RESUMO
Imatinib mesylate is remarkably effective in treating chronic myeloid leukemia and metastatic gastrointestinal stromal tumors. Meanwhile, anaplastic thyroid carcinoma (ATC) remains a fatal malignancy for which there are currently no effective curative interventions. In chronic myeloid leukemia and gastrointestinal stromal tumors, imatinib inhibits the constitutive tyrosine kinase activity of BCR-ABL and c-KIT, respectively. Reports suggest that imatinib may also be effective against ABL and platelet-derived growth factor receptor kinase-dependent pathological conditions. These mechanisms provide a wide scope of possible clinical applications for the drug. Potentially, diseases instigated by constitutive kinase activity that can be inhibited with imatinib should be treatable with this drug. We evaluated the effects of imatinib on the viability, cycling, and tyrosine phosphorylation of ATC cells in vitro. Our data indicate that imatinib has negligible antineoplastic activity against ATC cell lines within established therapeutically useful concentrations. No constitutive kinase activity was detected in these cell lines that could be exploited as a therapeutic target by imatinib. We conclude that imatinib mesylate monotherapy would not be effective in ATC patients. Current preclinical data do not warrant future clinical studies of imatinib monotherapy for ATC.
Assuntos
Antineoplásicos/farmacologia , Carcinoma/patologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Neoplasias da Glândula Tireoide/patologia , Antineoplásicos/administração & dosagem , Benzamidas , Carcinoma/metabolismo , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Genes abl , Humanos , Mesilato de Imatinib , Proteínas Oncogênicas/genética , Fosforilação/efeitos dos fármacos , Piperazinas/administração & dosagem , Proteínas Proto-Oncogênicas c-abl/metabolismo , Proteínas Proto-Oncogênicas c-kit , Pirimidinas/administração & dosagem , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Neoplasias da Glândula Tireoide/metabolismo , Tirosina/metabolismoRESUMO
Anaplastic thyroid carcinoma (ATC) is a fatal malignancy the clinical outcome of which is unaltered by current therapeutic modalities. A recent phase 1 clinical trial of combretastatin A4 phosphate (CA4P) produced a long-lasting total remission in a patient with ATC. CA4P is a tubulin-binding agent derived from the African bush willow, Combretum caffrum, which possesses tumor vascular-targeting activity. In order to discriminate primary antineoplastic effects from tumor antivascular activity, we evaluated CA4P cytotoxicity in eight human ATC cell lines and compared it to paclitaxel, another tubulin-binding agent with significant clinical activity. CA4P displayed significant cytotoxicity against the ATC cell lines, comparable to that of paclitaxel, and these effects were longer lasting in two cell lines compared to the duration of paclitaxel. We further investigated the effects of CA4P on xenograft tumors from four ATC cell lines injected in athymic nude mice. Significantly lower tumor weights were observed in animals treated with CA4P compared to those treated with vehicle alone. Continuous monitoring of xenograft tumor volumes from one of the ATC cell lines also revealed a significantly lower rate of tumor growth in the CA4P-treated mice compared to those receiving vehicle alone. These results suggest that antitumoral effects of CA4P can be consequent to a combination of primary antineoplastic effects as well as the potential destruction of tumor vasculature.