Gliotoxin is a dual inhibitor of farnesyltransferase and geranylgeranyltransferase I with antitumor activity against breast cancer in vivo.
Med Oncol
; 21(1): 21-30, 2004.
Article
em En
| MEDLINE
| ID: mdl-15034210
ABSTRACT
Gliotoxin is a natural mycotoxin with immunosuppressive and antimicrobial activity. Inhibition of farnesyltransferase (IC50 80 microM) and geranylgeranyltransferase I (IC50 17 microM) stimulated interest in the potential antitumor activity of this epidithiodioxopiperazine. Gliotoxin inhibited proliferation of six breast cancer cell lines in culture with mean +/- SD IC50 289 +/- 328 microM (range 38-985 microM); intracellular farnesylation of Lamin B and geranylgeranylation of Rap1A were inhibited in a dose-dependent manner. In randomized controlled studies using the N-methyl-N-nitrosourea rat mammary carcinoma model, gliotoxin had pronounced antitumor activity in vitro and little systemic toxicity when administered to 10 animals at 10 mg/kg by subcutaneous injection weekly for 4 wk compared with 10 controls. Single doses up to 25 mg/kg were well tolerated. The present studies confirm that gliotoxin is a dual inhibitor of farnesyltransferase and geranylgeranyltransferase I with pronounced antitumor activity and favorable toxicity profile against breast cancer in vitro and in vivo.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Alquil e Aril Transferases
/
Gliotoxina
/
Neoplasias Mamárias Experimentais
Tipo de estudo:
Clinical_trials
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Ano de publicação:
2004
Tipo de documento:
Article