RESUMO
2' and 7 Polyol carbonates of paclitaxel were synthesized and screened as potential paclitaxel prodrugs. Paclitaxel is released from 7-(2",3"-dihydroxypropylcarbonato) paclitaxel (Protaxel) at rates inversely proportional to pH, by an intramolecular cyclization. Compared to paclitaxel, maximum tolerated i.v. or i.p. doses (MTD) of Protaxel are about 2.5- to 3-fold higher; its efficacy is substantially higher in human cancer line xenografts in athymic mice, especially in prostate PC-3, breast MDA-MB 468 and ovary OVCAR-1.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Paclitaxel/análogos & derivados , Paclitaxel/síntese química , Paclitaxel/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Taxoides , Animais , Antineoplásicos/toxicidade , Neoplasias da Mama/tratamento farmacológico , Divisão Celular/efeitos dos fármacos , Estabilidade de Medicamentos , Tolerância a Medicamentos , Feminino , Meia-Vida , Humanos , Concentração de Íons de Hidrogênio , Masculino , Dose Máxima Tolerável , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/toxicidade , Pró-Fármacos/toxicidade , Neoplasias da Próstata/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Solubilidade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of dinucleoside 5-polyphosphates UpnU (n = 2-7) was synthesized. Their relative potencies as agonists at the G-protein-coupled receptors P2Y1, P2Y2, P2Y4, and P2Y6 were determined by intracellular calcium measurements using fluorescent imaging techniques. The correlation of phosphate chain length to activities at these receptors is discussed.