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1.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206129

RESUMO

Endometriosis is a common disease. Its pathogenesis still remains uncertain, but it is clear that cell proliferation, apoptosis and chronic inflammation play an important role in its development. This paper aimed to investigate the anti-proliferative and anti-inflammatory effects of a combined therapy with fotemustine and dexamethasone. Endometriosis was induced by intraperitoneal injections of uterine fragments from donor animals to recipient animals. Next, the pathology was allowed to develop for 7 days. On the seventh day, fotemustine was administered once and dexamethasone was administered daily for the next 7 days. On Day 14, the animals were sacrificed, and peritoneal fluids and lesions were explanted. In order to evaluate the gastrointestinal side effects of the drugs, stomachs were harvested as well. The combined therapy of fotemustine and dexamethasone reduced the proinflammatory mediator levels in the peritoneal fluid and reduced the lesions' area and diameter. In particular, fotemustine and dexamethasone administration reduced the heterogeneous development of endometrial stroma and glands (histological analysis of lesions) and hyperproliferation of endometriotic cells (immunohistochemical analysis of Ki67 and Western blot analysis of PCNA) through the mitogen-activated protein kinase (MAPK) signaling pathway. Combined fotemustine and dexamethasone therapy showed anti-inflammatory effects by inducing the synthesis of anti-inflammatory mediators at the transcriptional and post-transcriptional levels (Western blot analysis of NFκB, COX-2 and PGE2 expression). Fotemustine and dexamethasone administration had anti-apoptotic activity, restoring the impaired mechanism (TUNEL assay and Western blot analysis of Bax and Bcl-2). Moreover, no gastric disfunction was detected (histological analysis of stomachs). Thus, our data showed that the combined therapy of fotemustine and dexamethasone reduced endometriosis-induced inflammation, hyperproliferation and apoptosis resistance.


Assuntos
Dexametasona/farmacologia , Endometriose/tratamento farmacológico , Inflamação/tratamento farmacológico , Compostos de Nitrosoureia/farmacologia , Compostos Organofosforados/farmacologia , Animais , Apoptose/efeitos dos fármacos , Líquido Ascítico/metabolismo , Proliferação de Células/efeitos dos fármacos , Endometriose/complicações , Endometriose/genética , Endometriose/patologia , Endométrio/efeitos dos fármacos , Endométrio/patologia , Feminino , Humanos , Inflamação/complicações , Inflamação/genética , Inflamação/patologia , NF-kappa B/genética , Antígeno Nuclear de Célula em Proliferação/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/genética
2.
Environ Mol Mutagen ; 62(6): 350-363, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34117657

RESUMO

We have used whole genome sequencing (WGS) to determine mutational signatures induced in the T-cells of rats treated in vivo with N-propyl-N-nitrosourea (PNU) or procarbazine (PCZ). The signatures from the treated rats were different from the signature of background mutations. The main component of the spontaneous T-cell mutational signature was C➔T transition with all other single base substitutions evenly distributed. The PNU-induced mutational signature showed relatively equal contributions from C➔T and T➔C transitions, and T➔A transversions. The PCZ-induced signature was characterized by T➔C transitions, T➔A and, to a smaller extent, T➔G transversions. C➔G transversions were infrequent in either the PNU or PCZ signatures. WGS not only allowed mutational signature detection, but also measured quantitative responses to mutagen treatment: 10-40× increases in the number of mutations per clone were detected in T-cell clones from treated rats. The overall strand specificity of induced mutations for annotated rat genes was comparable to the strand specificity of mutations determined previously for the endogenous X-linked Pig-a gene. Our results provide valuable reference data for future applications of WGS in safety research and risk assessment.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Mutação , Compostos de Nitrosoureia/toxicidade , Procarbazina/toxicidade , Linfócitos T/efeitos dos fármacos , Animais , Antineoplásicos/toxicidade , Masculino , Mutagênicos/toxicidade , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Linfócitos T/metabolismo , Linfócitos T/patologia , Sequenciamento Completo do Genoma
3.
Inorg Chem ; 60(11): 7719-7731, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34004115

RESUMO

The non-heme iron-dependent enzyme SznF catalyzes a critical N-nitrosation step during the N-nitrosourea pharmacophore biosynthesis in streptozotocin. The intramolecular oxidative rearrangement process is known to proceed at the FeII-containing active site in the cupin domain of SznF, but its mechanism has not been elucidated to date. In this study, based on the density functional theory calculations, a unique mechanism was proposed for the N-nitrosation reaction catalyzed by SznF in which a four-electron oxidation process is accomplished through a series of complicated electron transferring between the iron center and substrate to bypass the high-valent FeIV═O species. In the catalytic reaction pathway, the O2 binds to the iron center and attacks on the substrate to form the peroxo bridge intermediate by obtaining two electrons from the substrate exclusively. Then, instead of cleaving the peroxo bridge, the Cε-Nω bond of the substrate is homolytically cleaved first to form a carbocation intermediate, which polarizes the peroxo bridge and promotes its heterolysis. After O-O bond cleavage, the following reaction steps proceed effortlessly so that the N-nitrosation is accomplished without NO exchange among reaction species.


Assuntos
Compostos de Nitrosoureia/metabolismo , Ferroproteínas não Heme/metabolismo , Biocatálise , Compostos Ferrosos/química , Compostos Ferrosos/metabolismo , Conformação Molecular , Nitrosação , Compostos de Nitrosoureia/química , Ferroproteínas não Heme/química , Oxirredução , Streptomyces/enzimologia
4.
Radiol Oncol ; 55(3): 347-353, 2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34051707

RESUMO

BACKGROUND: The aim of the study was to evaluate pretreatment inflammatory markers as prognostic factors in patients with unresectable uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion. PATIENTS AND METHODS: 54 patients (44% male, median age: 61 years) were retrospectively assessed. A median of 3 (range: 1-11) treatment sessions were performed with melphalan (92%) or fotemustin (8%). Inflammatory indices were calculated as follows: neutrophils/nl to lymphocytes/nl ratio (NLR), systemic immune-inflammation index ([platelets/nl × neutrophils/nl]/[lymphocytes/nl]; SII), and platelets/nl to lymphocytes/nl ratio (PLR). The cut-off for dichotomization purposes was set at the median (inflammatory indices, hepatic tumor burden) or the upper level of normal. Kaplan Meier analysis was performed for median overall survival (OS) in months, and Cox proportional hazard model for uni(UVA) and multivariate (MVA) hazard ratio (HR, 95%CI) analyses were performed. RESULTS: Median OS of the study cohort was 7.7 (6.3-10.9) months. In UVA OS was prolonged for low C reactive protein (CRP) (13.5 vs. 5.2; p = 0.0005), low SII (10.8 vs. 5.6; p = 0.0005), low NLR (11.1 vs. 6.3; p = 0.0045), low aspartate aminotransferase (AST) (11.5 vs. 5.6; p = 0.015), alanine aminotransferases (ALT) (11.5 vs. 5.6; p = 0.01), and tumor burden ≦ 50% (8.2 vs. 4.8; p = 0.007). MVA confirmed low CRP (HR: 0.29, 0.11-0.7; p = 0.005), low SII (HR: 0.19, 0.11-0.7; p = 0.008), and low ALT (HR: 0.13, 0.02-0.63; p = 0.011) as independent predictors for prolonged OS. Patients with ≦ 1, 2, 3 elevated significant MVA-factors survived a median of 14.9, 7.7, and 3.9 months, respectively (p = 0.0001). CONCLUSIONS: Pretreatment inflammatory markers (CRP, SII) and AST were independent prognostic survival markers in patients with uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion. A combination of factors may help to identify patients potentially benefitting from treatment.


Assuntos
Neoplasias Hepáticas/sangue , Melanoma/sangue , Neoplasias Uveais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Antineoplásicos/uso terapêutico , Aspartato Aminotransferases/sangue , Biomarcadores Tumorais/sangue , Plaquetas/citologia , Proteína C-Reativa/análise , Quimioterapia do Câncer por Perfusão Regional/métodos , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Linfócitos/citologia , Masculino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Melanoma/secundário , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Neutrófilos/citologia , Compostos de Nitrosoureia/uso terapêutico , Compostos Organofosforados/uso terapêutico , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Carga Tumoral , Neoplasias Uveais/sangue
5.
Proc Natl Acad Sci U S A ; 118(4)2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33468680

RESUMO

In biosynthesis of the pancreatic cancer drug streptozotocin, the tridomain nonheme-iron oxygenase SznF hydroxylates N δ and N ω' of N ω-methyl-l-arginine before oxidatively rearranging the triply modified guanidine to the N-methyl-N-nitrosourea pharmacophore. A previously published structure visualized the monoiron cofactor in the enzyme's C-terminal cupin domain, which promotes the final rearrangement, but exhibited disorder and minimal metal occupancy in the site of the proposed diiron cofactor in the N-hydroxylating heme-oxygenase-like (HO-like) central domain. We leveraged our recent observation that the N-oxygenating µ-peroxodiiron(III/III) intermediate can form in the HO-like domain after the apo protein self-assembles its diiron(II/II) cofactor to solve structures of SznF with both of its iron cofactors bound. These structures of a biochemically validated member of the emerging heme-oxygenase-like diiron oxidase and oxygenase (HDO) superfamily with intact diiron cofactor reveal both the large-scale conformational change required to assemble the O2-reactive Fe2(II/II) complex and the structural basis for cofactor instability-a trait shared by the other validated HDOs. During cofactor (dis)assembly, a ligand-harboring core helix dynamically (un)folds. The diiron cofactor also coordinates an unanticipated Glu ligand contributed by an auxiliary helix implicated in substrate binding by docking and molecular dynamics simulations. The additional carboxylate ligand is conserved in another N-oxygenating HDO but not in two HDOs that cleave carbon-hydrogen and carbon-carbon bonds to install olefins. Among ∼9,600 sequences identified bioinformatically as members of the emerging HDO superfamily, ∼25% conserve this additional carboxylate residue and are thus tentatively assigned as N-oxygenases.


Assuntos
Heme Oxigenase (Desciclizante)/ultraestrutura , Ferroproteínas não Heme/ultraestrutura , Oxigenases/ultraestrutura , Estreptozocina/química , Catálise/efeitos dos fármacos , Cristalografia por Raios X , Heme Oxigenase (Desciclizante)/química , Humanos , Ligantes , Compostos de Nitrosoureia/toxicidade , Ferroproteínas não Heme/química , Oxirredução , Oxigênio/química , Oxigenases/química , Neoplasias Pancreáticas/induzido quimicamente , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/patologia , Conformação Proteica/efeitos dos fármacos , Domínios Proteicos/genética , Estreptozocina/toxicidade
6.
J Enzyme Inhib Med Chem ; 36(1): 362-371, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33356659

RESUMO

One of the systems responsible for maintaining cellular redox homeostasis is the thioredoxin-dependent system. An equally important function of this system is the regulation of the expression of many proteins by the transcription factor NF-κB or the apoptosis regulating kinase (ASK-1). Since it has been shown that the Trx-dependent system can contribute to both the enhancement of tumour angiogenesis and growth as well as apoptosis of neoplastic cells, the search for compounds that inhibit the level/activity of Trx and/or TrxR and thus modulate the course of the neoplastic process is ongoing. It has been shown that many naturally occurring polyphenolic compounds inactivate elements of the thioredoxin system. In addition, the effectiveness of Trx is inhibited by imidazole derivatives, while the activity of TrxR is reduced by transition metal ions complexes, dinitrohalobenzene derivatives, Michael acceptors, nitrosourea and ebselen. In addition, research is ongoing to identify new selective Trx/TrxR inhibitors.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Tiorredoxina Dissulfeto Redutase/genética , Tiorredoxinas/genética , Antineoplásicos/síntese química , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Inibidores Enzimáticos/síntese química , Regulação Neoplásica da Expressão Gênica , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Imidazóis/química , Imidazóis/farmacologia , Isoindóis/química , Isoindóis/farmacologia , MAP Quinase Quinase Quinase 5/genética , MAP Quinase Quinase Quinase 5/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/patologia , Neovascularização Patológica/enzimologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Compostos de Nitrosoureia/química , Compostos de Nitrosoureia/farmacologia , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Oxirredução , Transdução de Sinais , Relação Estrutura-Atividade , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/metabolismo , Tiorredoxinas/antagonistas & inibidores , Tiorredoxinas/metabolismo
7.
Sci Total Environ ; 761: 143300, 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33243502

RESUMO

N-nitroso compounds form from the interaction between nitrosatable precursors and nitrite under acidic conditions. A majority of N-nitroso compounds tested show evidence of carcinogenicity in animal models. Formation of N-nitroso compounds may occur from exposure to precursors in drinking water, but the extent of formation depends on a number of factors, including concentration of substrates, presence of catalysts and inhibitors, and pH. The objective of this study was to examine these factors in pesticide-associated N-nitroso (PANN) compound formation in drinking water. In preliminary screening experiments, nine nitrosatable pesticides and degradation products were individually reacted at environmentally-relevant concentrations (≤ 20 µg L--1) with sodium nitrite (NaNO2) and hydrochloric acid (HCl) in ultra-pure water. Only ethylenethiourea (ETU) showed evidence of PANN compound formation in initial experiments and was further tested for N-nitrosoethylenethiourea (N-ETU) formation in a pooled groundwater sample (comprised of five tap water samples combined into one homogenous sample) collected from an agricultural region of Prince Edward Island in Canada, where nitrate contamination is a known concern. Evidence of N-ETU formation in the groundwater sample was observed within 30 min at concentrations 7.5, 10, and 20 µg L-1. Analysis of target compounds and semi-target PANN compounds was performed using ultra-high pressure liquid chromatography coupled with high resolution orbital ion trap mass spectrometry. These preliminary experiments serve to inform about potential PANN compound formation in groundwater. The results of this study suggest that ETU is capable of forming potentially carcinogenic N-ETU in water containing nitrite/nitrate at trace concentrations under acidic conditions. Thus, these findings suggest that N-ETU formation may be a concern for individuals exposed to low concentrations of ETU in groundwater.


Assuntos
Etilenotioureia , Água Subterrânea , Animais , Canadá , Humanos , Compostos de Nitrosoureia
8.
Gan To Kagaku Ryoho ; 47(10): 1477-1480, 2020 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-33130744

RESUMO

The patient was a 56-year-old woman. A modified LSG15(VCAP-AMP-VECP)regimen was initiated as the first-line treatment for acute adult T-cell leukemia/lymphoma. On day 13 from the initiation of the second course of chemotherapy, the onset of hand-foot syndrome(HFS)(hands: Grade 2; feet: Grade 1)occurred. Therefore, the administration of a heparin analog cream and betamethasone butyrate propionate ointment was initiated. On day 20 from the start of the second course of chemotherapy, the foot symptoms improved; however, hand symptoms deteriorated to Grade 3. Frequent use of alcohol-based hand hygiene products is associated with infection prevention during neutropenia, but was likely an exacerbating factor. The symptoms gradually improved after this was taken into consideration, and the usage was discontinued. At the start of the third course, the symptoms had improved to Grade 1, and chemotherapy was continued. On day 11, symptoms worsened(Grade 2). HFS management was performed similar to that in the second course, and symptoms improved again.


Assuntos
Síndrome Mão-Pé , Leucemia-Linfoma de Células T do Adulto , Linfoma , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina , Ciclofosfamida , Doxorrubicina , Etoposídeo , Feminino , Síndrome Mão-Pé/etiologia , Humanos , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Pessoa de Meia-Idade , Compostos de Nitrosoureia , Prednisolona , Vincristina , Vindesina
9.
Cancer Sci ; 111(12): 4567-4580, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32976684

RESUMO

Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm and is classified into four subtypes (acute, lymphoma, chronic, and smoldering) according to the Shimoyama classification, established in 1991 through several nationwide surveys based on the clinical diversity of patients diagnosed in 1983-1987 in Japan. Thereafter, no such studies have been conducted. Recently, we conducted a nationwide hospital survey using the method of the 1980s studies, collected baseline data on 996 ATL patients diagnosed in 2010-2011 from 126 hospitals, and reported their unique epidemiological characteristics. Here, we report the follow-up results of registered ATL patients with the goal of evaluating current prognoses and treatment modalities as of 2016-2017. Of 770 evaluable patients, 391 (50.8%) had acute-type, 192 (24.9%) had lymphoma-type, 106 (13.8%) had chronic-type, and 81 (10.5%) had smoldering-type ATL. The initial therapy regimens used for acute/lymphoma-type ATL were vincristine, cyclophosphamide, doxorubicin and prednisone, followed by doxorubicin, ranimustine, and prednisone and then by vindesine, etoposide, carboplatin, and prednisone (VCAP-AMP-VECP)-like in 38.5/41.7% and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like in 14.6/13.7% of patients. Allogeneic hematopoietic stem cell transplantation was used to treat 15.9/10.4% of acute/lymphoma-type ATL patients. The 4-year survival rates (the median survival time, days) for acute-, lymphoma-, unfavorable chronic-, favorable chronic-, and smoldering-type ATL were 16.8% (252), 19.6% (305), 26.6% (572), 62.1% (1937), and 59.8% (1851), respectively. The 4-year survival rates for acute- and lymphoma-type ATL improved compared with those reported in 1991, but those for chronic- and smoldering-type ATL were not. Further efforts are warranted to develop more efficient therapeutic strategies to improve the prognosis of ATL in Japan.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma de Células T do Adulto/mortalidade , Leucemia-Linfoma de Células T do Adulto/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Causas de Morte , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Pesquisas sobre Serviços de Saúde/estatística & dados numéricos , Hospitais/estatística & dados numéricos , Humanos , Japão/epidemiologia , Leucemia-Linfoma de Células T do Adulto/sangue , Leucemia-Linfoma de Células T do Adulto/classificação , Masculino , Pessoa de Meia-Idade , Compostos de Nitrosoureia/administração & dosagem , Prednisona/administração & dosagem , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Vincristina/administração & dosagem , Vindesina/administração & dosagem
10.
Environ Mol Mutagen ; 61(8): 797-806, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32729949

RESUMO

Procarbazine (PCZ) and N-propyl-N-nitrosourea (PNU) are rodent mutagens and carcinogens. Both induce GPI-anchored marker-deficient mutant-phenotype red blood cells (RBCs) in the flow cytometry-based rat RBC Pig-a assay. In the present study, we traced the origin of the RBC mutant phenotype by analyzing Pig-a mutations in the precursors of RBCs, bone marrow erythroid cells (BMEs). Rats were exposed to a total of 450 mg/kg PCZ hydrochloride or 300 mg/kg PNU, and bone marrow was collected 2, 7, and 10 weeks later. Using a flow cell sorter, we isolated CD59-deficient mutant-phenotype BMEs from PCZ- and PNU-treated rats and examined their endogenous X-linked Pig-a gene by next generation sequencing. Pig-a mutations consistent with the properties of PCZ and PNU were found in sorted mutant-phenotype BMEs. PCZ induced mainly A > T transversions with the mutated A on the nontranscribed strand of the Pig-a gene, while PNU induced mainly T > A transversions with the mutated T on the nontranscribed strand. The treatment-induced mutations were distributed across the protein coding sequence of the Pig-a gene. The causal relationship between BMEs and RBCs and the agent-specific mutational spectra in CD59-deicient BMEs indicate that the rat RBC Pig-a assay, scoring CD59-deficient mutant-phenotype RBCs in peripheral blood, detects Pig-a gene mutation.


Assuntos
Antineoplásicos/toxicidade , Células da Medula Óssea/efeitos dos fármacos , Antígenos CD59/genética , Proteínas de Membrana/genética , Mutação , Compostos de Nitrosoureia/toxicidade , Procarbazina/toxicidade , Animais , Células da Medula Óssea/imunologia , Masculino , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley
11.
Int J Mol Sci ; 21(14)2020 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-32664581

RESUMO

Glioblastoma multiforme (GBM) is a severe brain tumor whose ability to mutate and adapt to therapies is at the base for the extremely poor survival rate of patients. Despite multiple efforts to develop alternative forms of treatment, advances have been disappointing and GBM remains an arduous tumor to treat. One of the leading causes for its strong resistance is the innate upregulation of DNA repair mechanisms. Since standard therapy consists of a combinatory use of ionizing radiation and alkylating drugs, which both damage DNA, targeting the DNA damage response (DDR) is proving to be a beneficial strategy to sensitize tumor cells to treatment. In this review, we will discuss how recent progress in the availability of the DDR kinase inhibitors will be key for future therapy development. Further, we will examine the principal existing DDR inhibitors, with special focus on those currently in use for GBM clinical trials.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Reparo do DNA , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Glioblastoma/tratamento farmacológico , Terapia de Alvo Molecular , Antineoplásicos/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Ensaios Clínicos Fase I como Assunto , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Quebras de DNA de Cadeia Simples/efeitos dos fármacos , Dano ao DNA , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/genética , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Proteína Quinase Ativada por DNA/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/uso terapêutico , Glioblastoma/genética , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Compostos de Nitrosoureia/farmacologia , Compostos de Nitrosoureia/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Temozolomida/farmacologia , Temozolomida/uso terapêutico
12.
Oncogene ; 39(32): 5468-5478, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32616888

RESUMO

Melanoma stem cells (MSCs) are characterized by their unique cell surface proteins and aberrant signaling pathways. These stemness properties are either in a causal or consequential relationship to melanoma progression, treatment resistance and recurrence. The functional analysis of CD133+ and CD133- cells in vitro and in vivo revealed that melanoma progression and treatment resistance are the consequences of CD133 signal to PI3K pathway. CD133 signal to PI3K pathway drives two downstream pathways, the PI3K/Akt/MDM2 and the PI3K/Akt/MKP-1 pathways. Activation of PI3K/Akt/MDM2 pathway results in the destabilization of p53 protein, while the activation of PI3K/Akt/MKP-1 pathway results in the inhibition of mitogen-activated protein kinases (MAPKs) JNK and p38. Activation of both pathways leads to the inhibition of fotemustine-induced apoptosis. Thus, the disruption of CD133 signal to PI3K pathway is essential to overcome Melanoma resistance to fotemustine. The pre-clinical verification of in vitro data using xenograft mouse model of MSCs confirmed the clinical relevance of CD133 signal as a therapeutic target for melanoma treatment. In conclusion, our study provides an insight into the mechanisms regulating MSCs growth and chemo-resistance and suggested a clinically relevant approach for melanoma treatment.


Assuntos
Antígeno AC133/metabolismo , Melanoma/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Células-Tronco/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Fosfatase 1 de Especificidade Dupla/metabolismo , Humanos , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Compostos de Nitrosoureia/farmacologia , Compostos Organofosforados/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transdução de Sinais , Células-Tronco/efeitos dos fármacos , Células-Tronco/patologia
13.
J Am Chem Soc ; 142(27): 11818-11828, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32511919

RESUMO

The alkylating warhead of the pancreatic cancer drug streptozotocin (SZN) contains an N-nitrosourea moiety constructed from Nω-methyl-l-arginine (l-NMA) by the multi-domain metalloenzyme SznF. The enzyme's central heme-oxygenase-like (HO-like) domain sequentially hydroxylates Nδ and Nω' of l-NMA. Its C-terminal cupin domain then rearranges the triply modified arginine to Nδ-hydroxy-Nω-methyl-Nω-nitroso-l-citrulline, the proposed donor of the functional pharmacophore. Here we show that the HO-like domain of SznF can bind Fe(II) and use it to capture O2, forming a peroxo-Fe2(III/III) intermediate. This intermediate has absorption- and Mössbauer-spectroscopic features similar to those of complexes previously trapped in ferritin-like diiron oxidases and oxygenases (FDOs) and, more recently, the HO-like fatty acid oxidase UndA. The SznF peroxo-Fe2(III/III) complex is an intermediate in both hydroxylation steps, as shown by the concentration-dependent acceleration of its decay upon exposure to either l-NMA or Nδ-hydroxy-Nω-methyl-l-Arg (l-HMA). The Fe2(III/III) cluster produced upon decay of the intermediate has a small Mössbauer quadrupole splitting parameter, implying that, unlike the corresponding product states of many FDOs, it lacks an oxo-bridge. The subsequent decomposition of the product cluster to one or more paramagnetic Fe(III) species over several hours explains why SznF was previously purified and crystallographically characterized without its cofactor. Programmed instability of the oxidized form of the cofactor appears to be a unifying characteristic of the emerging superfamily of HO-like diiron oxidases and oxygenases (HDOs).


Assuntos
Proteínas de Bactérias/metabolismo , Compostos Férricos/metabolismo , Metaloproteínas/metabolismo , Compostos de Nitrosoureia/metabolismo , Estreptozocina/biossíntese , Proteínas de Bactérias/química , Proteínas de Bactérias/isolamento & purificação , Compostos Férricos/química , Hidroxilação , Metaloproteínas/química , Metaloproteínas/isolamento & purificação , Modelos Moleculares , Estrutura Molecular , Compostos de Nitrosoureia/química , Streptomyces/enzimologia , Estreptozocina/química
14.
Int J Hematol ; 111(3): 434-439, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31834619

RESUMO

The outcome of relapsed/refractory HIV-associated lymphoma remains poor, even in the era of combined antiretroviral therapy. However, recent reports showed the efficacy of autologous stem cell transplantation (ASCT). We conducted a single-arm, multicenter phase II study in patients with relapsed/refractory HIV-associated lymphoma to assess the safety and efficacy of ASCT. The study included 14 patients with relapsed/refractory HIV-associated lymphoma. Five patients who achieved partial remission or better after the standard salvage regimen proceeded to ASCT. Conditioning treatment involved ranimustine (300 mg/m2) on day - 6, etoposide (200 mg/m2) on days - 5 to - 3, cytarabine (200 mg/m2) on days - 5 to - 3, and L-PAM (140 mg/m2) on day - 2. All patients achieved engraftment and were alive on day 100 of ASCT. One-year and 2-year overall survival rates were both 40% and 1-year and 2-year progression-free survival rates were both 40%. Grade 2 or 3 diarrhea and oral mucositis were observed in 43% of patients. Cytomegalovirus antigenemia, retinitis, and bacterial infections were noted in 43%, 29%, and 29% of patients, respectively. Therapy-related death was not observed. Although the number of enrolled patients was insufficient for statistical analysis. ASCT was feasible and safe for relapsed/refractory HIV-associated lymphoma.Registration: This study is registered in UMIN-CTR (UMIN000003159).


Assuntos
Linfoma Relacionado a AIDS/terapia , Transplante de Células-Tronco de Sangue Periférico , Transplante Autólogo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/administração & dosagem , Etoposídeo/administração & dosagem , Estudos de Viabilidade , Humanos , Linfoma Relacionado a AIDS/mortalidade , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Compostos de Nitrosoureia/administração & dosagem , Segurança , Taxa de Sobrevida
15.
Eur J Cancer ; 123: 58-71, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31670077

RESUMO

BACKGROUND: Although a myriad of novel treatments entered the treatment paradigm for advanced melanoma, there is lack of head-to-head evidence. We conducted a network meta-analysis (NMA) to estimate each treatment's relative effectiveness and safety. METHODS: A systematic literature review (SLR) was conducted in Embase, MEDLINE and Cochrane to identify all phase III randomised controlled trials (RCTs) with a time frame from January 1, 2010 to March 11, 2019. We retrieved evidence on treatment-related grade III/IV adverse events, progression-free survival (PFS) and overall survival (OS). Evidence was synthesised using a Bayesian fixed-effect NMA. Reference treatment was dacarbazine. In accordance with RCTs, dacarbazine was pooled with temozolomide, paclitaxel and paclitaxel plus carboplatin. To increase homogeneity of the study populations, RCTs were only included if patients were not previously treated with novel treatments. RESULTS: The SLR identified 28 phase III RCTs involving 14,376 patients. Nineteen and seventeen treatments were included in the effectiveness and safety NMA, respectively. For PFS, dabrafenib plus trametinib (hazard ratio [HR] PFS: 0.21) and vemurafenib plus cobimetinib (HR PFS: 0.22) were identified as most favourable treatments. Both had, however, less favourable safety profiles. Five other treatments closely followed (dabrafenib [HR PFS: 0.30], nivolumab plus ipilimumab [HR PFS: 0.34], vemurafenib [HR PFS: 0.38], nivolumab [HR PFS: 0.42] and pembrolizumab [HR PFS: 0.46]). In contrast, for OS, nivolumab plus ipilimumab (HR OS: 0.39), nivolumab (HR OS: 0.46) and pembrolizumab (HR OS: 0.50) were more favourable than dabrafenib plus trametinib (HR OS: 0.55) and vemurafenib plus cobimetinib (HR OS: 0.57). CONCLUSIONS: Our NMA identified the most effective treatment options for advanced melanoma and provided valuable insights into each novel treatment's relative effectiveness and safety. This information may facilitate evidence-based decision-making and may support the optimisation of treatment and outcomes in everyday clinical practice.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/administração & dosagem , Azetidinas/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/uso terapêutico , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Dacarbazina/administração & dosagem , Dacarbazina/uso terapêutico , Humanos , Hidrazinas/administração & dosagem , Hidrazinas/uso terapêutico , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Interleucina-2/administração & dosagem , Interleucina-2/uso terapêutico , Ipilimumab/administração & dosagem , Ipilimumab/uso terapêutico , Lenalidomida/administração & dosagem , Lenalidomida/uso terapêutico , Melanoma/imunologia , Melanoma/patologia , Metanálise em Rede , Compostos de Nitrosoureia/administração & dosagem , Compostos de Nitrosoureia/uso terapêutico , Nivolumabe/administração & dosagem , Nivolumabe/uso terapêutico , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/uso terapêutico , Oximas/administração & dosagem , Oximas/uso terapêutico , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Pirimidinonas/administração & dosagem , Pirimidinonas/uso terapêutico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Sorafenibe/administração & dosagem , Sorafenibe/uso terapêutico , Taxa de Sobrevida , Temozolomida/administração & dosagem , Temozolomida/uso terapêutico , Resultado do Tratamento
16.
East Mediterr Health J ; 25(7): 481-494, 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31612980

RESUMO

Background: For metastatic colorectal cancer a series of novel therapies has emerged during the last decade but their use in routine clinical practice and their costs are not well documented. Aims: This study evaluated the clinical effectiveness of metastatic colorectal cancer patients in Lebanese oncologic units and estimated the costs. Methods: A prospective cohort study was conducted on metastatic colorectal cancer patients during 2008-2013. The type of medical management, overall survival and total costs from diagnosis to death were described. Cost analysis was performed using tariffs from 2013 in US dollars. Results: One hundred and seventy-nine metastatic patients were selected among which 84.9% had colorectal cancer involvement. The average follow-up from diagnosis until death or the latest news was 34.8 months. Around 49.7% were still alive at last follow-up date. Three lines of treatment accounted for 4.5%, 39.6% and 55.9% with an average duration of 14.5, 11.4 and 14.6 months respectively. A 73.2% of patients benefited from targeted therapy. The median overall survival was 20.8 months. The mean total costs of drugs was $22 256 in patients with standard therapy alone whereas the cost increased to $80 396 after the addition of targeted therapy. The mean global total cost was estimated at $64 805 per patient (min $3703; max $304 086). Conclusions: Targeted therapy associated to standard therapy is highly prevalent in Lebanon in metastatic disease and the associated medical cost substantial. This study is the first to show the clinical effectiveness and costs of targeted therapy in patients with metastatic colorectal cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Produtos Biológicos/economia , Produtos Biológicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Idoso , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Custos e Análise de Custo , Feminino , Humanos , Líbano , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos de Nitrosoureia , Estudos Prospectivos , Proteínas Proto-Oncogênicas p21(ras)/genética
17.
CNS Oncol ; 8(2): CNS32, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31290692

RESUMO

Aim: To assess the efficacy and safety of alternative fotemustine administration schedule in elderly patients with recurrent glioblastoma. Patients & methods: Patients aged >65 years with recurrent glioblastoma received fotemustine (80 mg/m2; days 1, 15, 30, 45 and 60, and subsequently every 4 weeks). Primary end point was progression-free survival (PFS) rate at 6 months. Main secondary end point was safety. Results: 58 patients were enrolled at two centers. PFS at 6 months was 47% (27 patients) and overall response rate was 29%. Median PFS and survival were 6 and 7 months, respectively, and longer in responders versus nonresponders. No grade 3-4 hematological toxicities occurred. Conclusion: The alternative fotemustine administration schedule was an effective and safe treatment for recurrent glioblastoma in elderly patients.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Compostos de Nitrosoureia/administração & dosagem , Compostos Organofosforados/administração & dosagem , Fatores Etários , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Compostos de Nitrosoureia/efeitos adversos , Compostos Organofosforados/efeitos adversos , Medição de Risco , Taxa de Sobrevida
18.
Transl Res ; 212: 26-35, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31153896

RESUMO

The role of adhesion G protein-coupled receptors (aGPCRs) in cancer has become increasingly evident in recent years. Yet, data supporting the contribution of this family of genes to hematological malignancies, particularly acute myeloid leukemia (AML) are limited. Here, we use publicly available genomic data to characterize the expression of the 33 aGPCRs in patients with AML and examine whether upregulation of these genes is associated with the clinical and molecular characteristics of patients. Upregulation in one or more of eight aGPCR genes (ADGRB1, ADGRC2, ADGRD1, ADGRE1, ADGRE2, ADGRE5, ADGRG1, and/or ADGRG3) was significantly associated with shorter overall survival (OS) (median OS: 11.8 vs 55.4 months; P < 0.0001). This was also significant in multivariate survival analysis (hazard ratio: 1.73; 95% confidence interval 1.11-2.69; P = 0.015) after adjusting for age, molecular risk status, and transplant status. High expression of the eight aGPCRs was significantly associated with older age (≥60; P = 0.011). Patients with high aGPCRs expression were more frequently classified in the poor molecular risk status group and less in the good risk status group compared with patients with low aGPCRs expression (31% vs 17% P = 0.049 and 14% vs 28% P = 0.027, respectively). Via Ingenuity Pathway Analysis, we identified the interleukin-8 signaling pathway among the most activated pathways in patients with high aGPCRs expression. Overall, our data suggest that particular aGPCRs are frequently upregulated in AML and associated with poor clinical outcome. Future functional and mechanistic analyses are needed to address the role of aGPCRs in AML.


Assuntos
Leucemia Mieloide Aguda/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Adesão Celular , Bases de Dados Genéticas , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Nitrosoureia , Receptores Acoplados a Proteínas G/genética , Regulação para Cima
19.
DNA Repair (Amst) ; 78: 128-141, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31039537

RESUMO

Alkylating agents have been used since the 60ties in brain cancer chemotherapy. Their target is the DNA and, although the DNA of normal and cancer cells is damaged unselectively, they exert tumor-specific killing effects because of downregulation of some DNA repair activities in cancer cells. Agents exhibiting methylating properties (temozolomide, procarbazine, dacarbazine, streptozotocine) induce at least 12 different DNA lesions. These are repaired by damage reversal mechanisms involving the alkyltransferase MGMT and the alkB homologous protein ALKBH2, and through base excision repair (BER). There is a strong correlation between the MGMT expression level and therapeutic response in high-grade malignant glioma, supporting the notion that O6-methylguanine and, for nitrosoureas, O6-chloroethylguanine are the most relevant toxic damages at therapeutically relevant doses. Since MGMT has a significant impact on the outcome of anti-cancer therapy, it is a predictive marker of the effectiveness of methylating anticancer drugs, and clinical trials are underway aimed at assessing the influence of MGMT inhibition on the therapeutic success. Other DNA repair factors involved in methylating drug resistance are mismatch repair, DNA double-strand break (DSB) repair by homologous recombination (HR) and DSB signaling. Base excision repair and ALKBH2 might also contribute to alkylating drug resistance and their downregulation may have an impact on drug sensitivity notably in cells expressing a high amount of MGMT and at high doses of temozolomide, but the importance in a therapeutic setting remains to be shown. MGMT is frequently downregulated in cancer cells (up to 40% in glioblastomas), which is due to CpG promoter methylation. Astrocytoma (grade III) are frequently mutated in isocitrate dehydrogenase (IDH1). These tumors show a surprisingly good therapeutic response. IDH1 mutation has an impact on ALKBH2 activity thus influencing DNA repair. A master switch between survival and death is p53, which often retains transactivation activity (wildtype) in malignant glioma. The role of p53 in regulating survival via DNA repair and the routes of death are discussed and conclusions as to cancer therapeutic options were drawn.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Reparo do DNA/efeitos dos fármacos , Compostos de Nitrosoureia/farmacologia , Medicina de Precisão/métodos , Temozolomida/farmacologia , Neoplasias Encefálicas/patologia , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Humanos , Compostos de Nitrosoureia/uso terapêutico , Temozolomida/uso terapêutico
20.
Nature ; 566(7742): 94-99, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30728519

RESUMO

Small molecules containing the N-nitroso group, such as the bacterial natural product streptozotocin, are prominent carcinogens1,2 and important cancer chemotherapeutics3,4. Despite the considerable importance of this functional group to human health, enzymes dedicated to the assembly of the N-nitroso unit have not been identified. Here we show that SznF, a metalloenzyme from the biosynthesis of streptozotocin, catalyses an oxidative rearrangement of the guanidine group of Nω-methyl-L-arginine to generate an N-nitrosourea product. Structural characterization and mutagenesis of SznF reveal two separate active sites that promote distinct steps in this transformation using different iron-containing metallocofactors. This biosynthetic reaction, which has little precedent in enzymology or organic synthesis, expands the catalytic capabilities of non-haem-iron-dependent enzymes to include N-N bond formation. We find that biosynthetic gene clusters that encode SznF homologues are widely distributed among bacteria-including environmental organisms, plant symbionts and human pathogens-which suggests an unexpectedly diverse and uncharacterized microbial reservoir of bioactive N-nitroso metabolites.


Assuntos
Metaloproteínas/metabolismo , Estreptozocina/biossíntese , Estreptozocina/química , Arginina/análogos & derivados , Domínio Catalítico/genética , Coenzimas/metabolismo , Cristalografia por Raios X , Guanidina/metabolismo , Ferro/metabolismo , Metaloproteínas/química , Metaloproteínas/genética , Modelos Moleculares , Família Multigênica , Compostos de Nitrosoureia/metabolismo , Streptomyces/enzimologia , Streptomyces/genética
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