Assuntos
Imagem de Difusão por Ressonância Magnética , Rabdomiossarcoma Embrionário/irrigação sanguínea , Rabdomiossarcoma Embrionário/diagnóstico por imagem , Neoplasias de Tecidos Moles/irrigação sanguínea , Neoplasias de Tecidos Moles/diagnóstico por imagem , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Nus , Microcirculação , Neovascularização Patológica , Fluxo Sanguíneo Regional , Rabdomiossarcoma Embrionário/metabolismo , Neoplasias de Tecidos Moles/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
PURPOSE: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Current chemotherapy regimes include the topoisomerase II poison etoposide and the transcription inhibitor actinomycin D. Poor clinical response necessitate identification of new agents to improve patient outcomes. METHODS: We assessed the in vitro cytotoxicity (MTT assay) of DNA intercalating agents in five established human RMS cell lines. These include novel classes of transcription inhibitors and topoisomerase poisons, previously shown to have potential as anti-cancer agents. RESULTS: Amongst the former agents, bisintercalating bis(9-aminoacridine-4-carboxamides) linked through the 9-position, and bis(phenazine-1-carboxamides) linked via their side chains, are compared with established transcription inhibitors. Amongst the latter, monofunctional acridine-4-carboxamides related to N-[2-(dimethylamino)ethyl]acridine-4-carboxamide, DACA, are compared with established topoisomerase poisons. CONCLUSIONS: Our findings specifically highlight the topoisomerase poison 9-amino-DACA, its 5-methylsulphone derivative, AS-DACA, and the bis(phenazine-1-carboxamide) transcription inhibitor MLN944/XR5944, currently in phase I trial, as candidates for further research into new agents for the treatment of RMS.
Assuntos
Avaliação Pré-Clínica de Medicamentos , Inibidores da Síntese de Ácido Nucleico/farmacologia , Rabdomiossarcoma Alveolar/tratamento farmacológico , Rabdomiossarcoma Embrionário/tratamento farmacológico , Rabdomiossarcoma/tratamento farmacológico , Inibidores da Topoisomerase , Acridinas/farmacologia , Aminoacridinas/farmacologia , Antígenos de Neoplasias/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Fenazinas/farmacologia , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma Alveolar/enzimologia , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Alveolar/metabolismo , Rabdomiossarcoma Embrionário/enzimologia , Rabdomiossarcoma Embrionário/genética , Rabdomiossarcoma Embrionário/metabolismoRESUMO
Myogenin immunostaining has been described as a useful marker of the alveolar subtype of rhabdomyosarcoma and as a tool for distinguishing it from the more common embryonal subtype. To add to the growing body of literature describing this phenomenon we analysed myogenin immunohistochemical staining in 152 tumors using a rhabdomyosarcoma tissue array. Results were analysed blinded to histological type by two independent investigators. Samples were excluded if any samples failed to stain with desmin and/or myogenin. Mean percentage of myogenin positive cells was significantly greater for ARMS (n = 31; mean percentage positivity 59% (95% confidence intervals +/- 7%) than ERMS (n = 41, mean percentage positivity 16%, 95% confidence intervals +/- 4; P < 0.0001). This data is consistent with previously published studies identifying strong nuclear myogenin staining in a high proportion of cells as a marker of alveolar histology.