RESUMO
Shwachman-Diamond syndrome (SDS) is an autosomal recessive inherited disorder characterized by bone marrow failure, exocrine pancreatic dysfunction, and skeletal abnormalities. SDS is typically caused by a pathogenic mutation in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. Patients with SDS have an increased risk of developing acute myeloid leukemia (AML) and myelodysplastic syndromes. We identified germline biallelic SBDS mutations (p.K62X and p.I167M) in a 50-year-old AML patient who had never experienced the typical symptoms of SDS. The K62X mutation is one of the most common pathogenic mutations, whereas the significance of the I167M mutation was unclear. Based on cellular experiments, we concluded that the I167M mutation contributed to the development of AML, and chemotherapy including topoisomerase inhibitors, which induce DNA double-strand breaks, may have been toxic to this patient. Our experience indicates that some asymptomatic Shwachman-Bodian-Diamond syndrome mutations contribute to the development of leukemia, and that careful treatment selection may be warranted for patients harboring these mutations.
Assuntos
Mutação em Linhagem Germinativa/genética , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/genética , Proteínas/genética , Síndrome de Shwachman-Diamond/genética , DNA/metabolismo , Reparo do DNA/efeitos dos fármacos , Feminino , Genes Recessivos/genética , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/etiologia , Síndrome de Shwachman-Diamond/complicações , Inibidores da Topoisomerase/efeitos adversosRESUMO
BACKGROUND/AIM: Although there are many reports of anticancer drug-induced neurotoxicity, most previous data have been derived from neuronal cell models grown in a variety of culture conditions. This has prevented accurate assessment of the potency of their neurotoxicity and of changes in drug sensitivity of neuronal cells during differentiation. In this study, a simple neuronal differentiation induction system was established and the relative potency of neurotoxicity of eight anticancer drugs was compared during neuronal cell differentiation. MATERIALS AND METHODS: Rat PC12 cells were induced to differentiate into neuronal cells by 50 ng/ml nerve growth factor in serum-free Dulbecco's modified Eagle's medium, followed by overlay of fresh nutrients at day 3, without medium change. Cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. RESULTS: During differentiation, PC12 cells became 1.1-to more than 10,000-fold resistant to anticancer drugs. Topoisomerase inhibitors (doxorubicin, SN-38, etoposide) were the most toxic to differentiated PC12 cells, followed by docetaxel, gefitinib, melphalan, 5-fluorouracil and methotrexate. Docetaxel showed the highest cytotoxicity against undifferentiated PC12 cells, but its cytotoxicity was dramatically reduced during differentiation. CONCLUSION: The present study demonstrated considerable variation in the neurotoxicity of anticancer drugs during the cell differentiation process. The present simple assay system may be useful to search for neuroprotective substances.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neurônios/efeitos dos fármacos , Inibidores da Topoisomerase/efeitos adversos , Animais , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Etoposídeo/efeitos adversos , Etoposídeo/farmacologia , Humanos , Irinotecano , Neoplasias/patologia , Células PC12 , Ratos , Inibidores da Topoisomerase/uso terapêuticoRESUMO
INTRODUCTION: Acute myeloid leukemia (AML) represents a disease with a very poor outcome and remains an area of significant unmet need necessitating novel therapeutic strategies. Among novel therapeutic agents, vosaroxin is a first-in-class anticancer quinolone derivative that targets topoisomerase II and induces site-selective double-strand breaks in DNA, leading to tumor cell apoptosis. Areas covered: Herein, the authors provide a comprehensive review of the preclinical development of vosaroxin. This includes coverage of vosaroxin's mechanism of action in addition to its pharmacology and of the main studies reported over the past few years with vosaroxin when used to treat adult AML. Expert opinion: Given that vosaroxin is associated with fewer potential side effects, it may be of benefit to elderly patients with relapsed/refractory AML and to those with additional comorbidities who have previously received an anthracycline and cytarabine combination. Furthermore, vosaroxin also was seen to be active in multidrug-resistant preclinical models. However, further studies have to be performed to better evaluate its place in the armamentarium against AML.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Naftiridinas/uso terapêutico , Tiazóis/uso terapêutico , Adulto , Idoso , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Mieloide Aguda/patologia , Naftiridinas/efeitos adversos , Naftiridinas/farmacologia , Tiazóis/efeitos adversos , Tiazóis/farmacologia , Inibidores da Topoisomerase/efeitos adversos , Inibidores da Topoisomerase/farmacologia , Inibidores da Topoisomerase/uso terapêuticoRESUMO
Anthracycline (ANT) is a topoisomerase-interacting agent that is used in most malignancy treatments. We investigated the efficacy of enalapril (angiotensin-converting enzyme inhibitor) in the prevention of ANT-induced cardiomyopathy. In this randomized, single-blind, and placebo-controlled study, 69 patients with a newly diagnosed malignancy for which ANT therapy was planned were randomly assigned to either a group receiving enalapril (n = 34) or placebo (n = 35). Echocardiography studies were performed before chemotherapy and at 6 months after randomization. Additionally, troponin I and creatinine kinase-MB (CK-MB) were measured 1 month after the initiation of chemotherapy. In the enalapril group, the mean left ventricular ejection fraction (LVEF) (p = 0.58) was the same at baseline and 6 months after randomization. Conversely, LVEF significantly decreased in the control group (p < 0.001). Additionally, LV end systolic volume and left atrial diameter were significantly increased compared with the baseline measures in the control group. According to the tissue Doppler study, the mitral annuli early diastolic (e') and peak systolic (s') velocities were significantly reduced, and the E (the peak early diastolic velocity)/e' ratio was significantly increased in the control group. Furthermore, the TnI and CK-MB levels were significantly higher in the control group than in the enalapril group. Enalapril appears efficacious in preserving systolic and diastolic function in cancer patients treated with ANTs.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Cardiomiopatias/prevenção & controle , Enalapril/uso terapêutico , Inibidores da Topoisomerase/efeitos adversos , Disfunção Ventricular Esquerda/prevenção & controle , Adulto , Biomarcadores/sangue , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/fisiopatologia , Cardiotoxicidade , Creatina Quinase Forma MB/sangue , Citoproteção , Ecocardiografia Doppler , Feminino , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/efeitos dos fármacos , Método Simples-Cego , Volume Sistólico/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento , Troponina I/sangue , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Traditional chemotherapies, interleukins, phosphorylase inhibitors, and proteasome inhibitors are important therapies available to patients with cutaneous T-cell lymphoma (CTCL). Traditional chemotherapies, both in combination and as single agents, are commonly used in relapsed, refractory CTCLs that behave in an aggressive manner. Interleukins, phosphorylase inhibitors, and proteasome inhibitors are less commonly used but data support a role in patients with more refractory disease.
Assuntos
Antineoplásicos/uso terapêutico , Linfoma Cutâneo de Células T/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/classificação , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Interleucinas/efeitos adversos , Interleucinas/uso terapêutico , Micose Fungoide/tratamento farmacológico , Inibidores de Proteassoma/efeitos adversos , Inibidores de Proteassoma/uso terapêutico , Síndrome de Sézary/tratamento farmacológico , Inibidores da Topoisomerase/efeitos adversos , Inibidores da Topoisomerase/uso terapêuticoRESUMO
Nogitecan hydrochloride(topotecan)has shown efficacy in patients with recurrent ovarian cancer, but has not been used widely in Japan. We evaluated the efficacy and adverse effects of topotecan in 12 patients (median age, 62 years) treated for recurrent ovarian cancer between 2000 and 2013. Four patients had relapsed after primary treatment, and 8 had relapsed at least twice. Seven patients had been treated with more than 3 prior regimens. Initial treatment of the 12 patients consisted of intravenous topotecan (1.0-1.4 mg/m2/day) for 5 consecutive days. Initial doses were based on previous chemotherapy and/ or renal function, with reduced doses administered to patients with severe adverse effects during prior courses of treatment. The 12 patients received a total of 54 courses of topotecan(range, 1-15 courses). Of these 12 patients, one achieved a partial response and 6 had stable disease. The median time to progression was 14.4 weeks. All 12 patients had grade 3-4 myelosuppression, while none had febrile neutropenia or severe non-hematologic toxicities. Patients who received higher doses or increased courses of chemotherapy had apparently more severe adverse events. These findings suggested that topotecan should be used as a second- or third-line treatment, rather than later, in patients with tumor recurrence, with its dose reduced according to the physical status of each patient. Such strategies may enhance both the efficacy and safety of topotecan in patients with recurrent ovarian cancer.
Assuntos
Neoplasias Ovarianas/tratamento farmacológico , Inibidores da Topoisomerase/uso terapêutico , Topotecan/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Recidiva , Tomografia Computadorizada por Raios X , Inibidores da Topoisomerase/efeitos adversos , Topotecan/efeitos adversos , Resultado do TratamentoRESUMO
In genetic toxicology, risk assessment has traditionally adopted linear dose-responses for any compound that causes genotoxic effects. Increasing evidence of non-linear dose-responses, however, suggests potential cellular tolerance to low levels of many genotoxicants with diverse modes of action. Such putative non-linear dose-responses need to be substantiated by strong mechanistic data that identifies the mechanisms responsible for the tolerance to low doses. This can be achieved by experimental demonstration of cytoprotective mechanisms and by providing experimental support for the existence of tolerance mechanisms against low dose effects. By highlighting key experiments into low dose mechanisms, this review aims to clarify which mechanistic data are required to support the use of non-linear dose-response models in risk assessment. Such key experiments are presented and discussed for alkylating agents, oxidants, particulate matter, nucleoside analogues, topoisomerase inhibitors and aneugens and exemplify the use of gene knockout models or transgenic models as well as chemical modulators of key effectors of relevant pathways and their impact on dose-response relationships. In vitro studies are particularly valuable to elucidate mechanisms of low-dose protection or lack thereof, while in vivo experiments are most appropriate for deriving a safe dose. In order to evaluate the existence of non-linear dose-response relationships for genotoxicants, we suggest that careful attention should be given to the mode of genotoxic action, relevant biomarkers of exposure, as well as to the existence and impact of potential cytoprotective mechanisms like detoxifying metabolism and DNA repair.
Assuntos
Dano ao DNA , Testes de Mutagenicidade/métodos , Mutagênicos/efeitos adversos , Alquilantes/toxicidade , Aneugênicos/efeitos adversos , Animais , Relação Dose-Resposta a Droga , Humanos , Modelos Químicos , Nucleosídeos/efeitos adversos , Oxidantes/efeitos adversos , Material Particulado/efeitos adversos , Medição de Risco , Inibidores da Topoisomerase/efeitos adversosRESUMO
Therapy-related myeloid neoplasms (t-MN) are a complication of cytotoxic treatment for primary tumors and autoimmune diseases. We report data on 277 t-MN patients, recruited between 1999 and 2013 by the Italian Network on Secondary Leukemias (104 retrospectively and 173 prospectively registered). Median age at t-MN diagnosis was 64 years (range, 21-87). Most frequent primary malignancies (PMs) were lymphoproliferative diseases and breast cancer. One hundred and thirty-three patients had received chemotherapy (CHT), 43 patients radiotherapy (RT), and 101 patients combined CHT/RT for PM. Median time between cytotoxic treatment and t-MN was 5.7 years, with t-MN following RT alone associated with significantly longer latency, compared to CHT or combined CHT/RT (mean, 11.2 vs. 7.1 years, P = 0.0005). The addition of topoisomerase-II inhibitors to alkylating agents was associated with shorter latency compared to alkylating agents alone (median, 6 vs. 8.4 years, P = 0.02). Median survival was 14.6 months from t-MN diagnosis, and was significantly longer in patients treated with allogeneic stem cell transplantation. Significant factors for survival at the multivariable analysis included age, adverse karyotype, and degree of anemia. Our data underline the prognostic importance of karyotype and age in t-MN, similar to de novo acute myeloid leukemia. Treatment approaches should not preclude the use of conventional treatments for younger t-MN patients, including allogeneic stem cell transplantation as potentially curative approach.
Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Raios gama/efeitos adversos , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/diagnóstico , Inibidores da Topoisomerase/efeitos adversos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anemia/genética , Anemia/mortalidade , Anemia/patologia , Anemia/terapia , Antineoplásicos Alquilantes/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Feminino , Humanos , Cariótipo , Leucemia Mieloide Aguda/induzido quimicamente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/mortalidade , Transtornos Linfoproliferativos/patologia , Transtornos Linfoproliferativos/terapia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida , Inibidores da Topoisomerase/administração & dosagem , Transplante HomólogoRESUMO
Drug-induced liver injury (DILI) due to chemotherapeutic drugs is a significant cause of morbidity and mortality. Most cases of chemotherapy-induced hepatotoxicity are idiosyncratic and do not have a unique clinical or histological signature that is distinct from other agents that cause DILI. The major mechanisms underlying chemotherapy-related hepatotoxicity are based on the production of reactive metabolites generated by phase I oxidation reactions, immunological injury, or alterations in mitochondrial function. Underlying liver disease and hepatic involvement by tumor are important modifiers of liver injury, and reversibility is not universal after drug cessation. Chemotherapy can also exacerbate underlying liver disease, particularly hepatitis B, leading to worsening hepatic function. Diagnosing DILI due to chemotherapeutic agents is particularly challenging because competing etiologies, such as hepatotoxicity from other medications, opportunistic infections, radiation therapy, and pre-existing liver disease, are frequent.
Assuntos
Antineoplásicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Inibidores de Proteínas Quinases/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Antimetabólitos Antineoplásicos/efeitos adversos , Antineoplásicos/metabolismo , Antineoplásicos Alquilantes/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Humanos , Compostos de Platina/efeitos adversos , Taxoides/efeitos adversos , Inibidores da Topoisomerase/efeitos adversosRESUMO
Rearrangements of the MLL gene involve multiple partners and are implicated in both therapy related acute leukemia [tAL] and infant acute leukemia. For these diseases, recently compiled clinical data confirms an elevated frequency of such breakpoints within a 4 kb tract between exon 11 and a region of structural instability adjacent to exon 12. Linked primarily to cases of tAL, interference with topoisomerase II activity may either contribute to the initial DNA lesion directly or indirectly by, for example, providing a physical block to transcription progression. Alternatively, sites of fragmentation may be mis-repaired, guided by intergenic spliced transcripts of the participating genes. Co-transcription of MLL and potential fusion partners may provide the localization that enhances the probability of gene interaction. An indirect role for the leukemogenic activity of topoisomerase II inhibitors would imply that the negative consequences of their use may be separated from their therapeutic effects.
Assuntos
Regulação Leucêmica da Expressão Gênica , Leucemia Aguda Bifenotípica/genética , Proteína de Leucina Linfoide-Mieloide/genética , Segunda Neoplasia Primária/genética , Proteínas de Fusão Oncogênica/genética , Adulto , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/metabolismo , Epistasia Genética , Éxons , Histona-Lisina N-Metiltransferase , Humanos , Lactente , Íntrons , Leucemia Aguda Bifenotípica/metabolismo , Leucemia Aguda Bifenotípica/patologia , Proteína de Leucina Linfoide-Mieloide/metabolismo , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/patologia , Proteínas de Fusão Oncogênica/metabolismo , Inibidores da Topoisomerase/efeitos adversos , Translocação GenéticaRESUMO
Genomic characterization of translocation breakpoints is relevant to identify possible mechanisms underlying their origin. The consistent association of anthracylines (e.g., epirubicin and idarubicin) in inducing therapy-related acute leukemias (t-AL) with mixed lineage leukemia (MLL) gene rearrangement suggests that MLL translocations are causative events for t-AL. Using asymmetric multiplex PCR strategy followed by direct DNA sequencing, we characterized the genomic breakpoints of the MLL and AFF1 genes in two patients who developed t-AL with t(4;11)(q21;q23). Chemotherapeutic treatment of the primary disease in both patients included topoisomerase II (topo II) targeting agents. In one case, the MLL breakpoint was located in intron 9 at nucleotide position chr11:118354284 while the AFF1 breakpoint was in intron 3 at nucleotide position chr4:87992070. The breakpoint junction sequences revealed an insertion of two nucleotides at the MLL-AFF1 junction. In the other patient, the MLL breakpoint was located in intron 11 at nucleotide position chr11:118359130-32 and the AFF1 break was in intron 3 at nucleotide position chr4:87996215-17. The MLL breakpoint found in the latter patient was identical to that of two previously reported cases, strongly suggesting the presence of a preferential site of DNA cleavage in the presence of topo II inhibitor. In addition, microhomologies at the breakpoint junctions were indicative of DNA repair by the non-homologous end joining (NHEJ) pathway. This study further supports the evidence that MLL breakpoints in therapy-related acute leukemia with MLL-AFF1 are clustered in the telomeric half of the breakpoint cluster region that contains topo II recognition sites.
Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 4/genética , Loci Gênicos , Leucemia Aguda Bifenotípica/genética , Inibidores da Topoisomerase/efeitos adversos , Sequência de Bases , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Epirubicina/efeitos adversos , Feminino , Humanos , Idarubicina/efeitos adversos , Leucemia Aguda Bifenotípica/induzido quimicamente , Leucemia Promielocítica Aguda/tratamento farmacológico , Pessoa de Meia-Idade , Dados de Sequência Molecular , Família Multigênica , Translocação GenéticaRESUMO
We report that daurinol, a novel arylnaphthalene lignan, is a promising potential anticancer agent with adverse effects that are less severe than those of etoposide, a clinical anticancer agent. Despite its potent antitumor activity, clinical use of etoposide is limited because of its adverse effects, including myelosuppression and the development of secondary leukemia. Here, we comprehensively compared the mechanistic differences between daurinol and etoposide because they have similar chemical structures. Etoposide, a topoisomerase II poison, is known to attenuate cancer cell proliferation through the inhibition of DNA synthesis. Etoposide treatment induces G(2)/M arrest, severe DNA damage, and the formation of giant nuclei in HCT116 cells. We hypothesized that the induction of DNA damage and nuclear enlargement due to abnormal chromosomal conditions could give rise to genomic instability in both tumor cells and in actively dividing normal cells, resulting in the toxic adverse effects of etoposide. We found that daurinol is a catalytic inhibitor of human topoisomerase IIa, and it induces S-phase arrest through the enhanced expression of cyclins E and A and by activation of the ATM/Chk/Cdc25A pathway in HCT116 cells. However, daurinol treatment did not cause DNA damage or nuclear enlargement in vitro. Finally, we confirmed the in vivo antitumor effects and adverse effects of daurinol and etoposide in nude mice xenograft models. Daurinol displayed potent antitumor effects without any significant loss of body weight or changes in hematological parameters, whereas etoposide treatment led to decreased body weight and white blood cell, red blood cell, and hemoglobin concentration.
Assuntos
Carcinoma/patologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/patologia , Etoposídeo/farmacologia , Doenças Hematológicas/induzido quimicamente , Inibidores da Topoisomerase/efeitos adversos , Inibidores da Topoisomerase/farmacologia , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzodioxóis/efeitos adversos , Benzodioxóis/farmacologia , Benzodioxóis/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Células HCT116 , Doenças Hematológicas/epidemiologia , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Nus , Modelos Biológicos , Naftalenos/efeitos adversos , Naftalenos/farmacologia , Naftalenos/uso terapêutico , Inibidores da Topoisomerase/uso terapêutico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Drugs with potential cardiac toxicity are prominent in cancer treatment, not only the old chemotherapeutic agents, but also the newer targeted drugs and biologic agents. As the long-term survival of patients with malignancies has improved and cancer turned into a chronic disease, physicians must take into account the short-term as well as long-term consequences of cancer treatment, such as chemotherapy-induced cardiotoxicity. We summarize some general characteristics and subsequently review specific antineoplastic agents that are associated with cardiac toxicity.