RESUMEN
Potential therapeutic applications of recently developed liposomes with a reduced affinity to the reticuloendothelial systems and a prolonged circulation time as targeting systems for lipophilic prodrugs were examined. In these studies, liposomes composed of phosphatidylcholine and cholesterol, additionally containing monosialoganglioside (GM1) or polyethylene glycol conjugated to phosphatidylethanolamine (PEG-PE), were used. Three antitumor lipophilic prodrugs, N-trifluoroacetyl-adriamycin-14-valerate (AD32), araC-diphosphate-diglyceride (araCdPdG), and 3',5'-o-dipalmitoyl-5-fluoro-2'-deoxyuridine (dpFUdR), were used to examine the effect of lipophilic prodrug incorporation into long-circulating liposomes and immunoliposomes on their biodistribution in mouse. Biodistribution studies with antibody-free liposomes containing lipophilic prodrugs showed that the activities of GM1 or PEG2000-PE in prolonging the circulation time of liposomes appeared to be preserved in the presence of each of the three lipophilic prodrugs at a drug/lipid molar ratio of 3:97. The effect of lipophilic prodrug incorporation on target binding of immunoliposomes was then examined using a mouse model. Incorporation of AD232 or dpFUdR into immunoliposomes, directed to the normal endothelium, did not affect the targetability of immunoliposomes, suggesting a potential effectiveness of these lipophilic prodrug-containing immunoliposomes in therapy for lung tumors. On the contrary, incorporation of araCdPdG resulted in significantly reduced target binding of immunoliposomes by yet unknown mechanism(s).
Asunto(s)
Antineoplásicos/administración & dosificación , Citarabina/análogos & derivados , Citidina Difosfato Diglicéridos/administración & dosificación , Doxorrubicina/análogos & derivados , Floxuridina/análogos & derivados , Liposomas , Profármacos/administración & dosificación , Animales , Anticuerpos Monoclonales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Sitios de Unión , Colesterol/química , Citarabina/administración & dosificación , Citarabina/química , Citarabina/farmacocinética , Citidina Difosfato Diglicéridos/química , Citidina Difosfato Diglicéridos/farmacocinética , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Doxorrubicina/farmacocinética , Portadores de Fármacos , Floxuridina/administración & dosificación , Floxuridina/química , Floxuridina/farmacocinética , Gangliósidos/química , Liposomas/química , Liposomas/farmacocinética , Masculino , Ratones , Ratones Endogámicos BALB C , Fosfatidilcolinas/química , Fosfatidiletanolaminas/química , Polietilenglicoles/química , Profármacos/química , Propiedades de SuperficieRESUMEN
In the present study, the "8 drugs in 1 day" regimen was tested in 54 children: 27 relapses (brain and/or spinal and/or meningeal sites), 10 refractory progressive diseases, 13 macroscopic residual tumors after partial excision and/or radiotherapy; in 4 cases, this regimen was prescribed as first line treatment. The response rate (complete and partial remission) was 46%. Results were very encouraging in medalloblastomas with a response rate of 76.5% whereas in brain stem gliomas it was only 23% and 33% in other astrocytomas. Immediate toxicity, mainly hematological, was very moderate. These results justify to propose this regimen as adjuvant chemotherapy, mostly in medulloblastomas and to plan other similar trials, using the most active drugs which seem presently to be alkylating and platinum-derived agents.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Adolescente , Adulto , Astrocitoma/tratamiento farmacológico , Neoplasias Cerebelosas/tratamiento farmacológico , Niño , Preescolar , Citarabina/administración & dosificación , Citidina Difosfato Diglicéridos/administración & dosificación , Dacarbazina/administración & dosificación , Femenino , Glioma/tratamiento farmacológico , Humanos , Hidroxiurea/administración & dosificación , Lactante , Lomustina/administración & dosificación , Masculino , Meduloblastoma/tratamiento farmacológico , Metilprednisolona/administración & dosificación , Procarbazina/administración & dosificación , Vincristina/administración & dosificaciónRESUMEN
The nucleoside 5'-diphosphate-L-1,2-dipalmitin derivatives of 1-beta-D-arabinofuranosylcytosine (ara-C), 9-beta-D-arabinofuranosyladenine (ara-A), and tubercidin have been synthesized, and their cytotoxicity has been evaluated against a mouse myeloma cell line (MPC-11) in vitro and against L1210 lymphoid leukemia both in vitro and in vivo. Sonication methods were utilized to solubilize these lipophilic derivatives in aqueous solution in order to facilitate such biological evaluation; the ara-A derivative resisted solubilization by several techniques. The nucleoside:phospholipid conjugates of ara-C and tubercidin both were cytotoxic towards the two cell lines, and detailed experiments were cytotoxic towards the two cell lines, and detailed experiments were carried out to show that the new derivatives (a) were not degraded in the medium prior to cellular uptake and (b) acted as prodrugs or molecular depots of the parent nucleoside analog. In addition, 1-beta-D-arabinofuranosylcytosine 5'-diphosphate'5'-L-1,2-dipalmitin was not a substrate for cytidine deaminase (cytidine aminohydrolase, EC 3.5.4.5), the primary enzyme responsible for the rapid catabolism of ara-C. In in vivo studies against L1210 lymphoid leukemia in mice, the 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-5'-L-1,2-dipalmitin showed an increased efficacy (increased life span, 260%) relative to the parent ara-C (increased life span, 89%) regardless of treatment schedule used, whereas the tubercidin 5'-diphosphate-5'-L-1,2-dipalmitin appeared extremely toxic even at low dosages. That 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-5'-L-1,2-dipalmitin was acting as a sustained release drug in vivo was demonstrated by utilizing a single dose administered on Days -1, 0, +1, and +2 relative to inoculation of the L1210 lymphoid leukemia cells on Day 0. Again, a much increased efficacy relative to the best treatment using ara-C was apparent. The potential advantages and the biochemical rationale for the development of these novel prodrugs are discussed.