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1.
Mol Cancer Ther ; 23(3): 285-300, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38102750

RESUMO

The estrogen receptor (ER) is a well-established target for the treatment of breast cancer, with the majority of patients presenting as ER-positive (ER+). Endocrine therapy is a mainstay of breast cancer treatment but the development of resistance mutations in response to aromatase inhibitors, poor pharmacokinetic properties of fulvestrant, agonist activity of tamoxifen, and limited benefit for elacestrant leave unmet needs for patients with or without resistance mutations in ESR1, the gene that encodes the ER protein. Here we describe palazestrant (OP-1250), a novel, orally bioavailable complete ER antagonist and selective ER degrader. OP-1250, like fulvestrant, has no agonist activity on the ER and completely blocks estrogen-induced transcriptional activity. In addition, OP-1250 demonstrates favorable biochemical binding affinity, ER degradation, and antiproliferative activity in ER+ breast cancer models that is comparable or superior to other agents of interest. OP-1250 has superior pharmacokinetic properties relative to fulvestrant, including oral bioavailability and brain penetrance, as well as superior performance in wild-type and ESR1-mutant breast cancer xenograft studies. OP-1250 combines well with cyclin-dependent kinase 4 and 6 inhibitors in xenograft studies of ER+ breast cancer models and effectively shrinks intracranially implanted tumors, resulting in prolonged animal survival. With demonstrated preclinical efficacy exceeding fulvestrant in wild-type models, elacestrant in ESR1-mutant models, and tamoxifen in intracranial xenografts, OP-1250 has the potential to benefit patients with ER+ breast cancer.


Assuntos
Neoplasias da Mama , Tetra-Hidronaftalenos , Animais , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Fulvestranto/farmacologia , Fulvestranto/uso terapêutico , Antagonistas do Receptor de Estrogênio/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Tamoxifeno , Estrogênios , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo
2.
Toxicol Sci ; 175(1): 24-34, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32077954

RESUMO

Transforming growth factor ß (TGFß) signaling has been recently shown to reduce antitumor response to PD-L1 blockade, leading to a renewed enthusiasm in developing anti-TGFß therapies for potential combination with cancer immunotherapy agents. Inhibition of TGFß signaling in nonclinical toxicology species is associated with serious adverse toxicities including cardiac valvulopathies and anemia. Previously, cardiovascular toxicities have been thought to be limited to small molecule inhibitors of TGFß receptor and not considered to be a liability associated with pan-TGFß neutralizing monoclonal antibodies (mAbs). Here, we report the toxicity findings associated with a potent pan-TGFß neutralizing mAb (pan-TGFß mAb; neutralizes TGFß1, 2, and 3) after 5 weekly intravenous doses of 10, 30, and 100 mg/kg, followed by a 4-week recovery period, in mice and cynomolgus monkeys. Mortality was observed due to acute bleeding and cardiovascular toxicity in mice at ≥ 30 mg/kg and prolonged menstruation in female monkeys at 100 mg/kg. Additional findings considered to be on-target exaggerated pharmacology included generalized bleeding and cardiovascular toxicity in mice and monkeys; histopathologic changes in the teeth, tongue, and skin in mice; and abnormal wound healing and microscopic pathology in the bone in monkeys. Importantly, our data indicate that the cardiovascular toxicities associated with the inhibition of TGFß signaling are not limited to small molecule inhibitors but are also observed following administration of a potent pan-TGFß inhibiting mAb.


Assuntos
Anticorpos Monoclonais Humanizados/toxicidade , Anticorpos Neutralizantes/toxicidade , Doenças Cardiovasculares/induzido quimicamente , Coração/efeitos dos fármacos , Fator de Crescimento Transformador beta/antagonistas & inibidores , Animais , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Neutralizantes/sangue , Cardiotoxicidade , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Linhagem Celular , Feminino , Hemorragia/induzido quimicamente , Hemorragia/metabolismo , Humanos , Macaca fascicularis , Masculino , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Medição de Risco , Fatores de Tempo , Testes de Toxicidade , Toxicocinética , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo
3.
Toxicol Pathol ; 43(7): 995-1003, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26059827

RESUMO

Three orally administered metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators caused skin lesions consistent with delayed type-IV hypersensitivity in cynomolgus macaques in 2- and 12-week toxicity studies. Several monkeys developed macroscopic skin lesions in multiple locations after 8 to 9 days of dosing; the most prominent effects involved the genital region of males and generalized erythema occurred in both sexes. Microscopic lesions occurred in both clinically affected and unaffected areas and were characterized by lymphocytic interface inflammation, subepidermal bullae, and individual keratinocyte vacuolation/necrosis. In the 12-week study, clinical effects in 2 animals resolved with continued dosing, whereas in others the inflammatory process progressed with 1 female exhibiting systemic lymphocytic inflammation in multiple tissues. The inflammatory infiltrate consisted of CD3 and CD4 positive T lymphocytes with minimal CD68 positive macrophages and only rare CD8 positive T lymphocytes. A subset of animals given a dosing holiday was subsequently rechallenged with similar lesions developing but with a more rapid clinical onset. These skin lesions were consistent with type-IV delayed hypersensitivity with some features comparable to bullous drug eruptions in humans. A relationship between these findings and the intended mode of action for these compounds could not be ruled out, given the occurrence across different chemotypes.


Assuntos
Antiparkinsonianos/toxicidade , Toxidermias/etiologia , Toxidermias/patologia , Compostos Heterocíclicos com 3 Anéis/toxicidade , Compostos Heterocíclicos de 4 ou mais Anéis/toxicidade , Piridinas/toxicidade , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Animais , Feminino , Imuno-Histoquímica , Macaca fascicularis , Masculino
4.
Toxicol Pathol ; 42(6): 970-83, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24067673

RESUMO

Thionamides such as propylthiouracil (PTU) and methimazole (MMI) have been used for more than 50 years to treat the more common causes of thyrotoxicosis/hyperthyroidism such as Graves' disease. Serious adverse effects associated with thionamides in humans include idiosyncratic liver damage, agranulocytosis, aplastic anemia, and vasculitis. Both prospective and retrospective clinical studies with these drugs have failed to identify predictive biomarker for these adverse effects. To assess whether rat is a good model for predicting drug-related adverse events in the liver and in the bone marrow, we conducted a comprehensive study in male rats with multiple doses of PTU and MMI. As expected, euthyroid animals became hypothyroid along with several secondary changes associated with hypothyroidism. There were slight reductions in red blood cell parameters along with some marginal effects on the bone marrow elements. However, there was no evidence of significant neutropenia and liver injury in both PTU-treated and MMI-treated cohorts. MMI-related effects were noted in the seminiferous tubules of the testes. Overall, 1-month daily treatment of euthyroid rats with PTU or MMI resulted in hypothyroidism, minor bone marrow effects, and several secondary effects associated with hypothyroidism, but without any evidence of adverse effects reported in humans including liver injury and agranulocytosis.


Assuntos
Metimazol/toxicidade , Propiltiouracila/toxicidade , Testículo/efeitos dos fármacos , Glândula Tireoide/efeitos dos fármacos , Animais , Masculino , Metimazol/administração & dosagem , Metimazol/sangue , Metimazol/farmacocinética , Propiltiouracila/administração & dosagem , Propiltiouracila/sangue , Propiltiouracila/farmacocinética , Ratos , Ratos Wistar , Testículo/química , Testículo/patologia , Glândula Tireoide/química , Glândula Tireoide/patologia , Testes de Toxicidade
5.
PLoS One ; 7(3): e34148, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22493658

RESUMO

The typical host response to infection of humans and some animals by M. tuberculosis is the accumulation of reactive oxygen species generating inflammatory cells into discrete granulomas, which frequently develop central caseous necrosis. In previous studies we showed that infection of immunologically naïve guinea pigs with M. tuberculosis leads to localized and systemic oxidative stress that results in a significant depletion of serum total antioxidant capacity and the accumulation of malondialdehyde, a bi-product of lipid peroxidation. Here we show that in addition, the generation of excessive reactive oxygen species in vivo resulted in the accumulation of oxidized low density lipoproteins (OxLDL) in pulmonary and extrapulmonary granulomas, serum and lung macrophages collected by bronchoalveolar lavage. Macrophages from immunologically naïve guinea pigs infected with M. tuberculosis also had increased surface expression of the type 1 scavenger receptors CD36 and LOX1, which facilitate the uptake of oxidized host macromolecules including OxLDL. Vaccination of guinea pigs with Bacillus Calmette Guerin (BCG) prior to aerosol challenge reduced the bacterial burden as well as the intracellular accumulation of OxLDL and the expression of macrophage CD36 and LOX1. In vitro loading of guinea pig lung macrophages with OxLDL resulted in enhanced replication of bacilli compared to macrophages loaded with non-oxidized LDL. Overall, this study provides additional evidence of oxidative stress in M. tuberculosis infected guinea pigs and the potential role OxLDL laden macrophages have in supporting intracellular bacilli survival and persistence.


Assuntos
Lipoproteínas LDL/metabolismo , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose Pulmonar/metabolismo , Animais , Vacina BCG/administração & dosagem , Antígenos CD36/metabolismo , Cobaias , Imuno-Histoquímica , Pulmão/metabolismo , Macrófagos Alveolares/imunologia , Tuberculose Pulmonar/microbiologia
6.
PLoS One ; 6(10): e26254, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22028843

RESUMO

The development of granulomatous inflammation with caseous necrosis is an important but poorly understood manifestation of tuberculosis in humans and some animal models. In this study we measured the byproducts of oxidative stress in granulomatous lesions as well as the systemic antioxidant capacity of BCG vaccinated and non-vaccinated guinea pigs experimentally infected with Mycobacterium tuberculosis. In non-vaccinated guinea pigs, oxidative stress was evident within 2 weeks of infection as measured by a decrease in the serum total antioxidant capacity and blood glutathione levels accompanied by an increase in malondialdehyde, a byproduct of lipid peroxidation, within lesions. Despite a decrease in total and reduced blood glutathione concentrations, there was an increase in lesion glutathione by immunohistochemistry in response to localized oxidative stress. In addition there was an increase in the expression of the host transcription factor nuclear erythroid 2 p45-related factor 2 (Nrf2), which regulates several protein and non-proteins antioxidants, including glutathione. Despite the increase in cytoplasmic expression of Nrf2, immunohistochemical staining revealed a defect in Nrf2 nuclear translocation within granulomatous lesions as well as a decrease in the expression of the Nrf2-regulated antioxidant protein NQO1. Treating M. tuberculosis-infected guinea pigs with the antioxidant drug N-acetyl cysteine (NAC) partially restored blood glutathione concentrations and the serum total antioxidant capacity. Treatment with NAC also decreased spleen bacterial counts, as well as decreased the lung and spleen lesion burden and the severity of lesion necrosis. These data suggest that the progressive oxidative stress during experimental tuberculosis in guinea pigs is due in part to a defect in host antioxidant defenses, which, we show here, can be partially restored with antioxidant treatment. These data suggest that the therapeutic strategies that reduce oxidant-mediated tissue damage may be beneficial as an adjunct therapy in the treatment and prevention of tuberculosis in humans.


Assuntos
Antioxidantes/metabolismo , Estresse Oxidativo , Tuberculose/metabolismo , Acetilcisteína/farmacologia , Animais , Carga Bacteriana/efeitos dos fármacos , Carga Bacteriana/imunologia , Progressão da Doença , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Glutationa/sangue , Cobaias , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Malondialdeído/metabolismo , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Mycobacterium tuberculosis/fisiologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Tuberculose/sangue , Tuberculose/patologia , Tuberculose/prevenção & controle , Vacinação
7.
Tuberculosis (Edinb) ; 91(5): 378-85, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21737349

RESUMO

There is increasing evidence that clinical isolates of Mycobacterium tuberculosis that belong to the W-Beijing genotype of newly emerging strains are often of very high virulence when tested in small animal models, including the mouse and guinea pig. In this report we provide further evidence to support this contention, and show that two W-Beijing strains are of very high virulence when introduced by low dose aerosol into outbred guinea pigs. In addition to severe lung pathology, each of these infections was associated with large influxes of activated CD4 and CD8 T cells into the lungs. Large influxes of macrophages were also observed, but the fraction of these showing evidence of activation by Class-II expression was relatively low. A progressive increase in neutrophils was also seen, with highest levels accumulating in the lungs of the W-Beijing infected animals. In the case of these two infections mRNA levels for TH1 cytokines was elevated early, but these then declined, and were replaced by increasing levels of message encoding for Foxp3, IL-10, and TGFß. These observations support the hypothesis that W-Beijing strains are potent inducers of regulatory T cells, and that this event may enhance survival and transmission of these bacilli.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Fatores de Transcrição Forkhead/metabolismo , Pulmão/imunologia , Pulmão/patologia , Mycobacterium tuberculosis/patogenicidade , RNA Mensageiro/imunologia , Tuberculose Pulmonar/patologia , Animais , Farmacorresistência Bacteriana Múltipla , Feminino , Citometria de Fluxo , Cobaias , Imuno-Histoquímica , Interleucina-10/imunologia , Mycobacterium tuberculosis/imunologia , Receptores de Fatores de Crescimento Transformadores beta/imunologia , Linfócitos T Reguladores/imunologia , Tuberculose Pulmonar/imunologia , Regulação para Cima , Virulência
8.
Tuberculosis (Edinb) ; 89(3): 203-9, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19251482

RESUMO

Virtually all new tuberculosis vaccine candidates are tested in animals using the laboratory strains H37Rv or Erdman. However, naturally occurring M. tuberculosis infections are caused by strains that are widely different in phenotype and genotype. Very little is known about the characteristics of these clinical isolates in terms of basic biology, virulence and in vivo pathogenicity. In this study, we have used a standardized aerosol infection of guinea pigs to compare in vivo differences between clinical strains of M. tuberculosis. Strains consisted of both drug sensitive and multi-drug resistant (MDR) strains of Beijing and non-Beijing varieties. Collectively, these clinical isolates tested in the guinea pig model exhibited a wide range of virulence. Infection with certain isolates caused severe and rapidly progressive pulmonary and extra-pulmonary lesion necrosis, some of which progressed to atypical cavitary lesions in draining mediastinal and tracheobronchial lymph nodes. The two MDR-TB strains used in this study exhibited low level virulence as determined by bacterial growth, lesion scores and survival. Since infections with clinical M. tuberculosis isolates produce such varied disease, it is unknown whether new tuberculosis vaccines being developed will provide the same level of protection as seen when tested using laboratory challenge strains. The use of appropriate animal models allows for this important question to be addressed.


Assuntos
Mycobacterium tuberculosis/patogenicidade , Tuberculose Pulmonar/microbiologia , Animais , Farmacorresistência Bacteriana Múltipla/genética , Feminino , Genótipo , Cobaias , Pulmão/patologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/crescimento & desenvolvimento , Especificidade da Espécie , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/patologia , Virulência
9.
Tuberculosis (Edinb) ; 88(4): 295-306, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18321783

RESUMO

Virulence is the measure of pathogenicity of a microorganism as determined by its ability to invade host tissues and to produce severe disease. In the low-dose aerosol guinea pig model the virulence of multiple strains of Mycobacterium tuberculosis was determined by measuring time of survival, bacterial loads in target organs, and the severity of pulmonary and extra-pulmonary lesions. Erdman K01, CSU93/CDC1551 and HN878 had shorter survival times compared to the common laboratory strain H37Rv. After 30 days of the infection bacilli had disseminated from the lungs resulting in microscopically visible lesions in peribronchial lymph nodes, peripancreatic lymph nodes, spleen, liver, pancreas, adrenal and heart. The extent of the lesion necrosis paralleled virulence when survival times were used as a measure as Erdman K01 and the two clinical isolates caused more necrosis and resulted in sooner death in infected animals than the H37Rv. The extent of extra-pulmonary lesion necrosis was a better predictor of virulence than the number of viable bacilli in the tissue. Overall, this study emphasizes the point that extra-pulmonary disease is a prominent feature of the guinea pig model and dissemination to organs not normally assayed such as the heart and adrenal glands should be taken into account in the assessment of the disease process.


Assuntos
Mycobacterium tuberculosis/patogenicidade , Virulência/fisiologia , Aerossóis , Animais , Modelos Animais de Doenças , Progressão da Doença , Feminino , Cobaias , Pulmão/microbiologia , Índice de Gravidade de Doença , Tuberculose Pulmonar/microbiologia
10.
Mol Endocrinol ; 20(11): 2784-95, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16887885

RESUMO

The steroid hormone progesterone (P) plays a pivotal role during ovulation. Mice lacking P receptor (Pgr) gene fail to ovulate due to a defect in follicular rupture. The P receptor (PGR)-regulated pathways that modulate ovulation, however, remain poorly understood. To identify these pathways, we performed gene expression profiling using ovaries from mice subjected to gonadotropin-induced superovulation in the presence and in the absence of CDB-2914, a synthetic PGR antagonist. Prominent among the genes that were down-regulated in response to CDB-2914 was endothelin (ET)-2, a potent vasoactive molecule. ET-2 mRNA was transiently induced in mural granulosa cells of the preovulatory follicles immediately preceding ovulation. This induction was absent in the ovaries of PGR null mice, indicating a critical role of this receptor in ET-2 expression. To investigate the functional role of ET-2 during ovulation, we employed selective antagonists of endothelin receptors, ETR-A and ETR-B. Mice treated with an ETR-B antagonist exhibited a dramatic (>85%) decline in the number of released oocytes. Strong expression of ETR-B was observed in the mural and cumulus granulosa cells of the preovulatory follicles as well as in the capillaries lining the inner border of the theca interna. We also identified cGMP-dependent protein kinase II, a previously reported PGR-regulated gene, as a downstream target of ET-2 during ovulation. Collectively, our studies uncovered a unique pathway in which ET-2, produced by PGR in mural granulosa cells, acts in a paracrine or autocrine manner on multiple cell types within the preovulatory follicle to control the final events leading to its rupture.


Assuntos
Endotelina-2/fisiologia , Ovulação/fisiologia , Receptor de Endotelina B/fisiologia , Receptores de Endotelina/fisiologia , Receptores de Progesterona/fisiologia , Animais , Antagonistas do Receptor de Endotelina B , Antagonistas dos Receptores de Endotelina , Endotelina-2/metabolismo , Feminino , Células da Granulosa/metabolismo , Camundongos , Camundongos Knockout , Modelos Biológicos , Norpregnadienos/administração & dosagem , Folículo Ovariano/metabolismo , Ovário/citologia , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovulação/efeitos dos fármacos , Progestinas/antagonistas & inibidores , RNA Mensageiro/metabolismo , Receptor de Endotelina B/metabolismo , Receptores de Endotelina/metabolismo , Receptores de Progesterona/genética , Transdução de Sinais/fisiologia
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