Kratz Felix
Macromolecular Prodrugs, Tumor Biology Center, Freiburg, Germany.
Expert Opin Investig Drugs. 2007 Jun;16(6):855-66. doi: 10.1517/13543784.16.6.855.
The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that demonstrates superior antitumor efficacy in murine tumor models and a favorable toxicity profile in mice, rats and dogs, including significantly reduced cardiotoxicity. After intravenous administration, DOXO-EMCH binds rapidly to the Cys-34 position of circulating albumin and accumulates in solid tumors due to passive targeting. In a clinical Phase I study, the dose of doxorubicin could be increased by a factor of 4.5-340 mg/m(2) when 75 mg/m(2) of free doxorubicin is considered to be the dose that can be administered as a single agent concomitant with the typical spectrum of side effects (i.e., myelotoxicity and mucositis). DOXO-EMCH was able to induce tumor regressions in anthracycline-sensitive tumors (i.e., breast cancer, small cell lung cancer and sarcoma). Phase II studies will be initiated at the beginning of 2007.
阿霉素的（6-马来酰亚胺己酰基）腙衍生物（DOXO-EMCH）是一种具有酸敏特性的阿霉素白蛋白结合前药，在小鼠肿瘤模型中显示出卓越的抗肿瘤疗效，在小鼠、大鼠和犬类中具有良好的毒性特征，包括显著降低的心脏毒性。静脉给药后，DOXO-EMCH迅速与循环白蛋白的Cys-34位点结合，并通过被动靶向作用在实体瘤中蓄积。在一项临床I期研究中，当游离阿霉素75mg/m²被认为是可作为单药给药并伴有典型副作用谱（即骨髓毒性和粘膜炎）的剂量时，阿霉素的剂量可增加4.5至340mg/m²。DOXO-EMCH能够在对蒽环类药物敏感的肿瘤（即乳腺癌、小细胞肺癌和肉瘤）中诱导肿瘤消退。II期研究将于2007年初启动。
