RESUMO
Recent advancements in comprehending peripheral T-cell lymphomas (PTCLs) validate and broaden our perspective, highlighting their diverse nature and the varying molecular mechanisms underlying the entities. Based on a comprehensive accumulated understanding, the PTCLs currently overcome the most challenging features of any disease: rarity, incredible heterogeneity, and a lack of any established standard of care. The treatments deployed in the front-line are extrapolated from regimens developed for other diseases. The recent approval of the three drugs brentuximab vedotin (BV), pralatrexate, and belinostat for patients with relapsed or refractory disease has provided clues about pathophysiology and future directions, though challenges satisfying post-marketing requirements (PMR) for those accelerated approvals have led to one of those drugs being withdrawn and put the other two in jeopardy. Edits of the front-line regimens, often called CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-plus approaches, look more like CHOP-minus strategies, as the toxicity of five-drug regimens often reduces the dose intensity of the added 'novel' drug, nullifying any hope of an advance. The turmoil in the field produced by the aforementioned, coupled with an ever-changing classification, has left the field uncertain about the path forward. Despite these challenges, empiric findings from studies of novel drug approaches, coupled with a logic emerging from studies of PTCL lymphomagenesis, have begun to illuminate, albeit faintly for some, a potential direction. The empiric finding that drugs targeting the discrete components of the PTCL epigenome, coupled with the description of multiple mutations in genes that govern epigenetic biology, offers, at the very least, an opportunity to finally be hypothesis-driven. The most recent recognition that the only combination of drugs shown to markedly improve progression-free survival (PFS) in patients with relapsed disease is one based on dual targeting of different and discrete components of that epigenetic biology has established a possibility that circumnavigating chemotherapy addition studies is both plausible, feasible, and likely the best prospect for a quantum advance in this disease. Herein, we analyze PTCL through a 2025 lens, highlighting and underscoring walls that have impeded progress. We will critically explore all the clues and the panoramic view of PTCL research.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Brentuximab Vedotin , Linfoma de Células T Periférico , Humanos , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/genética , Brentuximab Vedotin/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aminopterina/análogos & derivados , Aminopterina/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Sulfonamidas/uso terapêutico , Ciclofosfamida/uso terapêutico , Vincristina/uso terapêutico , Doxorrubicina/uso terapêuticoRESUMO
ABSTRACT: Patients with relapsed or refractory (R/R) mature natural killer cell and T-cell lymphoma have limited treatment options. To evaluate pralatrexate's performance and factors influencing its safety and efficacy in R/R peripheral T-cell lymphoma (PTCL), we performed a pooled analysis of data from 4 similarly designed, regulatory-mandated prospective clinical trials. Of 221 patients (median age, 59 years; 67.0% male) in the study population, 48.9% had PTCL not otherwise specified (PTCL-NOS), 21.3% angioimmunoblastic T-cell lymphoma, and 11.8% ALK-negative anaplastic large cell lymphoma (ALCL). Patients received pralatrexate for a median of 2.56 months (range, 0.03-24.18) and had a 40.7% objective response rate with a median duration of response of 9.1 months, progression-free survival 4.6 months, and overall survival 16.3 months. The most common treatment-related all-grade adverse events were stomatitis, thrombocytopenia, white blood cell count decrease, pyrexia, and vomiting. Subgroup exploratory analyses suggest improved efficacy with 1 prior line of chemotherapy vs 2 or ≥4 prior lines; PTCL-NOS or ALCL vs transformed mycosis fungoides; chemotherapy and transplant before pralatrexate vs chemotherapy alone or chemotherapy with other nontransplant treatments. In conclusion, these pooled analysis results further support using pralatrexate in patients with R/R PTCL. Prospective studies are needed to confirm the findings of subgroups analyses.
Assuntos
Aminopterina , Linfoma de Células T Periférico , Humanos , Aminopterina/análogos & derivados , Aminopterina/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Pessoa de Meia-Idade , Masculino , Feminino , Idoso , Adulto , Idoso de 80 Anos ou mais , Resultado do Tratamento , Recidiva , Adulto JovemRESUMO
Previously, we conducted a Phase I study of the combination of pralatrexate and romidepsin in patients with relapsed/refractory (R/R) lymphomas and subsequently conducted a multicenter Phase II study in patients with untreated or R/R mature T cell lymphomas (MTCL). Patients received pralatrexate 25 mg/m2 and romidepsin 12 mg/m2 every 2 weeks. Fourteen patients were evaluable for efficacy. Overall response rate was 35.7% with CR in 14.3% and disease control in 50%. The mDOR was 8.2 months, mPFS was 3.6 months, and mOS was 20.2 months. Gastrointestinal side effects were most common in up to 33%; there was only one hematologic toxicity of grade 3 anemia. Combining results of MTCL patients from the Phase I and II studies (N = 28), the ORR was 53.5% with CR in 21.4%, disease control in67.8%, and DOR of 7.2 months. The combination was safe however does not out-perform other combination strategies.Trial Registration: www.clinicaltrials.gov (NCT01947140).
Assuntos
Aminopterina , Protocolos de Quimioterapia Combinada Antineoplásica , Depsipeptídeos , Inibidores de Histona Desacetilases , Linfoma de Células T , Humanos , Aminopterina/análogos & derivados , Aminopterina/uso terapêutico , Aminopterina/administração & dosagem , Aminopterina/efeitos adversos , Depsipeptídeos/administração & dosagem , Depsipeptídeos/efeitos adversos , Depsipeptídeos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/patologia , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/administração & dosagem , Resultado do Tratamento , Antagonistas do Ácido Fólico/uso terapêutico , Antagonistas do Ácido Fólico/efeitos adversos , Antagonistas do Ácido Fólico/administração & dosagem , Idoso de 80 Anos ou maisRESUMO
Varicella zoster virus (VZV) is associated with herpes zoster (HZ) or herpes zoster ophthalmicus (HZO). All antiviral agents currently licensed for the management of VZV replication via modulating different mechanisms, and the resistance is on the rise. There is a need to develop new antiviral agents with distinct mechanisms of action and adequate safety profiles. Pralatrexate (PDX) is a fourth-generation anti-folate agent with an inhibitory activity on folate (FA) metabolism and has been used as an anti-tumor drug. We observed that PDX possessed potent inhibitory activity against VZV infection. In this study, we reported the antiviral effects and the underlying mechanism of PDX against VZV infection. The results showed that PDX not only inhibited VZV replication in vitro and in mice corneal tissues but also reduced the inflammatory response and apoptosis induced by viral infection. Furthermore, PDX treatment showed a similar anti-VSV inhibitory effect in both in vitro and in vivo models. Mechanistically, PDX inhibited viral replication by interrupting the substrate supply for de novo purine and thymidine synthesis. In conclusion, this study discovered the potent antiviral activity of PDX with a novel mechanism and presented a new strategy for VZV treatment that targets a cellular metabolic mechanism essential for viral replication. The present study provided a new insight into the development of broad-spectrum antiviral agents.
Assuntos
Aminopterina/análogos & derivados , Herpes Zoster , Estomatite Vesicular , Animais , Camundongos , Herpesvirus Humano 3 , Estomatite Vesicular/tratamento farmacológico , Herpes Zoster/tratamento farmacológico , Vírus da Estomatite Vesicular Indiana , Vesiculovirus , Antivirais/farmacologia , Antivirais/uso terapêutico , Replicação ViralRESUMO
Folic acid was reported to significantly improve chondrogenic differentiation of mesenchymal stem cells. In a similar mechanism of action, we investigated clinically approved antifolates by the U.S. Food and Drug Administration as chondrogenic-promoting compounds for tonsil-derived mesenchymal stem cells. A poly(ethylene glycol)-poly(l-alanine) thermogelling system was used as a three-dimensional cell culture matrix, where stem cells and antifolates could be incorporated simultaneously during a heat-induced in situ sol-to-gel transition. The antifolates could be supplied over several days by the sustained release of the drug from the thermogel. Initially, seven antifolates were prescreened based on cell viability and expression of a typical chondrogenic biomarker of type II collagen (COL II) at the mRNA level. Then, dapsone, pralatrexate, and trimethoprim were selected as candidate compounds in the second round screening, and detailed studies were carried out on the mRNA and protein expression of various chondrogenic biomarkers including COL II, SRY box transcription factor 9, and aggrecan. Three-dimensional cultures of stem cells in the thermogel in the absence of a chondrogenic promoter compound and in the presence of kartogenin (KGN) were performed as a negative control and positive control, respectively. The chondrogenic biomarkers were significantly increased in the selected antifolate-incorporating systems compared to the negative control system, without an increase in type I collagen (an osteogenic biomarker) expression. Pralatrexate was the best compound for inducing chondrogenic differentiation of the stem cells, even better than the positive control (KGN). Nuclear translocation of the core-binding factor ß subunit (CBFß) and enhanced nuclear runt-related transcription factor 1 (RUNX1) by antifolate treatment suggested that the chondrogenesis-enhancing mechanism is mediated by CBFß and RUNX1. An in silico modeling study confirmed the mechanism by proving the high binding affinity of pralatrexate to a target protein of filamin A compared with other antifolate candidates. To conclude, pralatrexate was rediscovered as a lead compound, and the polypeptide thermogel incorporating pralatrexate and mesenchymal stem cells can be a very effective system in promoting chondrogenic differentiation of stem cells and might be used in injectable tissue engineering for cartilage repair.
Assuntos
Aminopterina/análogos & derivados , Materiais Biocompatíveis/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Peptídeos/química , Temperatura , Aminopterina/química , Aminopterina/farmacologia , Materiais Biocompatíveis/química , Diferenciação Celular/efeitos dos fármacos , Condrogênese/efeitos dos fármacos , Géis/química , Humanos , Teste de MateriaisRESUMO
PURPOSE: Pralatrexate is a new generation antifolate treatment agent used for the treatment of relapsed or refractory peripheral T-cell lymphomas. This study aims to determine the general characteristics of the patients receiving pralatrexate therapy in Turkey, contributing to the literature on the effectiveness of pralatrexate therapy in peripheral T-cell lymphomas by determining the response levels of such patients to the therapy. The study also attempts to clinically examine the major side effects observed in patients during treatment with pralatrexate. METHODS: The study included patients with peripheral T-cell lymphoma followed up in the hematology units of several hospitals in Turkey. Overall, 20 patients aged 18 and over were included in the study. RESULTS: The median age at the time of diagnosis was 58.5 years. PTCL-NOS (Peripheral T-cell lymphoma, not otherwise specified) subtype was in 40% of patients, making the PTCL-NOS the most common subtype in the study. In general, most patients were diagnosed with disease at an advanced stage. Pralatrexate therapy was given to the patients at a median treatment line of 3.5. Pralatrexate dose reduction was required in only 3 patients (15%). Response to pralatrexate therapy with partial remission (PR) and above was observed in 11 (55%) of the patients. CONCLUSION: Pralatrexate seemed to be a promising novel treatment in relapsed refractory PTCL patients. However, patients receiving pralatrexate should be followed up carefully for skin reactions, mucosal side effects, thrombocytopenia and neutropenia.
Assuntos
Aminopterina/análogos & derivados , Linfoma de Células T Periférico/tratamento farmacológico , Aminopterina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , TurquiaRESUMO
Heart diseases are known as the most primary causes of mortality worldwide. Although many therapeutic approaches and medications are proposed for these diseases, the identification of novel therapeutics in fatal heart conditions is promptly demanded. Besides, the interplay between gene expression data and molecular docking provides several novel insights to discover more effective and specific drugs for the treatment of the diseases. This study aimed to discover potent therapeutic drugs in the heart diseases based on the expression profile of heart-specific genes exclusively. Initially, the heart-specific and highly expressed genes were identified by comparing the gene expression profile of different body tissues. Subsequently, the druggable-genes were identified using in silico techniques. The interaction between these druggable genes with more than 1600 FDA approved drugs was then investigated using the molecular docking simulation. By comprehensively analyzing RNA-sequencing data obtained from 949 normal tissue samples, 48 heart-specific genes were identified in both the heart development and function. Notably, of these, 24 heart-specific genes were capable to be considered as druggable genes, among which only MYBPC3, MYLK3, and SCN5A genes entered the molecular docking process due to their functions. Afterward, the pharmacokinetics properties of top 10 ligands with the highest binding affinity for these proteins were studied. Accordingly, methylergonovine, fosaprepitant, pralatrexate, daunorubicin, glecaprevir, digoxin, and venetoclax drugs were competent, in order to interact with the target proteins perfectly. It was shown that these medications can be used as specific drugs for the treatment of heart diseases after fulfilling further experiments in this regard.
Assuntos
Cardiopatias/tratamento farmacológico , Simulação de Acoplamento Molecular , Ácidos Aminoisobutíricos/uso terapêutico , Aminopterina/análogos & derivados , Aminopterina/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Ciclopropanos/uso terapêutico , Daunorrubicina/uso terapêutico , Digoxina/uso terapêutico , Reposicionamento de Medicamentos , Expressão Gênica , Cardiopatias/genética , Humanos , Lactamas Macrocíclicas/uso terapêutico , Leucina/análogos & derivados , Leucina/uso terapêutico , Ligantes , Metilergonovina/uso terapêutico , Morfolinas/uso terapêutico , Prolina/análogos & derivados , Prolina/uso terapêutico , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêuticoRESUMO
BACKGROUND: Pralatrexate (PDX) is a novel antifolate approved for the treatment of patients with relapsed/refractory peripheral T-cell lymphoma, but some patients exhibit intrinsic resistance or develop acquired resistance. Here, we evaluated the mechanisms underlying acquired resistance to PDX and explored potential therapeutic strategies to overcome PDX resistance. METHODS: To investigate PDX resistance, we established two PDX-resistant T-lymphoblastic leukemia cell lines (CEM and MOLT4) through continuous exposure to increasing doses of PDX. The resistance mechanisms were evaluated by measuring PDX uptake, apoptosis induction and folate metabolism-related protein expression. We also applied gene expression analysis and methylation profiling to identify the mechanisms of resistance. We then explored rational drug combinations using a spheroid (3D)-culture assay. RESULTS: Compared with their parental cells, PDX-resistant cells exhibited a 30-fold increase in half-maximal inhibitory concentration values. Induction of apoptosis by PDX was significantly decreased in both PDX-resistant cell lines. Intracellular uptake of [14C]-PDX decreased in PDX-resistant CEM cells but not in PDX-resistant MOLT4 cells. There was no significant change in expression of dihydrofolate reductase (DHFR) or folylpolyglutamate synthetase (FPGS). Gene expression array analysis revealed that DNA-methyltransferase 3ß (DNMT3B) expression was significantly elevated in both cell lines. Gene set enrichment analysis revealed that adipogenesis and mTORC1 signaling pathways were commonly upregulated in both resistant cell lines. Moreover, CpG island hypermethylation was observed in both PDX resistant cells lines. In the 3D-culture assay, decitabine (DAC) plus PDX showed synergistic effects in PDX-resistant cell lines compared with parental lines. CONCLUSIONS: The resistance mechanisms of PDX were associated with reduced cellular uptake of PDX and/or overexpression of DNMT3B. Epigenetic alterations were also considered to play a role in the resistance mechanism. The combination of DAC and PDX exhibited synergistic activity, and thus, this approach might improve the clinical efficacy of PDX.
Assuntos
Aminopterina/análogos & derivados , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Antagonistas do Ácido Fólico/farmacologia , Aminopterina/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Biomarcadores , Metilação de DNA , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica , Humanos , Células Tumorais CultivadasRESUMO
We report the case of a 59-year-old woman with stage IV erythrodermic mycosis fungoides (MF) and large cell transformation who, despite failing multiple previous treatments, achieved complete remission through a combination of pralatrexate and romidepsin followed by allogeneic hematopoietic stem cell transplantation (alloSCT). Further studies are needed in focussing on this combined regimen in treating cutaneous T-cell lymphoma (CTCL) and its efficacy as a bridging regimen in facilitating successful alloSCT.
Assuntos
Aminopterina/análogos & derivados , Antibióticos Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Micose Fungoide/terapia , Neoplasias Cutâneas/terapia , Aminopterina/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Micose Fungoide/patologia , Indução de Remissão , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
In this study, a series of green, interference-free fluorimetric detection methods of the excitation-emission matrix coupled with the second-order calibration methods were proposed for the determination of ibrutinib and pralatrexate in various complicated biological fluids. The second-order advantage of the proposed method can overcome the problem of poor selectivity caused by the wide spectra of the fluorescence method. Even in the presence of uncalibrated interferences and severe peak overlap, the signal of pure substance and accurate quantitative results were still obtained. The average recoveries of the three methods were 94.5-104.9% for Alternating Trilinear Decomposition (ATLD) algorithm, 95.5-105.8% for Alternating Normalization Weighted Error (ANWE) algorithm and 94.4-105.7% for Parallel Factor Analysis (PARAFAC) algorithm, respectively. For ATLD, ANWE and PARAFAC, the relative standard deviations (RSD) were lower than 9.2%, 6.8% and 9.2%, and the RMSEPs were less than 8.1, 8.4 and 8.6 ng mL-1, respectively. In addition, the elliptic joint confidence region (EJCR) was adopted to further prove the accuracy of the three methods. The results showed that the three methods can accurately be quantified without significant difference. Good figures of merit parameters were also obtained. Among them, the limit of detection (LOD) and limit of quantification (LOQ) of ibrutinib and pralatrexate were in the range of 0.11-0.76 ng mL-1 and 0.21-1.12 ng mL-1, respectively, which were lower than the corresponding blood concentrations. These results indicate that the proposed method provides a promising, alternative and universal analysis strategy for clinical drug monitoring.
Assuntos
Algoritmos , Aminopterina/análogos & derivados , Fluorometria , Adenina/análogos & derivados , Calibragem , Limite de Detecção , Piperidinas , Espectrometria de FluorescênciaRESUMO
Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of pralatrexate to treat advanced-stage cutaneous T-cell lymphomas, but outcomes in Japanese patients have not yet been reported. We herein describe two Japanese patients with heavily-pretreated relapsed/refractory mycosis fungoides that were successfully controlled by pralatrexate.
Assuntos
Micose Fungoide , Neoplasias Cutâneas , Aminopterina/análogos & derivados , Humanos , Japão , Micose Fungoide/tratamento farmacológico , Recidiva Local de Neoplasia , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
We present a retrospective multicenter study of pralatrexate treatment outcomes in an Australian practice setting for patients with relapsed/refractory T-cell lymphoma who had failed 1+ systemic therapies, treated via a compassionate access program. Endpoints assessed included response rates, toxicities, and subsequent therapies. Progression-free survival (PFS), time to next treatment (TTNT), event-free survival (EFS), overall survival (OS), and time to best response, were assessed by Kaplan-Meier analysis. The study included 31 patients, with median age 69 years. We demonstrated ORR of 35.5% (n = 11), including 4 complete responses (13%) and 7 partial responses (23%). The predicted median OS was 10 months, with EFS of 9 months, and PFS of 9 months. Median TTNT was 8 months. Mucositis was the most commonly observed toxicity. This study - the second largest real-world cohort reported to date - underscores the importance of pralatrexate in relapsed/refractory T-cell lymphoma, as well as its acceptable toxicity profile.
Assuntos
Linfoma de Células T , Recidiva Local de Neoplasia , Idoso , Aminopterina/análogos & derivados , Austrália/epidemiologia , Humanos , Linfoma de Células T/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus poses serious threats to the global public health and leads to worldwide crisis. No effective drug or vaccine is readily available. The viral RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target. A hybrid drug screening procedure was proposed and applied to identify potential drug candidates targeting RdRp from 1906 approved drugs. Among the four selected market available drug candidates, Pralatrexate and Azithromycin were confirmed to effectively inhibit SARS-CoV-2 replication in vitro with EC50 values of 0.008µM and 9.453 µM, respectively. For the first time, our study discovered that Pralatrexate is able to potently inhibit SARS-CoV-2 replication with a stronger inhibitory activity than Remdesivir within the same experimental conditions. The paper demonstrates the feasibility of fast and accurate anti-viral drug screening for inhibitors of SARS-CoV-2 and provides potential therapeutic agents against COVID-19.
Assuntos
Aminopterina/análogos & derivados , Antivirais/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Reposicionamento de Medicamentos , RNA Polimerase Dependente de RNA/antagonistas & inibidores , SARS-CoV-2/fisiologia , Aminopterina/química , Aminopterina/farmacologia , Animais , Azitromicina/química , Azitromicina/farmacologia , Chlorocebus aethiops , Simulação por Computador , Aprendizado Profundo , Simulação de Dinâmica Molecular , RNA Polimerase Dependente de RNA/química , Células Vero , Replicação Viral/efeitos dos fármacos , Tratamento Farmacológico da COVID-19RESUMO
BACKGROUND: Patients with relapsed or refractory peripheral T-cell lymphoma (R/R PTCL) treated with pralatrexate have previously shown superior overall survival (OS) compared to those who underwent conventional chemotherapy (CC, 15.4 vs. 4.07 months). We conducted an economic evaluation of pralatrexate from a societal perspective in Korea based on data from the PROPEL phase II study. METHODS: Using a Markov model with a weekly cycle, we simulated the experience of patients with R/R PTCL receiving pralatrexate or CC for 15 years. The model consists of five health states; initial treatment, treatment pause, subsequent treatment, stem cell transplantation (SCT) success, and death. Comparative effectiveness was based on PROPEL phase II single-arm study and its matched historical control analysis. Costs included drug, drug administration, monitoring, adverse event management, and SCT costs. RESULTS: The incremental cost-effectiveness ratio of the base case was $39,153 per quality-adjusted life-year (QALY) gained. The results of one-way sensitivity analysis ranged from $33,949 to $51,846 per QALY gained, which remained within an implicit willingness-to-pay (WTP) threshold of anticancer drugs in Korea. CONCLUSIONS: Pralatrexate is a cost-effective intervention with improved OS and incremental costs within the WTP limit. Pralatrexate could function as a new therapeutic option for patients suffering from life-threatening R/R PTCL.
Assuntos
Aminopterina/análogos & derivados , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/economia , Aminopterina/economia , Aminopterina/farmacologia , Aminopterina/uso terapêutico , Estudos de Casos e Controles , Análise Custo-Benefício , Feminino , Humanos , Masculino , Recidiva Local de NeoplasiaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Linfoma de Células T/patologia , Neoplasias Esplênicas/patologia , Adolescente , Aminopterina/administração & dosagem , Aminopterina/análogos & derivados , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Linfoma de Células T/tratamento farmacológico , Prednisona/administração & dosagem , Prognóstico , Neoplasias Esplênicas/tratamento farmacológicoRESUMO
While pralatrexate (PDX) has been successfully developed for the treatment of T-cell lymphoma, the mechanistic basis for its T-cell selectivity and acquired resistance remains elusive. In an effort to potentially identify synergistic combinations that might circumnavigate or delay acquired PDX resistance, we generated resistant cells lines over a broad concentration range. PDX-resistant cell lines H9-12 and H9-200 were developed, each exhibiting an IC50 of 35 and over 1000 nM, respectively. These lines were established in vitro from parental H9 cells. Expression analysis of the proteins known to be important determinants of antifolate pharmacology revealed increase expression of dihydrofolate reductase (DHFR) due to gene amplification, and reduced folate carrier1 downregulation, as the putative mechanisms of resistance in H9-12 and H9-200 cells. Cross resistance was only seen with methotrexate but not with romidepsin, azacitidine (AZA), decitabine, gemcitabine, doxorubicin, or bortezomib. Resistance to PDX was reversed by pretreatment with hypomethylating agents in a concentration-dependent fashion. Comparison of gene expression profiles of parental and resistant cell lines confirmed markedly different patterns of gene expression, and identified the dual specificity phosphatase four (DUSP4) as one of the molecular target of PDX activity. Reduced STAT5 phosphorylation following exposure to PDX was observed in the H9 but not in the H9-12 and H9-200 cells. These data suggest that combination with hypomethylating agents could be potent, and that DUSP4 and STAT5 could represent putative biomarkers of PDX activity.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética , Linfoma de Células T/genética , Aminopterina/análogos & derivados , Aminopterina/toxicidade , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Metilação de DNA , Fosfatases de Especificidade Dupla/metabolismo , Humanos , Concentração Inibidora 50 , Linfoma de Células T/metabolismo , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo , Fator de Transcrição STAT5/metabolismoAssuntos
Linfadenopatia Imunoblástica , Linfoma de Células T , Aminopterina/efeitos adversos , Aminopterina/análogos & derivados , Humanos , Linfadenopatia Imunoblástica/diagnóstico , Linfadenopatia Imunoblástica/tratamento farmacológico , Linfoma de Células T/diagnóstico , Linfoma de Células T/tratamento farmacológicoRESUMO
Angioimmunoblastic T-cell lymphoma (AITL) is a histological subtype of peripheral T-cell lymphoma associated with a poor prognosis. This post-hoc pooled analysis aims to provide insight about the efficacy of pralatrexate monotherapy in a subset of twenty-nine patients with relapsed or refractory (r/r) AITL drawn from two prospective registration trials completed in China and Japan. After a median of two prior lines of therapy, an overall response rate of 52% (15/29 patients; 95% CI 0.34, 0.70) was demonstrated. The estimated median duration of response, progression free survival (PFS) and overall survival (OS) were 6.4 months (196 days), 5.0 months (151 days), and 18.0 months (548 days), respectively. Grades 1-3 mucositis was observed in twenty-three patients (79.3%); and hemato-toxicity in twenty-six (89.7%) patients. Results of this analysis corroborate with data from two previously reported US retrospective cohorts, supporting the potential benefits of pralatrexate monotherapy in patients with r/r AITL.
Assuntos
Linfoma de Células T Periférico , Recidiva Local de Neoplasia , Aminopterina/análogos & derivados , China , Humanos , Japão , Linfoma de Células T Periférico/tratamento farmacológico , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Pralatrexate(PDX)has been approved for the treatment of relapsed/refractory peripheral T-cell lymphoma(PTCL), including angioimmunoblastic T-cell lymphoma(AITL). Oral mucositis is the most common and severe adverse effect of PDX that often leads to dose reduction or omission. Herein, we report a 65-year-old man with AITL, who received PDX treatment after a second relapse. This drug was effective; however, the adverse effects, such as oral mucositis, were severe. Therefore, leucovorin(LV)was administered to prevent the adverse effect, resulting in continuation of the PDX treatment for 8 months. LV administration minimizes adverse effects for patients receiving high-dose methotrexate. However, the optimal dose and schedule of LV in PDX treatment has not yet been established. In the future, clinical trials on the use of LV for PDX-induced oral mucositis are needed.