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1.
Clin Cancer Res ; 18(9): 2591-602, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22392910

RESUMO

PURPOSE: To evaluate the pharmacokinetics and tissue disposition of macromolecular camptothecin (CPT) drug conjugate, XMT-1001, and irinotecan (CPT-11) in mice bearing HT-29 xenograft tumors. EXPERIMENTAL DESIGN: The antitumor efficacy of XMT-1001 was evaluated in the mouse HT-29 human colon carcinoma xenograft model. XMT-1001 was administered intravenously to female athymic nude (nu/nu) mice bearing established HT-29 xenograft tumors (n = 10) at 15, 30, and 60 mg CPT equivalents/kg on weekly or biweekly schedules. The tumor growth inhibition and tumor growth delay endpoints were used for efficacy evaluation. In the pharmacokinetic study, XMT-1001 was administered intravenously at a pharmacologically relevant dose of 60 mg CPT equivalents/kg × 1 via tail vein or an equimolar dose of CPT-11 at 100 mg/kg i.p. × 1. Mice (n = 3 per time point) were euthanized from 0.083 to 336 hours after XMT-1001 administration and from 0.083 to 24 hours after CPT-11. Plasma, tumor, and tissues were collected from all animals. A liquid chromatography-tandem mass spectrometry assay was used to measure XMT-1001, conjugate release products, CPT-20-O-(N-succinimido-glycinate; CPT-SI) and CPT-20-O-(N-succinamidoyl-glycinate; CPT-SA), and CPT. RESULTS: After XMT-1001 administration, the majority of the plasma exposure is accounted for by conjugated CPT. XMT-1001 exhibited a prolonged exposure of conjugated drug, active conjugate primary release products, CPT-SI and CPT-SA, and active CPT, which was associated with greater antitumor response compared with CPT-11. CONCLUSIONS: XMT-1001 provides an extended systemic and tumor exposure of conjugated drug and shows improved antitumor effect compared with CPT-11.


Assuntos
Camptotecina/análogos & derivados , Neoplasias do Colo/tratamento farmacológico , Polímeros/farmacologia , Polímeros/farmacocinética , Acetais , Animais , Camptotecina/farmacocinética , Camptotecina/farmacologia , Cromatografia Líquida , DNA Topoisomerases Tipo I/química , DNA Topoisomerases Tipo I/metabolismo , Feminino , Humanos , Irinotecano , Camundongos , Camundongos Nus , Espectrometria de Massas em Tandem , Distribuição Tecidual , Inibidores da Topoisomerase I/farmacocinética , Inibidores da Topoisomerase I/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Anal Biochem ; 379(1): 40-4, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18486587

RESUMO

Glutathione (GSH), an intracellular tripeptide that combats oxidative stress, must be continually replaced due to loss through conjugation and destruction. Previous methods, estimating the synthesis of GSH in vivo, used constant infusions of labeled amino acid precursors. We developed a new method based on incorporation of (2)H from orally supplied (2)H(2)O into stable C-H bonds on the tripeptide. The incorporation of (2)H(2)O into GSH was studied in rabbits over a 2-week period. The method estimated N, the maximum number of C-H bonds in GSH that equilibrate with (2)H(2)O as amino acids. GSH was analyzed by liquid chromatography/mass spectrometry after derivatization to yield GSH-N-ethylmaleimide (GSNEM). A model, which simulated the expected abundance at each mass isotopomer for the GSNEM ion at various values for N, was used to find the best fit to the data. The plateau labeling fit best a model with N=6 of a possible 10 C-H bonds. Thus, the amino acid precursors do not completely equilibrate with (2)H(2)O prior to GSH synthesis. Advantages of this new method include replacing costly amino acid infusions with the oral administration of (2)H(2)O and a statistical basis for estimating N.


Assuntos
Óxido de Deutério/metabolismo , Glutationa/biossíntese , Algoritmos , Animais , Cromatografia Líquida , Óxido de Deutério/química , Glutationa/sangue , Glutationa/química , Espectrometria de Massas , Coelhos
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