RESUMO
The use of drug-antibody conjugates affords a method for the targeted delivery of anticancer drugs specifically to cancer cells. Monoclonal antibodies alone usually do not possess high therapeutic efficacy, however, they are capable of targeting tumor markers selectively. We have prepared taxoids with significantly higher cytotoxicity than paclitaxel and docetaxel. These taxoids now meet the high potency required for use in a targeted-delivery approach using monoclonal antibodies. The synthesis and biological evaluation of these taxoids are reported.
Assuntos
Antineoplásicos/síntese química , Sistemas de Liberação de Medicamentos/métodos , Taxoides/síntese química , Antineoplásicos/administração & dosagem , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Taxoides/administração & dosagem , Células Tumorais CultivadasRESUMO
To develop effective taxane-antibody immunoconjugates, we have prepared a series of modified taxanes that have both improved toxicity and solubility in aqueous systems as compared to paclitaxel (1a). These taxanes have been modified at either the C-10 or C-7 position and were found to be very cytotoxic against both normal and multi-drug-resistant (MDR) cells, as well as up to 30 times more soluble than paclitaxel in various buffer systems.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Paclitaxel/análogos & derivados , Taxoides/química , Taxoides/farmacologia , Antineoplásicos/administração & dosagem , Bioquímica/métodos , Neoplasias da Mama/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Dissulfetos/química , Portadores de Fármacos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/química , Paclitaxel/farmacologia , Polietilenoglicóis/química , Solubilidade , Relação Estrutura-Atividade , Taxoides/administração & dosagem , Células Tumorais CultivadasRESUMO
The targeted delivery of taxoids, in the form of taxane-antibody immunoconjugates, requires the preparation of taxoids containing moieties suitable for their conjugation to monoclonal antibodies. A series of taxoids incorporating a disulfide-containing linker at various positions of the taxoid framework have been prepared to investigate the most suitable position for conjugation. A second series of taxoids modified at the C-2 position aimed at increasing the potency of these taxanes has also been prepared.
