatória/tendências , Período Perioperatório , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia
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