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1.
Anticancer Drugs ; 29(4): 295-306, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29389804

RESUMO

Pancreatic cancer is a leading cause of cancer deaths in the USA and is characterized by an exceptionally poor long-term survival rate compared with other major cancers. The hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP) growth factor systems are frequently over-activated in pancreatic cancer and significantly contribute to cancer progression, metastasis, and chemotherapeutic resistance. Small molecules homologous to the 'hinge' region of HGF, which participates in its dimerization and activation, had been developed and shown to bind HGF with high affinity, antagonize HGF's actions, and possess anticancer activity. Encouraged by sequence homology between HGF's hinge region and a similar sequence in MSP, our laboratory previously investigated and determined that these same antagonists could also block MSP-dependent cellular responses. Thus, the purpose of this study was to establish that the dual HGF/MSP antagonist Norleual could inhibit the prosurvival activity imparted by both HGF and MSP to pancreatic cancer cells in vitro, and to determine whether this effect translated into an improved chemotherapeutic impact for gemcitabine when delivered in combination in a human pancreatic cancer xenograft model. Our results demonstrate that Norleual does indeed suppress HGF's and MSP's prosurvival effects as well as sensitizing pancreatic cancer cells to gemcitabine in vitro. Most importantly, treatment with Norleual in combination with gemcitabine markedly inhibited in-vivo tumor growth beyond the suppression observed with gemcitabine alone. These results suggest that dual functional HGF/MSP antagonists like Norleual warrant further development and may offer an improved therapeutic outcome for pancreatic cancer patients.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Fator de Crescimento de Hepatócito/antagonistas & inibidores , Oligopeptídeos/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Animais , Antimetabólitos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Sinergismo Farmacológico , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , Oligopeptídeos/farmacologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia , Proteínas Proto-Oncogênicas/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
2.
Muscle Nerve ; 50(4): 541-8, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24449511

RESUMO

INTRODUCTION: Dystrophinopathy in the young mdx mouse model of Duchenne muscular dystrophy is comparatively mild, requires induction, and is rarely assessed with tests of systemic muscle function in whole animals. METHODS: A modified TREAT-NMD induction protocol was used to evaluate respiratory and exercise performance, starting and ending with maximum oxygen consumption (VO2max ) tests. RESULTS: The initial and/or final VO2max , time to exhaustion, speed at exhaustion, and total expended calories were significantly lower in mdx mice. Episodic VO2 and VCO2 fluctuations occurred during training and resulted in dissociated patterns of VO2 and respiratory exchange ratio (RER). These fluctuations further resulted in significantly greater VO2 coefficient of variation and RER values and lower minimal VO2 values. CONCLUSIONS: Quantifying respiratory performance during exercise is a potentially useful means for studying pathophysiology in mdx mice, as it assesses intact animals over time, is more sensitive than some histological markers, and assesses systemic muscle function.


Assuntos
Distrofia Muscular de Duchenne/complicações , Condicionamento Físico Animal/fisiologia , Insuficiência Respiratória/etiologia , Animais , Colágeno/metabolismo , Estudos Transversais , Modelos Animais de Doenças , Metabolismo Energético/fisiologia , Teste de Esforço , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/etiologia , Consumo de Oxigênio , Condicionamento Físico Animal/efeitos adversos , Testes de Função Respiratória , Fatores de Tempo
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