RESUMO
PURPOSE: Ixabepilone, a semisynthetic analog of natural epothilone B, was developed for use in cancer treatment. This study extends previous findings regarding the efficacy of ixabepilone and its low susceptibility to tumor resistance mechanisms and describes the pharmacokinetics of this new antineoplastic agent. METHODS: The cytotoxicity of ixabepilone was assessed in vitro in breast, lung, and colon tumor cell lines and in vivo in human xenografts in mice. Antitumor activities of ixabepilone and taxanes were compared in multidrug-resistant models in vivo. Differential drug uptake of ixabepilone and paclitaxel was assessed in a P-glycoprotein (P-gp)-resistant colon cancer model in vitro. The pharmacokinetic profile of ixabepilone was established in mice and humans. RESULTS: Ixabepilone demonstrated potent cytotoxicity in a broad range of human cancer cell lines in vitro and in a wide range of xenografts in vivo. Ixabepilone was *3-fold more potent than docetaxel in the paclitaxel-resistant Pat-21 xenograft model (resistant due to overexpression of betaIII-tubulin and a lack of betaII-tubulin). Ixabepilone activity against P-gp-overexpressing breast and colon cancer was confirmed in in vivo models. Cellular uptake of ixabepilone, but not paclitaxel, was established in a P-gp-overexpressing model. The pharmacokinetics of ixabepilone was characterized by rapid tissue distribution and extensive tissue binding. CONCLUSIONS: Cytotoxicity studies against a range of tumor types in vitro and in vivo demonstrate that ixabepilone has potent and broad-spectrum antineoplastic activity. This is accompanied by favorable pharmacokinetics. Ixabepilone has reduced susceptibility to resistance due to P-gp overexpression, tubulin mutations, and alterations in beta-tubulin isotype expression.
Assuntos
Antineoplásicos , Epotilonas , Neoplasias , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Área Sob a Curva , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Epotilonas/farmacocinética , Epotilonas/farmacologia , Epotilonas/uso terapêutico , Feminino , Humanos , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Nus , Camundongos SCID , Transplante de Neoplasias , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Moduladores de Tubulina/farmacocinética , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Fractionation of a methanol extract of the leaves and twigs of Casearia sylvestris, as directed by activity against KB cell cytotoxicity, led to the isolation of three novel clerodane diterpenoids, casearvestrins A-C (1-3). The structures of 1-3 were deduced from one- and two-dimensional NMR experiments, including relative stereochemical assignments based on ROESY correlations and COSY coupling constants. All three compounds displayed promising bioactivity, both in cytotoxicity assays against a panel of tumor cell lines and in antifungal assays via the growth inhibition of Aspergillus niger in a disk diffusion assay.