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1.
Alcohol Clin Exp Res ; 34(10): 1793-802, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20626729

RESUMO

BACKGROUND: Drinking during pregnancy has been associated with learning disabilities in affected offspring. At present, there are no clinically effective pharmacotherapeutic interventions for these learning deficits. Here, we examined the effects of ABT-239, a histamine H3 receptor antagonist, on fetal ethanol-induced fear conditioning and spatial memory deficits. METHODS AND RESULTS: Long-Evans rat dams stably consumed a mean of 2.82 g ethanol/kg during a 4-hour period each day during pregnancy. This voluntary drinking pattern produced a mean peak serum ethanol level of 84 mg/dl. Maternal weight gain, litter size and birth weights were not different between the ethanol-consuming and control groups. Female adult offspring from the control and fetal alcohol-exposed (FAE) groups received saline or 1 mg ABT-239/kg 30 minutes prior to fear conditioning training. Three days later, freezing time to the context was significantly reduced in saline-treated FAE rats compared to control. Freezing time in ABT-239-treated FAE rats was not different than that in controls. In the spatial navigation study, adult male offspring received a single injection of saline or ABT-239 30 minutes prior to 12 training trials on a fixed platform version of the Morris Water Task. All rats reached the same performance asymptote on Trials 9 to 12 on Day 1. However, 4 days later, first-trial retention of platform location was significantly worse in the saline-treated FAE rats compared control offspring. Retention by ABT-239-treated FAE rats was similar to that by controls. ABT-239's effect on spatial memory retention in FAE rats was dose dependent. CONCLUSIONS: These results suggest that ABT-239 administered prior to training can improve retention of acquired information by FAE offspring on more challenging versions of hippocampal-sensitive learning tasks. Further, the differential effects of ABT-239 in FAE offspring compared to controls raises questions about the impact of fetal ethanol exposure on histaminergic neurotransmission in affected offspring.


Assuntos
Benzofuranos/uso terapêutico , Etanol/efeitos adversos , Deficiências da Aprendizagem/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Nootrópicos/uso terapêutico , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Pirrolidinas/uso terapêutico , Animais , Condicionamento Clássico/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Antagonistas dos Receptores Histamínicos/farmacologia , Deficiências da Aprendizagem/induzido quimicamente , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/psicologia , Ratos , Ratos Long-Evans , Receptores Histamínicos H3/efeitos dos fármacos
2.
Mol Cancer Ther ; 19(11): 2235-2244, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32967924

RESUMO

B7-H3, also referred to as CD276, is a member of the B7 family of immune regulatory proteins. B7-H3 is overexpressed on many solid cancers, including prostate cancer, renal cell carcinoma, melanoma, squamous cell carcinoma of the head and neck, non-small cell lung cancer, and breast cancer. Overexpression of B7-H3 is associated with disease severity, risk of recurrence and reduced survival. In this article, we report the preclinical development of MGC018, an antibody-drug conjugate targeted against B7-H3. MGC018 is comprised of the cleavable linker-duocarmycin payload, valine-citrulline-seco duocarmycin hydroxybenzamide azaindole (vc-seco-DUBA), conjugated to an anti-B7-H3 humanized IgG1/kappa mAb through reduced interchain disulfides, with an average drug-to-antibody ratio of approximately 2.7. MGC018 exhibited cytotoxicity toward B7-H3-positive human tumor cell lines, and exhibited bystander killing of target-negative tumor cells when cocultured with B7-H3-positive tumor cells. MGC018 displayed potent antitumor activity in preclinical tumor models of breast, ovarian, and lung cancer, as well as melanoma. In addition, antitumor activity was observed toward patient-derived xenograft models of breast, prostate, and head and neck cancer displaying heterogeneous expression of B7-H3. Importantly, MGC018 exhibited a favorable pharmacokinetic and safety profile in cynomolgus monkeys following repeat-dose administration. The antitumor activity observed preclinically with MGC018, together with the positive safety profile, provides evidence of a potentially favorable therapeutic index and supports the continued development of MGC018 for the treatment of solid cancers. GRAPHICAL ABSTRACT: http://mct.aacrjournals.org/content/molcanther/19/11/2235/F1.large.jpg.


Assuntos
Antígenos B7/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Inibidores de Checkpoint Imunológico/farmacologia , Imunoconjugados/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antígenos B7/genética , Antígenos B7/metabolismo , Efeito Espectador , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Técnicas de Silenciamento de Genes , Humanos , Inibidores de Checkpoint Imunológico/química , Inibidores de Checkpoint Imunológico/isolamento & purificação , Imunoconjugados/química , Imunoconjugados/isolamento & purificação , Camundongos , Neoplasias/metabolismo , Neoplasias/patologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Alcohol ; 44(7-8): 673-90, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20053520

RESUMO

Many children adversely affected by maternal drinking during pregnancy cannot be identified early in life using current diagnostic criteria for fetal alcohol spectrum disorder (FASD). We conducted a preliminary investigation to determine whether ethanol-induced alterations in placental gene expression may have some utility as a diagnostic indicator of maternal drinking during pregnancy and as a prognostic indicator of risk for adverse neurobehavioral outcomes in affected offspring. Pregnant Long-Evans rats voluntarily consumed either a 0 or 5% ethanol solution 4 h each day throughout gestation. Ethanol consumption produced a mean maternal daily intermittent peak serum ethanol concentration of 84 mg/dL. Placentas were harvested on gestational day 20 for gene expression studies. Microarray analysis of more than 28,000 genes revealed that the expression of 304 known genes was altered twofold or greater in placenta from ethanol-consuming dams compared with controls. About 76% of these genes were repressed in ethanol-exposed placentas. Gene expression changes involved proteins associated with central nervous system development; organ morphogenesis; immunological responses; endocrine function; ion homeostasis; and skeletal, cardiovascular, and cartilage development. To date, quantitative real-time polymerase chain reaction analysis has confirmed significant alterations in gene expression for 22 genes, including genes encoding for three calcium binding proteins, two matrix metalloproteinases, the cannabinoid 1, galanin 2 and toll-like receptor 4, iodothyronine deiodinase 2, 11-ß hydroxysteroid dehydrogenase 2, placental growth factor, transforming growth factor alpha, gremlin 1, and epithelial growth factor (EGF)-containing extracellular matrix protein. These results suggest that the expression of a sufficiently large number of placental mRNAs is altered after moderate drinking during pregnancy to warrant more detailed investigation of the placenta as a biomarker system for maternal drinking during pregnancy and as an early indicator of FASD. Furthermore, these results provide new insights into novel mechanisms on how ethanol may directly or indirectly mediate its teratogenic effects through alterations in placental function during pregnancy.


Assuntos
Etanol/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Placenta/metabolismo , Proteínas da Gravidez/genética , Animais , DNA Complementar/biossíntese , Etanol/sangue , Feminino , Idade Gestacional , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Placenta/química , Placenta/efeitos dos fármacos , Reação em Cadeia da Polimerase , Gravidez , RNA/análise , RNA Mensageiro/análise , Ratos , Ratos Long-Evans
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