RESUMO
During the last few years, many gene therapy strategies have been developed for various disease targets. The development of anticancer gene therapy strategies to selectively generate cytotoxic nucleoside or nucleotide analogs is an attractive goal. One such approach involves the delivery of herpes simplex virus thymidine kinase followed by the acyclic nucleoside analog ganciclovir. We have developed another gene therapy methodology for the treatment of cancer that has several significant attributes. Specifically, our approach involves the delivery of E. coli purine nucleoside phosphorylase, followed by treatment with a relatively non-toxic nucleoside prodrug that is cleaved by the enzyme to a toxic compound. This presentation describes the concept, details our search for suitable prodrugs, and summarizes the current biological data.
Assuntos
Escherichia coli/enzimologia , Terapia Genética , Neoplasias/terapia , Pró-Fármacos/farmacocinética , Purina-Núcleosídeo Fosforilase/metabolismo , Animais , Biotransformação , Flucitosina/farmacocinética , Ganciclovir/farmacocinética , Camundongos , Camundongos Nus , Purina-Núcleosídeo Fosforilase/genética , Simplexvirus/enzimologia , Timidina Quinase/genéticaRESUMO
A series of 5,5-disubstituted hydantoin derivatives was synthesized by alkylating 5,5-bis(mercaptomethyl)-2,4-imidazolidinedione (3) with various halomethylaromatic or halomethylheteroaromatic precursors, or by using the Buchener-Berg procedure on the required ketone. When evaluated for their ability to inhibit HIV-induced cell killing and virus production in CEM or MT-2 cells only compounds 2, 4n, 4o, and 4i demonstrated modest activity, the latter with an IC50 = 53 microM.