RESUMO
The design and synthesis of potent thiocarbamate inhibitors for carboxypeptidase G2 are described. The best thiocarbamate inhibitor N-(p-methoxybenzenethiocarbonyl)amino-L-glutamic acid 6d, chosen for preliminary investigations of in vitro antibody-directed enzyme prodrug therapy (ADEPT), abrogated the cytotoxicity of a combination of A5B7-carboxypeptidase G2 conjugate and prodrug PGP (N-p-{N,N-bis (2-chloroethyl)amino}phenoxycarbonyl-L-glutamate) toward LS174T cells. This is the first report of a small-molecule enzyme inhibitor proposed for use in conjunction with the ADEPT approach.
Assuntos
Anticorpos/farmacologia , Antineoplásicos/farmacologia , Inibidores Enzimáticos/síntese química , Pró-Fármacos/farmacologia , gama-Glutamil Hidrolase/antagonistas & inibidores , Mostarda de Anilina/análogos & derivados , Mostarda de Anilina/farmacologia , Cromatografia em Camada Fina , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Relação Estrutura-Atividade , Células Tumorais Cultivadas , gama-Glutamil Hidrolase/farmacologiaRESUMO
Polyethylene glycol modification of the antibody--enzyme conjugate, F(ab')2-A5B7-CPG2, extends its duration in the circulation of nude mice bearing human colonic cancer xenografts (LS174T). Increased concentration of modified conjugate is achieved in the tumour, but residual non-specific enzyme concentrations in normal tissue and blood demonstrate the fundamental requirement to remove or inactivate non-specifically held enzyme in this system.