Vigushin D M, Mirsaidi N, Brooke G, Sun C, Pace P, Inman L, Moody C J, Coombes R C
Department of Cancer Medicine, 6th Floor MRC Cyclotron Building, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Med Oncol. 2004;21(1):21-30. doi: 10.1385/MO:21:1:21.
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.
Gliotoxin是一种具有免疫抑制和抗菌活性的天然霉菌毒素。对法尼基转移酶（IC50为80微摩尔）和香叶基香叶基转移酶I（IC50为17微摩尔）的抑制作用激发了人们对这种环二硫代二氧哌嗪潜在抗肿瘤活性的兴趣。Gliotoxin抑制了六种乳腺癌细胞系在培养中的增殖，平均±标准差IC50为289±328微摩尔（范围为38 - 985微摩尔）；层粘连蛋白B的细胞内法尼基化和Rap1A的香叶基香叶基化受到剂量依赖性抑制。在使用N - 甲基 - N - 亚硝基脲大鼠乳腺癌模型的随机对照研究中，与10只对照组相比，每周皮下注射10毫克/千克的Gliotoxin，连续4周，给药10只动物时，其在体外具有显著的抗肿瘤活性，全身毒性较小。高达25毫克/千克的单剂量耐受性良好。目前的研究证实，Gliotoxin是法尼基转移酶和香叶基香叶基转移酶I的双重抑制剂，在体外和体内对乳腺癌均具有显著的抗肿瘤活性和良好的毒性特征。
