RESUMO
BACKGROUND: Cytochrome P450 1B1 (CYP1B1) is mostly expressed in tumours and displays unusual properties. Its two polymorphic forms were differently associated with anticancer drug sensitivity. We decipher here the role of this polymorphism in anticancer drug efficacy in vitro, in vivo and in the clinical setting. METHODS: From head-and-neck squamous cell carcinoma cell lines not expressing CYP1B1, we generated isogenic derivatives expressing the two forms. Proliferation, invasiveness, stem cell characteristics, sensitivity to anticancer agents and transcriptome were analysed. Tumour growth and chemosensitivity were studied in vivo. A prospective clinical trial on 121 patients with advanced head-and-neck cancers was conducted, and a validation-retrospective study was conducted. RESULTS: Cell lines expressing the variant form displayed high rates of in vitro proliferation and invasiveness, stemness features and resistance to DNA-damaging agents. In vivo, tumours expressing the variant CYP1B1 had higher growth rates and were markedly drug-resistant. In the clinical study, overall survival was significantly associated with the genotypes, wild-type patients presenting a longer median survival (13.5 months) than the variant patients (6.3 months) (p = 0.0166). CONCLUSIONS: This frequent CYP1B1 polymorphism is crucial for cancer cell proliferation, migration, resistance to chemotherapy and stemness properties, and strongly influences head-and-neck cancer patients' survival.
Assuntos
Citocromo P-450 CYP1B1/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Células-Tronco Neoplásicas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Cetuximab/administração & dosagem , Metilação de DNA , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/enzimologia , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Células-Tronco Neoplásicas/enzimologia , Regiões Promotoras Genéticas , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/enzimologiaRESUMO
OBJECTIVE: The molecular diagnosis of extreme forms of obesity, in which accurate detection of both copy number variations (CNVs) and point mutations, is crucial for an optimal care of the patients and genetic counseling for their families. Whole-exome sequencing (WES) has benefited considerably this molecular diagnosis, but its poor ability to detect CNVs remains a major limitation. We aimed to develop a method (CoDE-seq) enabling the accurate detection of both CNVs and point mutations in one step. METHODS: CoDE-seq is based on an augmented WES method, using probes distributed uniformly throughout the genome. CoDE-seq was validated in 40 patients for whom chromosomal DNA microarray was available. CNVs and mutations were assessed in 82 children/young adults with suspected Mendelian obesity and/or intellectual disability and in their parents when available (ntotal = 145). RESULTS: CoDE-seq not only detected all of the 97 CNVs identified by chromosomal DNA microarrays but also found 84 additional CNVs, due to a better resolution. When compared to CoDE-seq and chromosomal DNA microarrays, WES failed to detect 37% and 14% of CNVs, respectively. In the 82 patients, a likely molecular diagnosis was achieved in >30% of the patients. Half of the genetic diagnoses were explained by CNVs while the other half by mutations. CONCLUSIONS: CoDE-seq has proven cost-efficient and highly effective as it avoids the sequential genetic screening approaches currently used in clinical practice for the accurate detection of CNVs and point mutations.
Assuntos
Sequenciamento do Exoma/métodos , Deficiência Intelectual/genética , Obesidade/genética , Adolescente , Adulto , Algoritmos , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Feminino , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Mutação Puntual/genéticaRESUMO
BACKGROUND: Peanut allergy in children is often associated with allergies to tree nuts and/or legumes. The aim of this study was to analyze in cluster a cohort of children allergic to peanuts and assessed for cross-reactivity to nuts and legumes and to identify different phenotypes. METHODS: We included retrospectively 317 children with peanut allergy evaluated at the Allergy Unit of the Saint Vincent Hospital of Lille in the last 12 years. A complete workup for peanut allergy and nuts and legumes was carried out for each patient. A hierarchical agglomerative clustering method was used to search for clusters of individuals in the evaluated cohort. RESULTS: Cross-allergy to TN and/or other legumes was identified in 137 patients (43.2%), atopic dermatitis being a major risk factor (adjusted OR = 16 [95% CI: 7.4-37]; p < 0.001). Three phenotypes emerged from cluster analysis. Cluster 1 (72 patients) is characterized by high level of rAra h 2, low threshold reactive doses for peanut and high proportion of asthma; Cluster 2 (93 patients) is characterized by high threshold reactive doses for peanut and the lowest proportion of cross-allergy to TN and/or legumes; Cluster 3 (152 patients) has a high risk of cross-allergy to TN and/or legumes and most patients suffer from eczema. CONCLUSIONS: The three phenotypes highlighted by this study could be useful to identify children with high risk of cross-allergic reaction to TNs and legumes early after PA diagnosis.
Assuntos
Arachis/imunologia , Reações Cruzadas/imunologia , Fabaceae/imunologia , Hipersensibilidade a Nozes e Amendoim/imunologia , Nozes/imunologia , Criança , Pré-Escolar , Análise por Conglomerados , Feminino , Humanos , Masculino , Fenótipo , Estudos Retrospectivos , Testes CutâneosRESUMO
Human epidermal growth factor receptor 3 (HER3) is a member of the human epidermal growth factor receptor (HER) family. The main characteristic of HER3 is that it does not possess tyrosine kinase activity, unlike other HERs. The role of HER3 in tumorigenesis has now been recognized, particularly in head and neck squamous cell carcinomas (HNSCCs). Despite conflicting studies, HER3 was found to be overexpressed in HNSCC samples, and correlates with disease progression and poor survival, especially when it is coexpressed with other HERs. HER3 is a significant factor in HNSCC treatment resistance. Indeed, HER3 is a major mechanism described for cetuximab resistance because of modification of epidermal growth factor receptor (EGFR) internalization and by phosphotidylinositol-3-kinase (PI3K)/AKT signaling pathway activation. HER3 also affects resistance to tyrosine kinase inhibitors (TKIs) and thereby promotes treatment escape and radiotherapy resistance by activation of the survival signaling pathway. To counteract this, pharmacologic inhibitors of HER3 are currently in development and could significantly improve HNSCC treatment. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2412-E2418, 2016.
Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/genética , Receptor ErbB-3/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Cetuximab/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-3/antagonistas & inibidores , Transdução de SinaisRESUMO
Three series of indeno[1,2-c]isoquinolines bearing a ferrocenyl entity were synthesized and evaluated for DNA interaction, topoisomerase I and II inhibition, and cytotoxicity against breast human cancer cell lines. In the first and second series, the ferrocenyl scaffold was inserted as a linker between the two nitrogen atoms. In the last series, it was introduced at the end of the carbon chain. The present study showed that the ferrocenyl entity enhanced the topoisomerase II inhibition. Most compounds showed a potent growth inhibitory effect on MDA-MB-231 cell line with the IC50 in µM range.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Compostos Ferrosos/síntese química , Compostos Ferrosos/farmacologia , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/farmacologia , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Ferrosos/química , Humanos , Concentração Inibidora 50 , Isoquinolinas/química , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/química , Células Tumorais CultivadasRESUMO
BACKGROUND: The combination of irinotecan, a topoisomerase I inhibitor with cetuximab, an antibody against epidermal growth factor receptor, produces synergistic and beneficial effects in patients with irinotecan-refractory colorectal cancer. Our hypothesis was that synergistic effects could be due to anti-angiogenesis and anti-invasion, but not to cytotoxicity. MATERIALS AND METHODS: Cytotoxicity was assessed by viability test and flow cytometry. Anti-angiogenesis, anti-invasion were studied by the endothelial cell capillary-like network formation and transmigration through an extracellular matrix. Protein kinase B (PKB, frequently cited as AKT), and extracellular signal-regulated kinases (ERK) activation was assayed by cell-based enzyme-linked immunosorbent assay (ELISA). RESULTS: Combinations of SN-38 (the active of irinotecan) and cetuximab did not induce any synergistic cytotoxicity confirmed by viability test and cell-cycle analyses. Interestingly, their combination produced synergistic anti-angiogenesis and anti-invasion activities revealed by endothelial cell capillary-like network formation and cell invasion tests. Subsequently, their combination attenuated either expression or phosphorylation of AKT and ERK1/2 using cell-based ELISA. CONCLUSION: SN-38/cetuximab combination has synergistic anti-angiogenesis and anti-invasion activities mediated by down-regulation of phosphatidylinositol-3-kinases/AKT and mitogen-activated protein kinase/ERK pathways.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Movimento Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Sinergismo Farmacológico , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Western Blotting , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Adesão Celular/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cetuximab/administração & dosagem , Neoplasias do Colo/irrigação sanguínea , Neoplasias do Colo/patologia , Citometria de Fluxo , Humanos , Irinotecano , Invasividade Neoplásica , Neovascularização Patológica/patologia , Fosforilação/efeitos dos fármacosRESUMO
A series of 6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]chromeno[6,5-g][1,8]naphthyridin-7-one (4), 13-aza derivatives of benzo[b]acronycine, the isomeric 5-methoxy-2,2,13-trimethyl-2,13-dihydro-6H-benzo[b]chromeno[7,6-g][1,8]naphthyridin-6-one (5), and related cis-diols mono- and diesters were designed and synthesized. Their in vitro and in vivo biological activities were evaluated. As previously observed in the acronycine series, esters were the most potent derivatives exhibiting submicromolar activities; among them monoesters are particularly active. Racemic diacetate 21 showed a strong activity against KB-3-1 cell lines and was selected for in vivo evaluation and proved to be active, inhibiting tumor growth by more than 80%. After separation of the two enantiomers, compounds 21a and 21b were also evaluated against C38 colon adenocarcinoma; their activities were found to be significantly different.
Assuntos
Acronina/química , Adenocarcinoma/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Naftiridinas/síntese química , Naftiridinas/farmacologia , Adenocarcinoma/patologia , Animais , Carcinoma de Células Escamosas/patologia , Neoplasias do Colo/patologia , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ensaio de Desvio de Mobilidade Eletroforética , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The poor prognosis of children with high-grade glioma (HGG) and high-risk neuroblastoma, despite multidisciplinary therapeutic approaches, demands new treatments for these indications. F14512 is a topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells via the Polyamine Transport System (PTS) and increases topoisomerase II poisoning. Here, F14512 was evaluated in pediatric HGG and neuroblastoma cell lines. PTS activity and specificity were evaluated using a fluorescent spermine-coupled probe. The cytotoxicity of F14512, alone or in combination with ionizing radiation and chemotherapeutic agents, was investigated in vitro. The antitumor activity of F14512 was assessed in vivo using a liver-metastatic model of neuroblastoma. An active PTS was evidenced in all tested cell lines, providing a specific and rapid transfer of spermine-coupled compounds into cell nuclei. Competition experiments confirmed the essential role of PTS in the cell uptake and cytotoxicity of F14512. This cytotoxicity appeared greater in neuroblastoma cells compared with HGG cells but appeared independent of PTS activity levels. In vivo evaluation confirmed a marked and prolonged antitumoral effect in neuroblastoma cells. The combinations of F14512 with cisplatin and carboplatin were often found to be synergistic, and we demonstrated the significant radiosensitizing potential of F14512 in the MYCN-amplified Kelly cell line. Thus, F14512 appears more effective than etoposide in pediatric tumor cell lines, with greater efficacy in neuroblastoma cells compared with HGG cells. The synergistic effects observed with platinum compounds and the radiosensitizing effect could lead to a clinical development of the drug in pediatric oncology.
Assuntos
Antineoplásicos/farmacologia , Podofilotoxina/análogos & derivados , Espermina/química , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Carboplatina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Cisplatino/farmacologia , Etoposídeo/farmacologia , Feminino , Glioma/tratamento farmacológico , Glioma/radioterapia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Melfalan/farmacologia , Camundongos Endogâmicos BALB C , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Neuroblastoma/radioterapia , Podofilotoxina/química , Podofilotoxina/farmacologia , Podofilotoxina/uso terapêutico , Radiação IonizanteRESUMO
We have carried out a stratified phase II study of sorafenib (So) in patients with advanced angiosarcoma (n = 32) and epithelioid hemangioendothelioma (n = 13). This report concerns the correlative analysis of the predictive values of circulating pro/anti-angiogenetic biomarkers. Using the ELISA method (R&D Systems), circulating biomarkers (VEGF-A, in picograms per milliliter), thrombospondin-1 (TSP1, in micrograms per milliliter), stem cell factor (SCF, in picograms per milliliter), placental growth factor (PlGF, in picograms per milliliter), VEGF-C (in picograms per milliliter), and E-selectin (in nanograms per milliliter) were measured before So treatment and after 7 days. VEGF-A (mean value 475 vs. 541, p = 0.002), TSP1 (16 vs. 24, p = 0.0002), and PlGF (20.9 vs. 40.7, p = 0.0001) significantly increased during the treatment. Treatment did not affect the levels of SCF, VEGF-C, and E-selectin. Only two biomarkers were associated with better outcome as follows: VEGF-A and PlGF. Best objective response and non-progression at 180 days were associated with low level of VEGF-A at baseline (p = 0.04 and 0.03, respectively). There was a correlation between the circulating level of VEGF-A and time to progression (TTP) (r = -0.47, p = 0.001). Best objective response and non-progression at 180 days were not associated with baseline level of PIGF, but there was a correlation between the circulating level of PIGF at baseline and TTP. Low level of VEGF-A at baseline (<500) was significantly associated with better outcome.
Assuntos
Hemangioendotelioma Epitelioide/sangue , Hemangioendotelioma Epitelioide/tratamento farmacológico , Hemangiossarcoma/sangue , Hemangiossarcoma/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/sangue , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Ensaio de Imunoadsorção Enzimática , Humanos , Niacinamida/uso terapêutico , Sorafenibe , Resultado do TratamentoRESUMO
The prognosis of children with high-grade glioma or high-risk neuroblastoma remains poor. Cilengitide is a selective antagonist of αvß3 and αvß5 integrins, which are involved in tumor growth and development of metastasis. We have evaluated the effects of cilengitide on pediatric glioma and neuroblastoma cell lines for the first time. Expression levels of αvß3 and αvß5 were determined by flow cytometry in three neuroblastoma and five pediatric glioma cell lines compared with adult U87-MG before and after irradiation. Cell detachment, cytotoxicity, and cell growth under nonadhesive conditions were measured using the MTS assay. Cell death and apoptosis were assessed by annexin-V/propidium iodide staining. The varying αvß3 and αvß5 expression levels were unrelated to tumor grade. Irrespective of the αvß5 expression level, the pediatric cells expressing αvß3 were dose dependently sensitive to cilengitide. UW479 cells expressed only αvß5 integrin and were not sensitive to cilengitide, suggesting that cilengitide's action largely depends on αvß3 inhibition. Cell detachment resulted in a higher cytotoxicity in pediatric glioma compared with U87-MG cells, which seem able to grow despite the significant cilengitide-induced cell detachment. Growth kinetics on polyHEMA showed that only pediatric glioma cells were sensitive to anoikis and so died after cilengitide-induced detachment. Furthermore, irradiation of glioma cells increased αvß3 expression slightly but not cilengitide sensitivity. Cilengitide's action on glioma and neuroblastoma cells appears to be dependent on αvß3 expression and sensitivity to anoikis. Cilengitide is able to target pediatric glioma and neuroblastoma cells in vitro directly and efficiently. Tumor context could validate these promising observations.
Assuntos
Anoikis/efeitos dos fármacos , Antineoplásicos/farmacologia , Adesão Celular/efeitos dos fármacos , Glioma/patologia , Neuroblastoma/patologia , Venenos de Serpentes/farmacologia , Fatores Etários , Anoikis/efeitos da radiação , Adesão Celular/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Citometria de Fluxo , Glioma/metabolismo , Humanos , Integrina alfaVbeta3/antagonistas & inibidores , Integrina alfaVbeta3/metabolismo , Gradação de Tumores , Neuroblastoma/metabolismo , Radioterapia Adjuvante , Receptores de Vitronectina/antagonistas & inibidores , Receptores de Vitronectina/metabolismo , Fatores de TempoRESUMO
Carbonic anhydrase (CA) IX expression is increased upon hypoxia and has been proposed as a therapeutic target since it has been associated with poor prognosis, tumor progression and pH regulation. We report the synthesis and the pharmacological evaluation of a new class of human carbonic anhydrase (hCA) inhibitors, 4-(5-aryl-2-hydroxymethyl-pyrazol-1-yl)-benzenesulfonamides. A molecular modeling study was conducted in order to simulate the binding mode of this new family of enzyme inhibitors within the active site of hCA IX. Pharmacological studies revealed high hCA IX inhibitory potency in the parameters nanomolar range. This study showed that the position of sulfonamide group in meta of the 1-phenylpyrazole increase a selectivity hCA IX versus hCA II of our compounds. An in vitro antiproliferative screening has been performed on the breast cancer MDA-MB-231 cell using doxorubicin as cytotoxic agent and in presence of selected CA IX inhibitor. The results shown that the cytotoxic efficiency of doxorubicin in an hypoxic environment, expressed in IC50 value, is restored at 20% level with 1µM CA IX inhibitor.
Assuntos
Antígenos de Neoplasias/química , Inibidores da Anidrase Carbônica/síntese química , Anidrases Carbônicas/química , Pirazóis/química , Sulfonamidas/química , Antígenos de Neoplasias/metabolismo , Sítios de Ligação , Anidrase Carbônica IX , Inibidores da Anidrase Carbônica/metabolismo , Inibidores da Anidrase Carbônica/toxicidade , Anidrases Carbônicas/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Cinética , Simulação de Acoplamento Molecular , Ligação Proteica , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/toxicidade , BenzenossulfonamidasRESUMO
The synthesis of new acridinone and dioxophenothiazine derivatives along with their tubulin polymerization inhibitory and antiproliferative activities is reported. The analysis of correlation for cytotoxic and antitubulin potential of tested compounds showed that 4-methoxyphenylethyl derivatives 18a and 19a were highly cytotoxic but were regarded to have no significant antitubulin activity. However, the introduction of a 3-hydroxy substituent leading to compounds 18e and 19e, strongly increased the antitubulin potential but was associated with a loss of the antiproliferative activity. Modeling studies, topoisomerase inhibition assays and cell cycle analysis have been performed to better investigate the mechanism of action of such compounds.
Assuntos
Acridonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Tubulina (Proteína)/metabolismo , Acridonas/síntese química , Acridonas/química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Fenotiazinas/síntese química , Fenotiazinas/química , Fenotiazinas/farmacologia , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A library of substituted chromeno[3,4-b]indoles was developed as Lamellarin isosters. Synthesis was achieved from indoles after a four-step pathway sequence involving C-3 iodination, a Suzuki cross-coupling reaction, and a one pot deprotection/lactonisation step. Twenty final compounds were tested in order to determine their activity against topoisomerase I and kinases, the two major biological activities of Lamellarins. One newly synthesized derivative exhibited a strong topoisomerase activity comparable to reference compounds such as campthotecin and Lamellarin with only a weak kinase inhibition. Two other lead compounds were identified as new nanomolar DYRK1A inhibitors and several other drugs affected the kinases in the sub-micromolar range. These results will enable us to use the chromeno[3,4-b]indole as a pharmacophore to develop potent treatments for neurological or oncological disorders in which DYRK1A is fully involved.
Assuntos
Cumarínicos/química , Cumarínicos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Indóis/química , Indóis/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Cumarínicos/síntese química , DNA Topoisomerases Tipo I/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Humanos , Indóis/síntese química , Isoquinolinas/síntese química , Modelos Moleculares , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologia , Quinases DyrkRESUMO
Several previous reports suggest that thrombospondin (TSP-1) may be a mediator of the antiangiogenic effects of low-dose metronomic cyclophosphamide-based chemotherapy (MC). We conducted a randomized phase II trial evaluating megestrol acetate (n = 44) versus MC (n = 44) in patients having exhausted all standard treatments. We measured the TSP-1 levels at baseline and D15. We did not observe significant differences in TSP-1 at baseline in the two arms (p = 0.07). TSP-1 levels decreased in patients receiving metronomic cyclophosphamide (from 16.6 ± 7.2 µg/ml to 12.8 ± 7.4 µg/ml; p = 0.057). The TSP-1 level was stable in patients receiving megestrol acetate. Nevertheless, the TSP-1 level driven by MC did not correlate to clinical benefit.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Biomarcadores Tumorais/análise , Ciclofosfamida/administração & dosagem , Neoplasias/tratamento farmacológico , Trombospondina 1/sangue , Administração Metronômica , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , França , Humanos , Neoplasias/sangue , Neoplasias/mortalidade , Neoplasias/patologia , Fatores de Tempo , Resultado do TratamentoRESUMO
The endocannabinoid system is implicated in numerous physiopathological processes while more and more pieces of evidence wave the link between this complex machinery and cancer related phenomenon. In these lines, we confirmed the effects of 2-arachidonoylglycerol (2-AG), the main endocannabinoid, on neuroblastoma cells proliferation in vitro, and proved that some N-phenylmaleimide compounds that were previously shown as MAGL inhibitors can also inhibit type 2 topoisomerase. We also shed light on their antiproliferative effects on a neuroblastoma cell line. In order to establish a link between MAGL inhibition, topoisomerase inhibition and the effects on N1E-115 cells, we tested combinations of maleimides or known endocannabinoid metabolism inhibitors and 2-AG, the major MAGL substrate, on N1E-115 cells. However, none of the inhibitors tested, except the carbamate CAY10499, managed to increase 2-AG's effects. Even the MAGL reference inhibitor JZL184 failed to induce a stronger inhibition of proliferation.
Assuntos
Antineoplásicos/farmacologia , Ácidos Araquidônicos/farmacologia , Moduladores de Receptores de Canabinoides/farmacologia , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Glicerídeos/farmacologia , Maleimidas/farmacologia , Monoacilglicerol Lipases/antagonistas & inibidores , Neuroblastoma/enzimologia , Inibidores da Topoisomerase II/farmacologia , Benzodioxóis/farmacologia , Carbamatos/farmacologia , Endocanabinoides , Etoposídeo/farmacologia , Humanos , Oxidiazóis/farmacologia , Piperidinas/farmacologia , Células Tumorais CultivadasRESUMO
Nuclear topoisomerase I (Top1) is involved in the relaxation of DNA supercoiling and plays a pivotal role in the coordination of essential DNA processes such as transcription, replication, DNA recombination and DNA damage signalling. For all these reasons, Top1 has been an attractive target for the development of anticancer drugs, which poison Top1 by trapping the enzyme on its DNA cleavage sites, which results in irreversible DNA lesions that are responsible for their cytotoxicity. They derive from the natural compound camptothecin and two derivatives are approved in the clinic, topotecan and irinotecan; other compounds such as indolocarbazoles and indenoisoquinolines are in development. However, the efficacy of these drugs is often limited by the problem of resistance, which involves various mechanisms at different steps of drug action, from drug transport and/or metabolism to the signalling and/or repair of the DNA lesions that are generated. A better understanding of these mechanisms is a major concern for the future development of new Top1 inhibitors and the identification of biomarkers that could be used to predict tumour response to these drugs in the clinic and to adapt the treatment to each patient.
Assuntos
DNA Topoisomerases Tipo I/fisiologia , Inibidores da Topoisomerase I/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Dano ao DNA , Reparo do DNA/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Irinotecano , Inibidores da Topoisomerase I/farmacocinética , Topotecan/farmacocinética , Topotecan/uso terapêuticoRESUMO
Antimetabolites are cytotoxic agents, which have been developed for more than 50â years. Which cancer patient did not receive or will not receive 5-fluorouracil or methotrexate during the evolution his or her disease? Antimetabolites are defined as interfering with the synthesis of the DNA constituents; they are structural analogues, either of purine and pyrimidine bases (or the corresponding nucleosides), or of folate cofactors, which are involved at several steps of purine and pyrimidine biosynthesis. Their first mechanism of action is, therefore, to induce depletion in nucleotides inducing in turn an inhibition of DNA replication. However, some of them are able to get inserted fraudulently into nucleic acids, inducing structural abnormalities leading to cell death by other mechanisms, including DNA breaks. We present in this paper, for the three classes of antimetabolites, both ancient and recent molecules as well as molecules still in clinical trials, without exhaustivity.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Neoplasias/tratamento farmacológico , Purinas/antagonistas & inibidores , Pirimidinas/antagonistas & inibidores , Replicação do DNA/efeitos dos fármacos , Humanos , Leucemia/tratamento farmacológicoRESUMO
Human nuclear topoisomerases II (Top2) are involved in the relaxation of DNA supercoiling during transcription and replication but also play a pivotal role in the segregation of newly replicated chromosomes and in chromatin remodelling. Top2 have been used as targets for the development of anticancer drugs. These inhibitors include anthracyclines (doxorubcin, daunorubicin, epirubicin) and epipodophyllotoxins (etoposide), which are widely used in the clinic. These drugs poison Top2 by trapping the enzyme on its DNA cleavage sites, which results in irreversible double-strand breaks that are responsible for cell death. They also include Top2 catalytic inhibitors such as bisdioxopiperazines (ICRF-187 and merbarone), which inhibit Top2 binding to its substrate. Efficacy of Top2 inhibitors is still limited by the problem of resistance, which involves various mechanisms from drug transport and/or metabolism to the signalling and/or repair of Top2-mediated DNA lesions. Secondary malignancies induced by the poisoning of Top2ß are also a major clinical issue. A better understanding of these mechanisms is critical for the future development of new Top2 inhibitors and the identification of biomarkers that could be used to predict tumour response to these drugs in the clinic and to adapt the treatment to each patient.
Assuntos
DNA Topoisomerases Tipo II/fisiologia , Inibidores da Topoisomerase II/uso terapêutico , Transportadores de Cassetes de Ligação de ATP/fisiologia , Antraciclinas/uso terapêutico , Pontos de Checagem do Ciclo Celular/fisiologia , Adutos de DNA/metabolismo , Dano ao DNA , Reparo do DNA/fisiologia , Replicação do DNA/fisiologia , DNA Topoisomerases Tipo II/química , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Podofilotoxina/uso terapêutico , Transcrição GênicaRESUMO
Last years saw the development of anti-angiogenic strategies in the treatment of cancers. Cilengitide (EMD121974; Merck KGaA, Darmstadt, Germany) is a new drug targeting αvß3 and αvß5 integrins thanks to a specific peptide called RGD sequence. Cilengitide acts in correlations between endothelial cells, tumor cells and extracellular matrix. The promising results obtained with Cilengitide in vitro, used alone or in combination with cytotoxic chemotherapy or ionizing radiations, could give many hopes especially for the treatment of cerebral tumors. Clinical trials are nowadays ongoing in this indication. The aim of this review is to take stock of the situation on the mechanisms of action of the integrin inhibitor Cilengitide (EMD121974; Merck KGaA, Darmstadt, Germany) with a focus on the first pre-clinical and clinical results.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Integrinas/antagonistas & inibidores , Terapia de Alvo Molecular , Venenos de Serpentes/uso terapêutico , Animais , Neoplasias Encefálicas/metabolismo , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios de Seleção de Medicamentos Antitumorais , Matriz Extracelular/fisiologia , Humanos , Integrina alfaVbeta3/antagonistas & inibidores , Integrinas/fisiologia , Receptores de Vitronectina/antagonistas & inibidoresRESUMO
A number of mono- or diaminoalkylated indeno[1,2-c]isoquinolin-5,11-diones analogs of 1 were synthesized and evaluated for their DNA binding affinities, topoisomerase inhibition properties and antiproliferative activities against human cancer cell lines (HL60). Impact of the side chain connected to the aromatic D ring and to the N6 lactam position on the biological profile will be discussed.