RESUMO
Fluoropyrimidines (FLs) [5-Fluorouracil, Capecitabine] are used in the treatment of several solid tumors. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for FL detoxification, and its deficiency could lead to severe, life-threatening or fatal toxicity after FL administration. Testing with a pharmacogenetic panel of four deleterious variants in the dihydropyrimidine dehydrogenase gene (DPYD) (DPYD*2A, DPYD*13, c.2846A > T, c.1129-5923C > G) prior to FL treatment, is recommended by scientific consortia (e.g., CPIC, DPWG) and drug regulatory agencies (e.g., EMA). However, this panel identifies < 20% of patients at risk of severe FL-related toxicity. Cumulative recent evidence highlights the potential clinical value of rare (minor allele frequency < 1%) and novel DPYD genetic variants for identifying an additional fraction of DPD-deficient patients at increased risk of severe FL-related toxicity. In this review, we aimed to comprehensively describe the available evidence regarding the potential clinical predictive role of novel and rare DPYD variants as toxicity markers in FL-treated patients, and to discuss the challenges and opportunities in tailoring FL treatment based upon clinical application of such markers. Although we must overcome existing barriers to the clinical implementation, the available data support that comprehensive assessment of the DPYD sequence, including rare and novel genetic variants, may significantly enhance the pre-emptive identification of at-risk patients, compared to the current targeted approach.
Assuntos
Di-Hidrouracila Desidrogenase (NADP) , Medicina de Precisão , Humanos , Di-Hidrouracila Desidrogenase (NADP)/genética , Fluoruracila/uso terapêutico , Fluoruracila/efeitos adversos , Capecitabina/uso terapêutico , Capecitabina/efeitos adversos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Antimetabólitos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/efeitos adversosRESUMO
Objective: Neoadjuvant chemotherapy (NACT) has become the standard of care for patients with triple-negative breast cancer (TNBC) with tumors > 1 cm or positive axillary nodes. Pathologic complete response (pCR) has been used as an endpoint to select patients for treatment scaling. This study aimed to examine the benefit of adding adjuvant capecitabine for TNBC patients who did not achieve pCR after standard NACT in a real-world scenario. Methods: This retrospective cohort study included all patients with TNBC who underwent NACT between 2010 and 2020. Clinicopathological data were obtained from the patient records. Univariate and multivariate analyses were conducted at the 5 years follow-up period. Results: We included 153 patients, more than half of whom had stage III (58.2%) and high-grade tumors (60.8%). The overall pCR rate was 34.6%, and 41% of the patients with residual disease received adjuvant capecitabine. Disease-specific survival (DSS) among the patients who achieved pCR was significantly higher (p<0.0001). Residual disease after NACT was associated with detrimental effects on DSS. In this cohort, we did not observe any survival benefit of adding adjuvant capecitabine for patients with TNBC subjected to NACT who did not achieve pCR (p=0.52). Conclusion: Our study failed to demonstrate a survival benefit of extended capecitabine therapy in patients with TNBC with residual disease after NACT. More studies are warranted to better understand the indication of systemic treatment escalation in this scenario.
Assuntos
Capecitabina , Terapia Neoadjuvante , Neoplasias de Mama Triplo Negativas , Humanos , Capecitabina/administração & dosagem , Capecitabina/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Quimioterapia Adjuvante , Adulto , Antimetabólitos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/administração & dosagem , IdosoRESUMO
Hypomethylating agent treatment for myeloid leukemia associated with Down syndrome (ML-DS) has been scarcely reported. Herein, we collected information on azacitidine treatment for ML-DS in Japan. Forty-eight cycles of azacitidine treatment were performed for 12 patients, including 11 relapsed or refractory (R/R) patients. In 40 cycles, azacitidine was used as monotherapy. No azacitidine-related death was observed. One cycle concurrently administered with methotrexate-based intrathecal therapy was discontinued due to toxicities. Only 4 of the 19 cycles given in non-remission achieved complete or partial remission. In conclusion, although most toxicities were acceptable, azacitidine monotherapy might be insufficient for R/R ML-DS cases.
Assuntos
Antimetabólitos Antineoplásicos , Azacitidina , Síndrome de Down , Leucemia Mieloide , Humanos , Síndrome de Down/complicações , Síndrome de Down/tratamento farmacológico , Azacitidina/uso terapêutico , Azacitidina/efeitos adversos , Masculino , Feminino , Estudos Retrospectivos , Antimetabólitos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/efeitos adversos , Japão/epidemiologia , Pré-Escolar , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/complicações , Criança , Adolescente , Lactente , AdultoRESUMO
BACKGROUND: There are no reports of concurrent chemoradiotherapy for gastric cancer with peritoneal oligometastases. CASE DESCRIPTION: A 70-year-old man with gastric cancer and peritoneal oligometastases received concurrent adaptive radiotherapy and oral S-1. After radiotherapy, S-1 was discontinued, and 2 years later the tumor had completely regressed, with no recurrence or metastasis 6 years after radiotherapy. CONCLUSION: Peritoneal oligometastatic gastric cancer may be a candidate for curative treatment with concurrent adaptive radiotherapy and oral S-1.
Assuntos
Quimiorradioterapia , Ácido Oxônico , Neoplasias Peritoneais , Neoplasias Gástricas , Tegafur , Humanos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Neoplasias Gástricas/tratamento farmacológico , Masculino , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/terapia , Idoso , Ácido Oxônico/uso terapêutico , Ácido Oxônico/administração & dosagem , Tegafur/uso terapêutico , Tegafur/administração & dosagem , Combinação de Medicamentos , Antimetabólitos Antineoplásicos/uso terapêuticoRESUMO
BACKGROUND: Concurrent chemoradiotherapy now represents the standard of care in locally advanced unresectable squamous cell carcinoma of the head and neck, and the administration of cisplatin in triweekly or weekly schedules is the most commonly used chemotherapeutic agent. However, the chemotherapeutic agent and its scheduling with radiation is still an area of investigation with safer toxicity profile and better response rates. Gemcitabine is a potent radiosensitizer, and non-cytotoxic concentration results in decreased systemic toxicity while maintaining radiosensitization properties. Furthermore, data are emerging for low-dose and long-duration infusion where this strategy is found to be effective and a safe alternative to standard brief infusion. Based on these two strategies, that is, non-cytotoxic concentration with long duration, we have explored the unique possibility of further lowering the toxicity profile without compromising the efficacy. METHOD: Eligible patients of locally advanced unresectable squamous cell carcinoma of the head and neck underwent radiation treatment with concurrent gemcitabine. A total dose of 70 Gy in 35 fractions over a period of seven weeks with conventional fractionation schedule was delivered with cord off after 44 Gy. Concurrent gemcitabine was administered intravenously for over two hours once a week, 1-2 h before radiation and for seven consecutive weeks at 50 mg/m2. RESULT: Fifty-two patients was enrolled in this study, out of which 41 completed the treatment. Fifty-nine percent completed treatment within seven weeks. Sixty-four percent were found to have received more than five cycles. Mean follow-up of patients was found to be 4.9 months. Sixty-eight percent had complete response. Stage III patients achieved more complete response compared to stage IV. There was no site-wise difference in achieving complete response. Patients who have received less than five chemo cycles or completed the treatment in more than seven weeks had less complete response. Sixty-one percent had severe mucositis while 39% developed mild/moderate mucositis. Considering skin toxicity, 80% were found to have mild/moderate skin toxicity, while only 20% suffered from severe grades of skin toxicity. CONCLUSION: Gemcitabine in low-dose and long-duration infusion is a potent radiosensitizer with safer hematological toxicity and manageable local toxicities.
Assuntos
Carcinoma de Células Escamosas , Quimiorradioterapia , Desoxicitidina , Gencitabina , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Quimiorradioterapia/métodos , Quimiorradioterapia/efeitos adversos , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Pessoa de Meia-Idade , Masculino , Feminino , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Idoso , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Adulto , Resultado do Tratamento , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/efeitos adversos , Esquema de Medicação , Radiossensibilizantes/administração & dosagem , Radiossensibilizantes/uso terapêutico , Estadiamento de NeoplasiasRESUMO
INTRODUCTION: This is the first report of a patient who developed cardiogenic shock after receiving oral chemotherapy with capecitabine and was treated with venoarterial extracorporeal membrane oxygenation combined with continuous renal replacement therapy. CLINICAL FINDINGS: A 58-year-old man developed an arrhythmia that rapidly progressed to cardiogenic shock and cardiac arrest after receiving oral capecitabine tablets to treat a rectal malignancy. INTERVENTIONS: The patient was treated with venoarterial extracorporeal membrane oxygenation in combination with continuous renal replacement therapy. OUTCOME: The patient made a full recovery and was discharged from the hospital. CONCLUSION: The use of comprehensive supportive treatments such as extracorporeal membrane oxygenation combined with continuous renal replacement therapy in patients with capecitabine-induced cardiac arrest can rapidly reduce drug concentrations, eliminate harmful substances, and improve the prognosis.
Assuntos
Antimetabólitos Antineoplásicos , Capecitabina , Oxigenação por Membrana Extracorpórea , Parada Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Capecitabina/efeitos adversos , Capecitabina/uso terapêutico , Parada Cardíaca/induzido quimicamente , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Terapia de Substituição Renal Contínua , Choque Cardiogênico/induzido quimicamente , Choque Cardiogênico/terapia , Resultado do Tratamento , Neoplasias Retais/tratamento farmacológicoRESUMO
5-Fluorouracil (5-FU) is a well-known chemotherapy drug extensively used in the treatment of breast cancer. It works by inhibiting cancer cell proliferation and inducing cell death through direct incorporation into DNA and RNA via thymidylate synthase (TS). Circular RNAs (circRNAs), a novel family of endogenous non-coding RNAs (ncRNAs) with limited protein-coding potential, contribute to 5-FU resistance. Their identification and targeting are crucial for enhancing chemosensitivity. CircRNAs can regulate tumor formation and invasion by adhering to microRNAs (miRNAs) and interacting with RNA-binding proteins, regulating transcription and translation. MiRNAs can influence enzymes responsible for 5-FU metabolism in cancer cells, affecting their sensitivity or resistance to the drug. In the context of 5-FU resistance, circRNAs can target miRNAs and regulate biological processes such as cell proliferation, cell death, glucose metabolism, hypoxia, epithelial-to-mesenchymal transition (EMT), and drug efflux. This review focuses on the function of circRNAs in 5-FU resistance, discussing the underlying molecular pathways and biological mechanisms. It also presents recent circRNA/miRNA-targeted cancer therapeutic strategies for future clinical application.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Fluoruracila , RNA Circular , Humanos , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , RNA Circular/genética , RNA Circular/metabolismo , Antimetabólitos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Regulação Neoplásica da Expressão Gênica , Transição Epitelial-Mesenquimal/genética , MicroRNAs/genética , MicroRNAs/metabolismo , AnimaisRESUMO
BACKGROUND: Locally advanced pancreatic cancer (LAPC) comprises 40% of pancreatic cancer diagnoses and has a relatively poor prognosis. Trans-arterial micro perfusion (TAMP)-mediated chemotherapy delivery to the primary tumor is a novel approach worthy of investigation. The RR1 (dose escalation) and RR2 (observational) studies examined the safety and preliminary efficacy of TAMP-delivered gemcitabine for LAPC. PATIENTS AND METHODS: RR1 and RR2 data were pooled. Both studies enrolled patients with LAPC with histologically confirmed adenocarcinoma. Participant data, including age, sex, race, stage, previous treatments, toxicity, disease progression, and death, were collected. Median number of cycles and average treatment dosage were calculated. Overall survival (OS) was determined for the whole group and separately for patients who received and did not receive previous treatments. Aims of the analysis were to assess procedure safety, OS, and evaluate factors associated with OS. RESULTS: The median age of the 43 patients enrolled in RR1 and RR2 was 72 years (range, 51-88 years). Median OS for the 35 eligible patients with stage III disease was 12.6 months (95% CI, 2.1-54.2 months). Previous chemoradiation was associated with significantly longer OS [27.1 months (95% CI, 8.4-40.6 months)] compared to previous systemic chemotherapy [14.6 months (95% CI, 6.4-54.2 months)] or no prior treatment [7.0 months (95% CI, 2.1-35.4 months)] (Pâ <â .001). The most common adverse events were GI related (abdominal pain, emesis, and vomiting); the most common grade 3 toxicity was sepsis. CONCLUSION: Study results indicate that TAMP-mediated gemcitabine delivery in patients with LAPC is potentially safe, feasible, and provides potential clinical benefits. CLINICAL TRIAL REGISTRATION: NCT02237157 (RR1) and NCT02591082 (RR2).
Assuntos
Desoxicitidina , Gencitabina , Neoplasias Pancreáticas , Humanos , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Desoxicitidina/efeitos adversos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Pessoa de Meia-Idade , Idoso , Feminino , Masculino , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologiaRESUMO
INTRODUCTION: Severe cutaneous adverse reactions (SCARs) arising from drug interactions can carry life-threatening implications and result in lasting effects. SCARs can be triggered by various factors, with trimethoprim/sulfamethoxazole identified as a primary culprit. Anticonvulsants and antineoplastic agents have been noted as secondary triggers. Notably, antineoplastics linked to SCARs include immunomodulatory agents. The higher mortality rates among cancer patients with SCARs underscore the significance of comprehending cancer--specific risk factors. Our objective is to present the case of a boy with acute lymphocytic leukemia (ALL) who developed Stevens-Johnson syndrome (SJS) following MTX treatment. CASE REPORT: We present the case of a three-year-old male patient diagnosed with ALL who developed Stevens-Johnson syndrome (SJS) subsequent to the administration of MTX, following the "BFM 2009" protocol. He had undergone intrathecal MTX administration on six previous occasions. Our patient received IVIG at a dose of 2g/kg along with steroids, resulting in partial clinical improvement after 21 days. An innovative protocol was developed, involving IVIG before MTX infusion and dexamethasone before MTXi, with folinic acid rescue. Intravenous immunoglobulin (IVIG) mitigates SJS/TEN via type IV hypersensitivity down-regulation and apoptosis curbing. CONCLUSION: As far as we know, the prophylactic use of IVIG to counteract SCARs in a pediatric leukemia patient represents uncharted territory. Moreover, research into the immune system dynamics within these patients and the preservation of indispensable treatments should involve allergist-immunologists as part of the multidisciplinary team attending to neoplastic conditions.
Assuntos
Metotrexato , Leucemia-Linfoma Linfoblástico de Células Precursoras , Síndrome de Stevens-Johnson , Humanos , Masculino , Síndrome de Stevens-Johnson/tratamento farmacológico , Síndrome de Stevens-Johnson/etiologia , Síndrome de Stevens-Johnson/diagnóstico , Pré-Escolar , Metotrexato/uso terapêutico , Metotrexato/efeitos adversos , Metotrexato/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Imunoglobulinas Intravenosas/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/uso terapêuticoAssuntos
Combinação de Medicamentos , Ácido Oxônico , Neoplasias Gástricas , Tegafur , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Tegafur/administração & dosagem , Tegafur/uso terapêutico , Ácido Oxônico/administração & dosagem , Ácido Oxônico/uso terapêutico , Quimioterapia Adjuvante , Ensaios Clínicos Fase III como Assunto , Seguimentos , Estadiamento de Neoplasias , Estudos de Equivalência como Asunto , Antimetabólitos Antineoplásicos/uso terapêuticoRESUMO
The development of gemcitabine (GEM) resistance severely limits the treatment efficacy in pancreatic cancer (PC) and increasing evidence highlights the vital roles of circular RNAs (circRNAs) in the tumorigenesis, progression and drug resistance of PC. However, the circRNAs underlying GEM resistance development of PC remains to be clarified. The current research aims to unveil the roles of circ_0036627 in dictating the aggressiveness and GEM sensitivity in PC. We reported the increased expression of circ_0036627 in PC tissues and PC cell lines. Elevated circ_0036627 expression level was correlated with advanced tumour grade and poor overall survival in PC patients. Functional assays and in vivo experiments demonstrated that circ_0036627 overexpression was required for the proliferation, migration invasion and GEM resistance in PC cells. circ_0036627 knockdown suppressed tumour development in vivo. The molecular analysis further showed that circ_0036627 increased S100A16 expression by sponging microRNA-145 (miR-145), a tumour-suppressive miRNA that could significantly attenuate PC cell proliferation, migration, invasion and GEM resistance. Furthermore, our findings suggested that S100A16 acted as an oncogenic factor to promote aggressiveness and GEM resistance in PC cells. In conclusion, the current findings provide new mechanistic insights into PC aggressiveness and GEM resistance, suggesting the critical role of circ_0036627/miR-145/S100A16 axis in PC progression and drug resistance development and offering novel therapeutic targets for PC therapy.
Assuntos
Movimento Celular , Proliferação de Células , Desoxicitidina , Resistencia a Medicamentos Antineoplásicos , Gencitabina , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neoplasias Pancreáticas , RNA Circular , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , RNA Circular/genética , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Animais , Movimento Celular/genética , Movimento Celular/efeitos dos fármacos , Masculino , Proteínas S100/genética , Proteínas S100/metabolismo , Camundongos , Feminino , Camundongos Nus , Pessoa de Meia-Idade , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêuticoRESUMO
PURPOSE: Fluoropyrimidine-related toxicity and mortality risk increases significantly in patients carrying certain DPYD genetic variants with standard dosing. We implemented DPYD genotyping at a multisite cancer center and evaluated its impact on dosing, toxicity, and hospitalization. METHODS: In this prospective observational study, patients receiving (reactive) or planning to receive (pretreatment) fluoropyrimidine-based chemotherapy were genotyped for five DPYD variants as standard practice per provider discretion. The primary end point was the proportion of variant carriers receiving fluoropyrimidine modifications. Secondary end points included mean relative dose intensity, fluoropyrimidine-related grade 3+ toxicities, and hospitalizations. Fisher's exact test compared toxicity and hospitalization rates between pretreatment carriers, reactive carriers, and wild-type patients. Univariable and multivariable logistic regression identified factors associated with toxicity and hospitalization risk. Kaplan-Meier methods estimated time to event of first grade 3+ toxicity and hospitalization. RESULTS: Of the 757 patients who received DPYD genotyping (median age 63, 54% male, 74% White, 19% Black, 88% GI malignancy), 45 (5.9%) were heterozygous carriers. Fluoropyrimidine was modified in 93% of carriers who started treatment. In 442 patients with 3-month follow-up, 64%, 31%, and 30% of reactive carriers, pretreatment carriers, and wild-type patients had grade 3+ toxicity, respectively (P = .085); 64%, 25%, and 13% were hospitalized (P < .001). Reactive carriers had 10-fold higher odds of hospitalization compared with wild-type patients (P = .001), whereas no significant difference was noted between pretreatment carriers and wild-type patients. Time-to-event of toxicity and hospitalization were significantly different between genotype groups (P < .001), with reactive carriers having the earliest onset and highest incidence. CONCLUSION: DPYD genotyping prompted fluoropyrimidine modifications in most carriers. Pretreatment testing reduced toxicities and hospitalizations compared with reactive testing, thus normalizing the risk to that of wild-type patients, and should be considered standard practice.
Assuntos
Di-Hidrouracila Desidrogenase (NADP) , Genótipo , Hospitalização , Humanos , Masculino , Feminino , Di-Hidrouracila Desidrogenase (NADP)/genética , Pessoa de Meia-Idade , Hospitalização/estatística & dados numéricos , Estudos Prospectivos , Idoso , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Institutos de Câncer , AdultoRESUMO
BACKGROUND: The early diagnosis of gastric cancer (GC) and overcoming chemotherapy resistance is challenging. The aberrant expression of zinc finger protein 281 (ZNF281) and the over-activation of the Wnt/ß-catenin pathway are oncogenic factors and confer tumor chemoresistance. ZNF281 modulates the Wnt/ß-catenin pathway to influence malignant tumor behavior. However, the role of ZNF281 in GC chemotherapy and the relationship with the Wnt/ß-catenin pathway have not been elucidated by researchers. METHODS: We explored differences in ZNF281 expression in Pan-cancer and normal tissues, the effect of its expression on prognosis of patients treated with 5-fluorouracil (5-FU). Cox regression was utilized to determine whether ZNF281 is an independent prognostic factor. Enrichment analysis was performed to explore the mechanism underlying ZNF281's role in 5-FU treatment. We assessed the relationship between ZNF281 and the tumour microenvironment (TME) and combined bulk-RNA and single-cell RNA data to analyse the relationship between ZNF281 and immune infiltration. In vitro experiments verified the effects of ZNF281 knockdown on proliferation, invasion, migration, apoptosis, DNA damage of GC cells with 5-FU treated and the Wnt/ß-catenin pathway proteins. RESULTS: ZNF281 was highly expressed in seven cancers and correlates with the prognosis. It is an independent prognostic factor in 5-FU treatment. ZNF281 correlates with TME score, CD8T cell abundance. ZNF281 is primarily associated with DNA repair and the Wnt/ß-catenin pathway. ZNF281 knockdown enhanced the effect of 5-FU on phenotypes of GC cells. CONCLUSION: We identified and verified ZNF281 as one of the potential influencing factors of 5-FU treatment in GC and may be associated with the Wnt/ß-catenin pathway. Low ZNF281 may contribute to improved 5-FU sensitivity in GC patients.
Assuntos
Fluoruracila , Neoplasias Gástricas , Via de Sinalização Wnt , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Fluoruracila/uso terapêutico , Fluoruracila/farmacologia , Humanos , Prognóstico , Antimetabólitos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/farmacologia , Proliferação de Células , Linhagem Celular Tumoral , Microambiente Tumoral , Resistencia a Medicamentos Antineoplásicos , Apoptose/efeitos dos fármacos , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Masculino , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genéticaRESUMO
The capacity of T cells to initiate anti-leukemia immune responses is determined by the ability of their receptors (TCRs) to recognize leukemia neoantigens. Epigenetic mechanisms including DNA methylation contribute to shaping the TCR repertoire composition and diversity. The DNA hypomethylating agents (HMAs) have been widely used in the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Whether DNA HMAs directly influence TCR gene loci methylation patterns remains unknown. By analyzing public datasets, we compared methylation patterns across TCR loci in AML patients and healthy controls. We also explored how HMAs influence TCR loci DNA methylation in patients with AML. While methylation patterns are largely conserved across the TCR loci, certain V genes exhibit high interindividual variability. Although overall methylation levels within the TCR loci did not show significant differences, specific sites, including 32 TRAV and 12 TRBV sites exhibited distinct methylation patterns when comparing T cells from healthy donors to those from patients with AML. In leukemic cells, decitabine treatment demethylates sites across the TRAV and TRBV genes. While not as significant, a similar pattern of demethylation is observed in T cells. Pretreatment AML samples exhibit higher methylation beta values in differentially methylated positions (DMPs) compared with non-DMPs. Methylation levels of certain TRAV and TRBV genes in leukemic cells are associated with patients' risk status. The presence of disease specific TCR loci methylated signatures that are associated with clinical outcome presents an opportunity for therapeutic intervention. HMAs can modulate the TCR loci methylation patterns, yet whether they could reprogram the TCR repertoire composition remains to be explored.
Assuntos
Metilação de DNA , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/imunologia , Decitabina/farmacologia , Decitabina/uso terapêutico , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/imunologia , Epigênese Genética , Antimetabólitos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/farmacologiaRESUMO
Gemcitabine (GEM) is widely employed in the treatment of various cancers, including pancreatic cancer. Despite their clinical success, challenges related to GEM resistance and toxicity persist. Therefore, a deeper understanding of its intracellular mechanisms and potential targets is urgently needed. In this study, through mass spectrometry analysis in data-dependent acquisition mode, we carried out quantitative proteomics (three independent replications) and thermal proteome profiling (TPP, two independent replications) on MIA PaCa-2 cells to explore the effects of GEM. Our proteomic analysis revealed that GEM led to the upregulation of the cell cycle and DNA replication proteins. Notably, we observed the upregulation of S-phase kinase-associated protein 2 (SKP2), a cell cycle and chemoresistance regulator. Combining SKP2 inhibition with GEM showed synergistic effects, suggesting SKP2 as a potential target for enhancing the GEM sensitivity. Through TPP, we pinpointed four potential GEM binding targets implicated in tumor development, including in breast and liver cancers, underscoring GEM's broad-spectrum antitumor capabilities. These findings provide valuable insights into GEM's molecular mechanisms and offer potential targets for improving treatment efficacy.
Assuntos
Desoxicitidina , Gencitabina , Proteômica , Proteínas Quinases Associadas a Fase S , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Humanos , Proteômica/métodos , Linhagem Celular Tumoral , Proteínas Quinases Associadas a Fase S/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Regulação para Cima/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
BACKGROUND: Keratoacanthoma (KA) is a benign neoplasm that affects mainly photodamaged skin. It is locally destructive and may rarely spread. Surgery is not always suitable and usually disfiguring. Thus, non-operative modalities represent good alternatives. OBJECTIVE: To assess and compare the efficacy of intralesional methotrexate (MTX) and 5-flurouracil (5-FU) in the treatment of KA. PATIENTS AND METHODS: Randomized controlled trial included 20 patients with biopsy proven KA divided into 2 equal groups; group (A) received intralesional MTX, 25 mg/ml and group (B) received intralesional 5-FU, 50 mg/ml every 2 weeks till complete clearance or for a maximum 5 sessions. RESULTS: In the MTX group, complete clearance was observed in 7 patients (70%) compared to 8 patients (80%) in the 5- FU group with no statistically significant difference. However, the median number of injections needed to achieve complete response in the MTX group was 3 sessions versus only 2 sessions in the 5-FU group. LIMITATIONS: the small sample size due to the relatively low incidence of KAs in our population. CONCLUSION: Intralesional therapy is a good alternative to surgery in selected cases of KA. Both drugs showed comparable efficacy, but 5-FU may give faster results, hence increasing patient satisfaction and compliance.
Assuntos
Fluoruracila , Injeções Intralesionais , Ceratoacantoma , Metotrexato , Humanos , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Ceratoacantoma/tratamento farmacológico , Ceratoacantoma/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Resultado do Tratamento , Adulto , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Idoso de 80 Anos ou maisRESUMO
Pancreatic ductal adenocarcinoma (PDAC)/pancreatic cancer, is a highly aggressive malignancy with poor prognosis. Gemcitabine-based chemotherapy remains the cornerstone of PDAC treatment. Nonetheless, the development of resistance to gemcitabine among patients is a major factor contributing to unfavorable prognostic outcomes. The resistance exhibited by tumors is modulated by a constellation of factors such as genetic mutations, tumor microenvironment transforms, environmental contaminants exposure. Currently, comprehension of the relationship between environmental pollutants and tumor drug resistance remains inadequate. Our study found that PFOS/6:2 Cl-PFESA exposure increases resistance to gemcitabine in PDAC. Subsequent in vivo trials confirmed that exposure to PFOS/6:2 Cl-PFESA reduces gemcitabine's efficacy in suppressing PDAC, with the inhibition rate decreasing from 79.5 % to 56.7 %/38.7 %, respectively. Integrative multi-omics sequencing and molecular biology analyses have identified the upregulation of ribonucleotide reductase catalytic subunit M1 (RRM1) as a critical factor in gemcitabine resistance. Subsequent research has demonstrated that exposure to PFOS and 6:2 Cl-PFESA results in the upregulation of the RRM1 pathway, consequently enhancing chemotherapy resistance. Remarkably, the influence exerted by 6:2 Cl-PFESA exceeds that of PFOS. Despite 6:2 Cl-PFESA being regarded as a safer substitute for PFOS, its pronounced effect on chemotherapeutic resistance in PDAC necessitates a thorough evaluation of its potential risks related to gastrointestinal toxicity.
Assuntos
Ácidos Alcanossulfônicos , Carcinoma Ductal Pancreático , Desoxicitidina , Resistencia a Medicamentos Antineoplásicos , Fluorocarbonos , Gencitabina , Neoplasias Pancreáticas , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Humanos , Fluorocarbonos/toxicidade , Ácidos Alcanossulfônicos/toxicidade , Linhagem Celular Tumoral , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Animais , Ribonucleosídeo Difosfato Redutase , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Antimetabólitos Antineoplásicos/uso terapêutico , Feminino , Camundongos , Masculino , Camundongos NusRESUMO
BACKGROUND: As new treatment options for patients with higher-risk myelodysplastic syndromes are emerging, identification of prognostic markers for hypomethylating agent (HMA) treatment and understanding mechanisms of their delayed and short-term responses are essential. Early fetal hemoglobin (HbF) induction has been suggested as a prognostic indicator for decitabine-treated patients. Although epigenetic mechanisms are assumed, responding patients' epigenomes have not been thoroughly examined. We aimed to clarify HbF kinetics and prognostic value for azacytidine treated patients, as well as the epigenetic landscape that might influence HbF re-expression and its clinical relevance. RESULTS: Serial HbF measurements by high-performance liquid chromatography (n = 20) showed induction of HbF only among responders (p = 0.030). Moreover, HbF increase immediately after the first azacytidine cycle demonstrated prognostic value for progression-free survival (PFS) (p = 0.032, HR = 0.19, CI 0.24-1.63). Changes in methylation patterns were revealed with methylated DNA genome-wide sequencing analysis (n = 7) for FOG-1, RCOR-1, ZBTB7A and genes of the NuRD-complex components. Targeted pyrosequencing methodology (n = 28) revealed a strong inverse correlation between the degree of γ-globin gene (HBG2) promoter methylation and baseline HbF levels (p = 0.003, rs = - 0.663). A potential epigenetic mechanism of HbF re-expression in azacytidine responders was enlightened by targeted methylation analysis, through hypomethylation of site -53 of HBG2 promoter (p = 0.039, rs = - 0.504), which corresponds to MBD2-NuRD binding site, and to hypermethylation of the CpG326 island of ZBTB7A (p = 0.05, rs = 0.482), a known HbF repressor. These changes were associated to blast cell clearance (pHBG2 = 0.011, rs = 0.480/pZBTB7A = 0.026, rs = 0.427) and showed prognostic value for PFS (pZBTB7A = 0.037, HR = 1.14, CI 0.34-3.8). CONCLUSIONS: Early HbF induction is featured as an accessible prognostic indicator for HMA treatment and the proposed potential epigenetic mechanism of HbF re-expression in azacytidine responders includes hypomethylation of the γ-globin gene promoter region and hypermethylation of the CpG326 island of ZBTB7A. The association of these methylation patterns with blast clearance and their prognostic value for PFS paves the way to discuss in-depth azacytidine epigenetic mechanism of action.
Assuntos
Azacitidina , Metilação de DNA , Epigênese Genética , Hemoglobina Fetal , Síndromes Mielodisplásicas , Humanos , Hemoglobina Fetal/genética , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Azacitidina/farmacologia , Feminino , Masculino , Idoso , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/genética , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Prognóstico , Idoso de 80 Anos ou mais , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Antimetabólitos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/farmacologiaRESUMO
Background and purpose: Capecitabine can be used as first-line treatment for advanced breast cancer. However, real-world data on efficacy of capecitabine in this setting is sparse. The purpose of the study is to evaluate outcomes of patients with Human Epidermal Growth Factor Receptor (HER2)-normal advanced breast cancer treated with capecitabine monotherapy as first-line treatment. MATERIAL AND METHODS: The study utilized the Danish Breast Cancer Group (DBCG) database and was conducted retrospectively across all Danish oncology departments. Inclusion criteria were female patients, with HER2-normal advanced breast cancer treated with capecitabine monotherapy as the first-line treatment from 2010 to 2020. The primary endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 494 patients were included. Median OS was 16.4 months (95% confidence interval [CI]: 14.5-18.0), and median PFS was 6.0 months (95% CI: 5.3-6.7). Patients with estrogen receptor (ER)-positive disease had significantly longer OS (median: 22.8 vs. 10.5 months, p < 0.001) and PFS (median: 7.4 vs. 4.9 months, p = 0.003), when compared to ER-negative patients. Stratifying by age, patients under 45 years displayed a median PFS of 4.1 months, while those aged 45-70 years and over 70 years had median PFS of 5.7 and 7.2 months, respectively (p = 0.01). INTERPRETATION: In this nationwide study, the efficacy of capecitabine as a first-line treatment for HER2-normal advanced breast cancer is consistent with other, mainly retrospective, studies. However, when assessed against contemporary and newer treatments, its effectiveness appears inferior to alternative chemotherapies or targeted therapies.