title: The antitumour activity of the prodrug N-L-leucyl-doxorubicin and its parent compound doxorubicin in human tumour xenografts.
abstract: 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.
authors.affiliation: Norwegian Radium Hospital, Norway, U.K.
authors.forename: K
authors.initials: K
authors.lastname: Breistøl
authors.forename: H R
authors.initials: HR
authors.lastname: Hendriks
authors.forename: D P
authors.initials: DP
authors.lastname: Berger
authors.forename: S P
authors.initials: SP
authors.lastname: Langdon
authors.forename: H H
authors.initials: HH
authors.lastname: Fiebig
authors.forename: O
authors.initials: O
authors.lastname: Fodstad
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011355:Prodrugs / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; C073409:N-leucyldoxorubicin; D004317:Doxorubicin