Gliotoxin is a dual inhibitor of farnesyltransferase and geranylgeranyltransferase I with antitumor activity against breast cancer in vivo.

Autor:	Vigushin, D M, Mirsaidi, N, Brooke, G, Sun, C, Pace, P, Inman, L, Moody, C J, Coombes, R C
Předmět:	ANIMAL experimentation BREAST tumors CELL division CELL lines COMPARATIVE studies DOSE-effect relationship in pharmacology IMMUNOSUPPRESSIVE agents RESEARCH methodology MEDICAL cooperation RATS RESEARCH STATISTICAL sampling TRANSFERASES EVALUATION research TREATMENT effectiveness PHARMACODYNAMICS
Zdroj:	Medical Oncology; Mar2004, Vol. 21 Issue 1, p21-30, 10p
Abstrakt:	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. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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