RESUMO
PURPOSE: This study aimed to clarify the molecular mechanism mediating the cytotoxicity of axitinib, a selective inhibitor of the vascular endothelial growth factor receptor (VEGFR), in sunitinib-resistant renal cell carcinoma (RCC). METHODS: In our previous study (Sakai et al. in BJU Int 112:E211-E220, 2013), a human RCC cell line, ACHN, resistant to sunitinib (ACHN/R), was developed from a parental cell line (ACHN/P). Differences in molecular phenotypes following treatment with sunitinib or axitinib between these two cell lines were compared. RESULTS: ACHN/R showed an approximately fivefold higher IC50 of sunitinib than ACHN/P; however, there was no significant difference in the sensitivity to axitinib between these two cell lines. In ACHN/R, despite the lack of a difference in the phosphorylated (p)-Akt or STAT-3 expression between treatment with sunitinib and axitinib, the expression of p-p44/42 mitogen-activated protein kinase (MAPK) and p-VEGFR-2 after treatment with axitinib was markedly down-regulated compared with those after treatment with sunitinib. Furthermore, additional treatment of ACHN/R with an inhibitor of MAPK kinase significantly enhanced the cytotoxic activity of sunitinib, but not that of axitinib. In vivo growth of ACHN/R in nude mice after treatment with axitinib was significantly inhibited compared with that following treatment with sunitinib, accompanying the marked inhibition of angiogenesis. CONCLUSIONS: Antitumor activity of axitinib in RCC cells even after the acquisition of resistance to sunitinib could be explained, at least in part, by the inactivation of p44/42 MAPK and VEGFR-2, which were persistently phosphorylated in sunitinib-resistant RCC cells under treatment with sunitinib.
Assuntos
Carcinoma de Células Renais/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Imidazóis/farmacologia , Indazóis/farmacologia , Neoplasias Renais/patologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/farmacologia , Axitinibe , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/genética , Ensaio de Imunoadsorção Enzimática , Humanos , Imuno-Histoquímica , Indóis/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Pirróis/farmacologia , Sunitinibe , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: The objective of this study was to investigate the mechanism mediating the acquisition of a resistant phenotype to sorafenib in renal cell carcinoma (RCC). METHODS: A parental mouse RCC cell line, RenCa (RenCa/P), was continuously exposed to increasing doses of sorafenib, and a cell line resistant to sorafenib (RenCa/R), showing an approximately sixfold higher IC(50) than that of RenCa/P, was established. Changes in the expression of several molecules in these cell lines following sorafenib treatment were evaluated by western blotting, and the effects of sorafenib treatment on the in vivo growth patterns were compared. RESULTS: There were no significant differences in sensitivities to potential agents against RCC between RenCa/P and RenCa/R. Among several apoptosis-related proteins, the expression of clusterin in RenCa/R was significantly greater than that in RenCa/P. Following treatment with sorafenib, the expression level of phosphorylated p44/42 mitogen-activated protein kinase (MAPK) in RenCa/P, but not that in RenCa/R, was significantly decreased. Furthermore, additional treatment with a specific inhibitor of the MAPK signaling pathway significantly increased the sensitivity of RenCa/R to sorafenib, but not that of RenCa/P. There was no significant difference between the in vivo growth patterns of RenCa/P and RenCa/R in mice without sorafenib treatment; however, the growth inhibitory effect of sorafenib on the RenCa/P tumor was significantly greater than that on the RenCa/R tumor. CONCLUSIONS: These findings suggest that the upregulation of clusterin and continuous activation of the MAPK pathway during sorafenib treatment may be involved in the acquisition of a resistance to sorafenib in RCC.
Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Renais , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias Renais , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Animais , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Clusterina/biossíntese , Modelos Animais de Doenças , Concentração Inibidora 50 , Camundongos , Niacinamida/farmacologia , Sorafenibe , TranscriptomaRESUMO
BACKGROUND: Although lasers and intense pulsed light sources have improved the capability of injuring veins without affecting the overlying skin, work is needed to improve the procedure. OBJECTIVE: To create a method for predicting skin reaction to pulsed light. METHODS: Twenty patients were divided into four groups according to skin type (I-IV). An industrial thermometer equipped with a laser-aiming system was adapted to the intense pulsed light source handpiece. Patients received shots of increasing intensity while the skin temperature was measured. RESULTS: Fluence and temperature data were analyzed by logistic regression to evaluate possible injury. The stepwise method selected skin type and temperature variation as predictors of skin injury. Logistic curves indicated the maximum temperature variation tolerable for each skin type. More pigmented skin types tolerated less temperature increase. CONCLUSION: Skin type can predict cutaneous reaction to intense pulsed light through measurements of temperature variation. This method may help achieve successful selective photothermolysis.
Assuntos
Fototerapia , Fenômenos Fisiológicos da Pele/efeitos da radiação , Pele/efeitos da radiação , Feminino , Humanos , Modelos Logísticos , Valores de Referência , Temperatura , Coxa da PernaRESUMO
The surgical treatment of telangiectasis synchronous to sclerotherapy is presented in this paper. Two female patients with extensive telangiectasis of the lower limbs comprise our report. They were considered typical cases for application of the proposed technique: abolishing venous reflux. The adjacent veins were resected through skin incisions of about 2 mm with crochet hooks, under local anesthesia, immobilized with adhesive tape. Sclerotherapy was performed simultaneously. The cosmetic result was excellent in both cases, with complete removal of the telangiectasis. This procedure should be considered the method of choice in the treatment of telangiectasis resulting from obvious venous reflux.
Assuntos
Escleroterapia , Telangiectasia/cirurgia , Drenagem , Feminino , Humanos , Pessoa de Meia-Idade , Telangiectasia/diagnóstico , Telangiectasia/terapia , Varizes/diagnóstico , Varizes/cirurgia , Varizes/terapiaRESUMO
Os autores estudaram 17 doencas submetidas a cirurgia preconizada por Thompson para tratamento de linfedema. Em um doente foram realizadas tres operacoes; em seis, duas cirurgias e nos restantes apenas uma.Treze doentes se beneficiaram com a cirurgia atraves da regressao do fibredema de 50 a 90% e da reducao substancial dos surtos de celulite e erisipela. Descrevem os outros metodos de cirurgia do linfedema analisando vantagens e desvantagens