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1.
Br J Cancer ; 125(5): 687-698, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34140638

RESUMO

BACKGROUND: CGM097 inhibits the p53-HDM2 interaction leading to downstream p53 activation. Preclinical in vivo studies support clinical exploration while providing preliminary evidence for dosing regimens. This first-in-human phase I study aimed at assessing the safety, MTD, PK/PD and preliminary antitumor activity of CGM097 in advanced solid tumour patients (NCT01760525). METHODS: Fifty-one patients received oral treatment with CGM097 10-400 mg 3qw (n = 31) or 300-700 mg 3qw 2 weeks on/1 week off (n = 20). Choice of dose regimen was guided by PD biomarkers, and quantitative models describing the effect of CGM097 on circulating platelet and PD kinetics. RESULTS: No dose-limiting toxicities were reported in any regimens. The most common treatment-related grade 3/4 AEs were haematologic events. PK/PD models well described the time course of platelet and serum GDF-15 changes, providing a tool to predict response to CGM097 for dose-limiting thrombocytopenia and GDF-15 biomarker. The disease control rate was 39%, including one partial response and 19 patients in stable disease. Twenty patients had a cumulative treatment duration of >16 weeks, with eight patients on treatment for >32 weeks. The MTD was not determined. CONCLUSIONS: Despite delayed-onset thrombocytopenia frequently observed, the tolerability of CGM097 appears manageable. This study provided insights on dosing optimisation for next-generation HDM2 inhibitors. TRANSLATIONAL RELEVANCE: Haematologic toxicity with delayed thrombocytopenia is a well-known on-target effect of HDM2 inhibitors. Here we have developed a PK/PD guided approach to optimise the dose and schedule of CGM097, a novel HDM2 inhibitor, using exposure, platelets and GDF-15, a known p53 downstream target to predict patients at higher risk to develop thrombocytopenia. While CGM097 had shown limited activity, with disease control rate of 39% and only one patient in partial response, the preliminary data from the first-in-human escalation study together with the PK/PD modeling provide important insights on how to optimize dosing of next generation HDM2 inhibitors to mitigate hematologic toxicity.


Assuntos
Fator 15 de Diferenciação de Crescimento/sangue , Isoquinolinas/administração & dosagem , Neoplasias/tratamento farmacológico , Piperazinas/administração & dosagem , Administração Oral , Adulto , Idoso , Animais , Biomarcadores Tumorais/sangue , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Isoquinolinas/efeitos adversos , Isoquinolinas/farmacocinética , Masculino , Camundongos , Pessoa de Meia-Idade , Neoplasias/sangue , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Clin Cancer Res ; 28(6): 1087-1097, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-34921024

RESUMO

PURPOSE: Well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma are characterized by co-amplification of the murine double minute-2 (MDM2) and cyclin-dependent kinase-4 (CDK4) oncogenes. Siremadlin, a p53-MDM2 inhibitor, was combined with ribociclib, a CDK4/6 inhibitor, in patients with locally advanced/metastatic WDLPS or DDLPS who had radiologically progressed on, or despite, prior systemic therapy. PATIENTS AND METHODS: In this proof-of-concept, phase Ib, dose-escalation study, patients received siremadlin and ribociclib across different regimens until unacceptable toxicity, disease progression, and/or treatment discontinuation: Regimen A [4-week cycle: siremadlin once daily (QD) and ribociclib QD (2 weeks on, 2 weeks off)], Regimen B [3-week cycle: siremadlin once every 3 weeks; ribociclib QD (2 weeks on, 1 week off)], and Regimen C [4-week cycle: siremadlin once every 4 weeks; ribociclib QD (2 weeks on, 2 weeks off)]. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of siremadlin plus ribociclib in one or more regimens. RESULTS: As of October 16, 2019 (last patient last visit), 74 patients had enrolled. Median duration of exposure was 13 (range, 1-174) weeks. Dose-limiting toxicities occurred in 10 patients, most of which were Grade 3/4 hematologic events. The RDE was siremadlin 120 mg every 3 weeks plus ribociclib 200 mg QD (Regimen B). Three patients achieved a partial response, and 38 achieved stable disease. One patient (Regimen C) died as a result of treatment-related hematotoxicity. CONCLUSIONS: Siremadlin plus ribociclib demonstrated manageable toxicity and early signs of antitumor activity in patients with advanced WDLPS or DDLPS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Lipossarcoma , Aminopiridinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quinase 4 Dependente de Ciclina/genética , Humanos , Imidazóis/uso terapêutico , Lipossarcoma/tratamento farmacológico , Lipossarcoma/genética , Lipossarcoma/patologia , Proteínas Proto-Oncogênicas c-mdm2/genética , Purinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico
3.
Clin Cancer Res ; 28(5): 870-881, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34862243

RESUMO

PURPOSE: This phase I, dose-escalation study investigated the recommended dose for expansion (RDE) of siremadlin, a p53-MDM2 inhibitor, in patients with wild-type TP53 advanced solid or hematologic cancers. PATIENTS AND METHODS: Initial dosing regimens were: 1A (day 1; 21-day cycle; dose 12.5-350 mg) and 2A (days 1-14; 28-day cycle; dose 1-20 mg). Alternative regimens included 1B (days 1 and 8; 28-day cycle) and 2C (days 1-7; 28-day cycle). The primary endpoint was incidence of dose-limiting toxicities (DLT) during cycle 1. RESULTS: Overall, 115 patients with solid tumors and 93 with hematologic malignancies received treatment. DLTs occurred in 8/92 patients with solid tumors and 10/53 patients with hematologic malignancies. In solid tumors, an RDE of 120 mg was defined in 1B. In hematologic tumors, RDEs were defined in 1A: 250 mg, 1B: 120 mg, and 2C: 45 mg. More patients with hematologic malignancies compared with solid tumors experienced grade 3/4 treatment-related adverse events (71% vs. 45%), most commonly resulting from myelosuppression. These were more frequent and severe in patients with hematologic malignancies; 22 patients exhibited tumor lysis syndrome. Overall response rates at the RDEs were 10.3% [95% confidence interval (CI), 2.2-27.4] in solid tumors and 4.2% (95% CI, 0.1-21.1), 20% (95% CI, 4.3-48.1), and 22.2% (95% CI, 8.6-42.3) in acute myeloid leukemia (AML) in 1B, 1A, and 2C, respectively. CONCLUSIONS: A common safety profile was identified and preliminary activity was noted, particularly in AML. Comprehensive investigation of dosing regimens yielded recommended doses/regimens for future combination studies.


Assuntos
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Neoplasias , Relação Dose-Resposta a Droga , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Humanos , Imidazóis , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Dose Máxima Tolerável , Neoplasias/tratamento farmacológico , Pirimidinas , Pirróis , Proteína Supressora de Tumor p53/genética
4.
Clin Cancer Res ; 28(1): 106-115, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34615719

RESUMO

PURPOSE: This phase II study determined the efficacy of lacnotuzumab added to gemcitabine plus carboplatin (gem-carbo) in patients with advanced triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Female patients with advanced TNBC, with high levels of tumor-associated macrophages not amenable to curative treatment by surgery or radiotherapy were enrolled. Lacnotuzumab was dosed at 10 mg/kg every 3 weeks, ± a dose on cycle 1, day 8. Gemcitabine (1,000 mg/m2) and carboplatin (dose in mg calculated by area under the curve [mg/mL/min] × (glomerular filtration rate [mL/min] + 25 [mL/min]) were dosed every 3 weeks. Treatment continued until unacceptable toxicity, disease progression, or discontinuation by physician/patient. RESULTS: Patients received lacnotuzumab + gem-carbo (n = 34) or gem-carbo (n = 15). Enrollment was halted due to recruitment challenges owing to rapid evolution of the therapeutic landscape; formal hypothesis testing of the primary endpoint was therefore not performed. Median progression-free survival was 5.6 months [90% confidence interval (CI), 4.47-8.64] in the lacnotuzumab + gem-carbo arm and 5.5 months (90% CI, 3.45-7.46) in the gem-carbo arm. Hematologic adverse events were common in both treatment arms; however, patients treated with lacnotuzumab experienced more frequent aspartate aminotransferase, alanine aminotransferase, and creatine kinase elevations. Pharmacokinetic results showed that free lacnotuzumab at 10 mg/kg exhibited a typical IgG pharmacokinetic profile and target engagement of circulating colony-stimulating factor 1 ligand. CONCLUSIONS: Despite successful target engagement and anticipated pharmacokinetic profile, lacnotuzumab + gem-carbo showed comparable antitumor activity to gem-carbo alone, with slightly poorer tolerability. However, the data presented in this article would be informative for future studies testing agents targeting the CSF1-CSF1 receptor pathway in TNBC.


Assuntos
Neoplasias de Mama Triplo Negativas , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina , Desoxicitidina/análogos & derivados , Feminino , Humanos , Fator Estimulador de Colônias de Macrófagos , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/patologia , Gencitabina
5.
Toxicol Appl Pharmacol ; 252(2): 112-22, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21081137

RESUMO

The European InnoMed-PredTox project was a collaborative effort between 15 pharmaceutical companies, 2 small and mid-sized enterprises, and 3 universities with the goal of delivering deeper insights into the molecular mechanisms of kidney and liver toxicity and to identify mechanism-linked diagnostic or prognostic safety biomarker candidates by combining conventional toxicological parameters with "omics" data. Mechanistic toxicity studies with 16 different compounds, 2 dose levels, and 3 time points were performed in male Crl: WI(Han) rats. Three of the 16 investigated compounds, BI-3 (FP007SE), Gentamicin (FP009SF), and IMM125 (FP013NO), induced kidney proximal tubule damage (PTD). In addition to histopathology and clinical chemistry, transcriptomics microarray and proteomics 2D-DIGE analysis were performed. Data from the three PTD studies were combined for a cross-study and cross-omics meta-analysis of the target organ. The mechanistic interpretation of kidney PTD-associated deregulated transcripts revealed, in addition to previously described kidney damage transcript biomarkers such as KIM-1, CLU and TIMP-1, a number of additional deregulated pathways congruent with histopathology observations on a single animal basis, including a specific effect on the complement system. The identification of new, more specific biomarker candidates for PTD was most successful when transcriptomics data were used. Combining transcriptomics data with proteomics data added extra value.


Assuntos
Ciclosporinas/toxicidade , Perfilação da Expressão Gênica/métodos , Marcadores Genéticos/genética , Gentamicinas/toxicidade , Túbulos Renais Proximais/efeitos dos fármacos , Proteômica/métodos , Animais , Biomarcadores/análise , Relação Dose-Resposta a Droga , Túbulos Renais Proximais/patologia , Túbulos Renais Proximais/fisiologia , Masculino , Ratos , Ratos Wistar
6.
AAPS J ; 23(2): 28, 2021 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-33554304

RESUMO

We report on a retrospective model-based assessment of the predictive value of translating antitumor drug activity from in vivo experiments to a phase I clinical study in cancer patients treated with the MDM2 inhibitor, HDM201. Tumor growth inhibition models were developed describing the longitudinal tumor size data in human-derived osteosarcoma xenograft rats and in 96 solid tumor patients under different HDM201 treatment schedules. The model structure describing both datasets captures the delayed drug effect on tumor growth via a series of signal transduction compartments, including a resistance component. The models assumed a drug-killing effect on both sensitive and resistant cells and parameterized to estimate two tumor static plasma drug concentrations for sensitive (TSCS) and resistant cells (TSCR). No change of TSCS and TSCR with schedule was observed, implying that antitumor activity for HDM201 is independent of treatment schedule. Preclinical and clinical model-derived TSCR were comparable (48 ng/mL vs. 74 ng/mL) and demonstrating TSCR as a translatable metric for antitumor activity in clinic. Schedule independency was further substantiated from modeling of clinical serum growth differentiation factor-15 (GDF-15) as a downstream marker of p53 pathway activation. Equivalent cumulative induction of GDF-15 was achieved across schedules when normalized to an equivalent total dose. These findings allow for evaluation of optimal dosing schedules by maximizing the total dose per treatment cycle while mitigating safety risk with periods of drug holiday. This approach helped guide a phase I dose escalation study in the selection of an optimal dose and schedule for HDM201.


Assuntos
Imidazóis/administração & dosagem , Modelos Biológicos , Osteossarcoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Administração Oral , Adolescente , Adulto , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Fator 15 de Diferenciação de Crescimento/sangue , Fator 15 de Diferenciação de Crescimento/metabolismo , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Pessoa de Meia-Idade , Osteossarcoma/sangue , Osteossarcoma/genética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Pirróis/efeitos adversos , Pirróis/farmacocinética , Ratos , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
7.
J Alzheimers Dis ; 13(1): 17-30, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18334753

RESUMO

Alzheimer's disease is the most prevalent form of dementia associated with aging in the human population for which there is no biomarker for accurate and effective diagnosis at its early stage or monitoring of disease progression. In this study, we used 2-D DIGE to identify Alzheimer's disease-related proteins in the brains of APP23 mice used as a model for studying cerebral amyloidosis. Protein expression profiles in the brain of 2- and 24-month old female transgenic mice, displaying pre-plaque and plaque phenotypes, respectively, and 24-month old wild-type mice were compared to identify if changes at the protein level could be implicated in the early molecular events leading to cerebral amyloidosis. Seven such proteins were identified including kinesin heavy chain, dihydropyrimidinase related protein 2, beta-tubulin, two isomers of 3-phosphoglycerate dehydrogenase, ubiquinol cytochrome c reductase, and heat shock protein 84. The dysregulation of these proteins may have implications on pathways such as the mitochondrial respiratory chain, axonal transport, axon guidance, L-Serine biosynthesis and cytoskeletal reorganization, and thereby may represent events that precede and participate in the formation of senile plaque. Other detected protein changes were observed only in the plaque phenotype, and so are likely to be a consequence of plaque deposition and/or associated with neurodegenerative/repair processes. These proteins provide a basis for further dissecting the early mechanisms of Alzheimer's disease, and exploring their implications as relevant biomarker candidates of incipient Alzheimer's disease and progression in man.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Eletroforese em Gel Bidimensional/métodos , Fenótipo , Placa Amiloide/metabolismo , Proteômica/instrumentação , Amiloidose/genética , Amiloidose/metabolismo , Animais , Bases de Dados de Ácidos Nucleicos , Perfilação da Expressão Gênica/métodos , Camundongos , Camundongos Transgênicos
8.
Cancer Res ; 78(21): 6257-6267, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30135191

RESUMO

Activation of p53 by inhibitors of the p53-MDM2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. Here, we report distinct mechanisms by which the novel, potent, and selective inhibitor of the p53-MDM2 interaction HDM201 elicits therapeutic efficacy when applied at various doses and schedules. Continuous exposure of HDM201 led to induction of p21 and delayed accumulation of apoptotic cells. By comparison, high-dose pulses of HDM201 were associated with marked induction of PUMA and a rapid onset of apoptosis. shRNA screens identified PUMA as a mediator of the p53 response specifically in the pulsed regimen. Consistent with this, the single high-dose HDM201 regimen resulted in rapid and marked induction of PUMA expression and apoptosis together with downregulation of Bcl-xL in vivo Knockdown of Bcl-xL was identified as the top sensitizer to HDM201 in vitro, and Bcl-xL was enriched in relapsing tumors from mice treated with intermittent high doses of HDM201. These findings define a regimen-dependent mechanism by which disruption of MDM2-p53 elicits therapeutic efficacy when given with infrequent dosing. In an ongoing HDM201 trial, the observed exposure-response relationship indicates that the molecular mechanism elicited by pulse dosing is likely reproducible in patients. These data support the clinical comparison of daily and intermittent regimens of p53-MDM2 inhibitors.Significance: Pulsed high doses versus sustained low doses of the p53-MDM2 inhibitor HDM201 elicit a proapoptotic response from wild-type p53 cancer cells, offering guidance to current clinical trials with this and other drugs that exploit the activity of p53. Cancer Res; 78(21); 6257-67. ©2018 AACR.


Assuntos
Antineoplásicos/administração & dosagem , Imidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Proteína Supressora de Tumor p53/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Apoptose , Área Sob a Curva , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazóis/farmacologia , Estimativa de Kaplan-Meier , Dose Máxima Tolerável , Camundongos , Transplante de Neoplasias , Pirimidinas/farmacologia , Pirróis/farmacologia , RNA Interferente Pequeno/metabolismo , Fatores de Tempo , Proteína bcl-X/metabolismo
9.
Proteome Sci ; 4: 7, 2006 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-16643650

RESUMO

Cerebrospinal fluid (CSF) potentially carries an archive of peptides and small proteins relevant to pathological processes in the central nervous system (CNS) and surrounding brain tissue. Proteomics is especially well suited for the discovery of biomarkers of diagnostic potential in CSF for early diagnosis and discrimination of several neurodegenerative diseases. ProteinChip surface-enhanced laser-desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) is one such approach which offers a unique platform for high throughput profiling of peptides and small proteins in CSF. In this study, we evaluated methodologies for the retention of CSF proteins < 20 kDa in size, and identify a strategy for screening small proteins and peptides in CSF. ProteinChip array types, along with sample and binding buffer conditions, and matrices were investigated. By coupling the processing of arrays to a liquid handler reproducible and reliable profiles, with mean peak coefficients of variation < 20%, were achieved for intra- and inter-assays under selected conditions. Based on peak m/z we found a high degree of overlap between the tested array surfaces. The combination of CM10 and IMAC30 arrays was sufficient to represent between 80-90% of all assigned peaks when using either sinapinic acid or alpha-Cyano-4-hydroxycinnamic acid as the energy absorbing matrices. Moreover, arrays processed with SPA consistently showed better peak resolution and higher peak number across all surfaces within the measured mass range. We intend to use CM10 and IMAC30 arrays prepared in sinapinic acid as a fast and cost-effective approach to drive decisions on sample selection prior to more in-depth discovery of diagnostic biomarkers in CSF using alternative but complementary proteomic strategies.

10.
Toxicology ; 209(2): 101-7, 2005 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-15767020

RESUMO

Haptens are classified as low molecular chemicals with an intrinsic potential to covalently modify proteins, and many of them are strong inducers of contact hypersensitivity (CHS). CHS is T cell mediated, and hapten-specific T cells have been shown to interact with hapten-modified, MHC-associated peptides. However, the most common contact sensitizer in the industrialized world is nickel. In contrast to classical haptens, nickel ions do not form covalent bonds to proteins, but rather become caught in reversible coordination complexes. We here review work demonstrating that some T cells, indeed, may react to such Ni complexes on the MHC/peptide-surface absolutely comparable to other haptens. In other cases, Ni ions unlike classical haptens, may activate T cells by crosslinking their receptors to MHC molecules, independent of the nature of the associated peptide. Moreover, Ni-interacting proteins appear to make use of the reversibility of Ni-binding, and to mediate the transfer of Ni-ions to the receptor-MHC interphase. We have demonstrated such properties for human serum albumin (HSA) as well as for transferrin and identified numerous new Ni-binding proteins in human B-cell lines or dendritic cells by affinity purification and mass spectroscopy. These proteins include a notable number of known heat shock proteins and chaperones, implying that Ni may functionally interfere with these stress proteins.


Assuntos
Haptenos/imunologia , Hipersensibilidade/imunologia , Metais/imunologia , Níquel/imunologia , Receptores de Antígenos de Linfócitos T/efeitos dos fármacos , Animais , Proteínas de Transporte/imunologia , Epitopos , Haptenos/toxicidade , Humanos , Complexo Principal de Histocompatibilidade/imunologia , Metais/toxicidade , Níquel/toxicidade , Receptores de Antígenos de Linfócitos T/imunologia
11.
Proteomics ; 5(14): 3614-22, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16097032

RESUMO

Metal-protein interactions are vitally important in all living organisms. Metalloproteins, including structural proteins and metabolic enzymes, participate in energy transfer and redox reactions or act as metallochaperones in metal trafficking. Among metal-associated diseases, T cell mediated allergy to nickel (Ni) represents the most common form of human contact hypersensitivity. With the aim to elucidate disease-underlying mechanisms such as Ni-specific T cell activation, we initiated a proteomic approach to identify Ni-interacting proteins in human B cells. As antigen presenting cells, B cells are capable of presenting MHC-associated Ni-epitopes to T cells, a prerequisite for hapten-specific T cell activation. Using metal-affinity enrichment, 2-DE and MS, 22 Ni-interacting proteins were identified. In addition to known Ni-binding molecules such as tubulin, actin or cullin-2, we unexpectedly discovered that at least nine of these 22 proteins belong to stress-inducible heat shock proteins or chaperonins. Enrichment was particularly effective for the hetero-oligomeric TRiC/CCT complex, which is involved in MHC class I processing. Blue Native/SDS electrophoresis analysis revealed that Ni-NTA-beads specifically retained the complete protein machinery, including the associated chaperonin substrate tubulin. The apparent Ni-affinity of heat shock proteins suggests a new function of these molecules in human Ni allergy, by linking innate and adaptive immune responses.


Assuntos
Linfócitos B/metabolismo , Metais/metabolismo , Western Blotting , Linhagem Celular , Cromatografia de Afinidade , Eletroforese em Gel Bidimensional , Humanos , Ligação Proteica , Proteômica
12.
Toxicol Pathol ; 31(5): 471-9, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14692614

RESUMO

Toxicogenomics represents the merging of toxicology with technologies that have been developed, together with bioinformatics, to identify and quantify global gene expression changes. It represents a new paradigm in drug development and risk assessment, which promises to generate a wealth of information towards an increased understanding of the molecular mechanisms that lead to drug toxicity and efficacy, and of DNA polymorphisms responsible for individual susceptibility to toxicity. Gene expression profiling, through the use of DNA microarray and proteomic technologies will aid in establishing links between expression profiles, mode of action and traditional toxic endpoints. Such patterns of gene expression, or 'molecular fingerprints' could be used as diagnostic or predictive markers of exposure, that is characteristic of a specific mechanism of induction of that toxic or efficacious effect. It is anticipated that toxicogenomics will be increasingly integrated into all phases of the drug development process particularly in mechanistic and predictive toxicology, and biomarker discovery. This review provides an overview of the expression profiling technologies applied in toxicogenomics. and discusses the promises as well as the future challenges of applying this discipline to the drug development process.


Assuntos
Desenho de Fármacos , Toxicogenética , Animais , Biomarcadores , Biologia Computacional , Perfilação da Expressão Gênica , Genômica , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Proteômica , Toxicologia
13.
J Mol Microbiol Biotechnol ; 7(3): 140-7, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15263818

RESUMO

To elucidate the mechanisms of pH response in an acid-tolerant Sinorhizobium medicae strain we have identified acid-activated gene transcription and now complement this approach by using a proteomic analysis to identify the changes that occur following exposure to acidity. Protein profiles of persistently or transiently acid-stressed S. medicae cells were compared to those grown in pH neutral, buffered media. Fifty pH-regulated proteins were identified; N-terminal sequences for 15 of these were obtained using the Edman degradation. Transient acid exposure downregulated GlnA and GlnK and upregulated a hypothetical protein. Continuing acid exposure downregulated ClpP, an ABC transporter, a hypothetical protein, a lipoprotein, the Trp-like repressor WrbA1 and upregulated DegP, fructose bisphosphate aldolase, GroES, malate dehydrogenase and two hypothetical proteins. These findings implicate proteolytic, chaperone and transport processes as key components of pH response in S. medicae.


Assuntos
Proteínas de Bactérias/genética , Regulação Bacteriana da Expressão Gênica/genética , Concentração de Íons de Hidrogênio , Proteoma , Sinorhizobium/genética , Sequência de Aminoácidos , Dados de Sequência Molecular , Fragmentos de Peptídeos/química
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