Breistøl K, Hendriks H R, Berger D P, Langdon S P, Fiebig H H, Fodstad O
Norwegian Radium Hospital, Norway, U.K.
Eur J Cancer. 1998 Sep;34(10):1602-6. doi: 10.1016/s0959-8049(98)00152-x.
The antitumour activity of the investigational agent N-L-leucyl-doxorubicin (Leu-DOX) was compared with that of doxorubicin (DOX) in human tumour xenografts growing subcutaneously in athymic nude mice. Leu-DOX was developed as a prodrug of DOX, and may be converted into the clinically active parent compound by hydrolytic enzymes present in or on tumour cells. It has been suggested that a better therapeutic index with a reduced cardiac toxicity and higher efficacy might be obtained. Both compounds were administered intravenously weekly for 2 weeks, each at maximum tolerated doses of 8 mg/kg and 28 mg/kg for DOX and Leu-DOX, respectively. The panel of xenografts represented three different tumour types. Leu-DOX showed antitumour activity, defined as tumour growth inhibition > 50% and specific growth delay > 1.0, in 10 of the 16 tumours, including two of five breast, five of seven small cell and three of four non-small cell lung carcinomas. In comparison, DOX was active in one breast, four small cell lung and two lung adenocarcinoma xenografts. In all the DOX sensitive lung tumours, Leu-DOX showed higher efficacy than the parent compound. Based on the results of the present study, and since phase I clinical trials with Leu-DOX have already been performed, phase II clinical evaluation of Leu-DOX in patients with breast and lung cancer is recommended.
在无胸腺裸鼠皮下生长的人肿瘤异种移植模型中，对研究药物N-L-亮氨酰-阿霉素（Leu-DOX）和阿霉素（DOX）的抗肿瘤活性进行了比较。Leu-DOX是作为DOX的前药开发的，可能会被肿瘤细胞内或表面存在的水解酶转化为具有临床活性的母体化合物。有人认为，它可能具有更好的治疗指数，心脏毒性降低且疗效更高。两种化合物均每周静脉注射给药2周，DOX和Leu-DOX的最大耐受剂量分别为8mg/kg和28mg/kg。异种移植模型组代表三种不同的肿瘤类型。Leu-DOX在16种肿瘤中的10种中显示出抗肿瘤活性，定义为肿瘤生长抑制>50%且特定生长延迟>1.0，包括5种乳腺癌中的2种、7种小细胞肺癌中的5种和4种非小细胞肺癌中的3种。相比之下，DOX在1种乳腺癌、4种小细胞肺癌和2种肺腺癌异种移植模型中具有活性。在所有对DOX敏感的肺肿瘤中，Leu-DOX显示出比母体化合物更高的疗效。基于本研究结果，并且由于已经进行了Leu-DOX的I期临床试验，建议对乳腺癌和肺癌患者进行Leu-DOX的II期临床评估。
