Superior therapeutic efficacy of N-L-leucyl-doxorubicin versus doxorubicin in human melanoma xenografts correlates with higher tumour concentrations of free drug.
N-L-leucyl-doxorubicin (Leu-DOX), a prodrug of doxorubicin (DOX), has previously shown antitumour activity against human ovarian, breast and lung carcinomas in nude mice. In the present study, the efficacy of Leu-DOX was compared with free DOX in inhibiting the growth of four DOX-sensitive and -resistant malignant melanoma xenografts. In an attempt to elucidate mechanisms underlying any differential effect, a sensitive high-performance liquid chromatography (HPLC) method was established for measuring plasma and tumour concentrations of the two drugs and their main metabolites. Leu-DOX was more effective than free DOX in inhibiting xenograft growth. At equitoxic intravenous doses of Leu-DOX (28 mg/kg) and DOX (8 mg/kg) administered to tumour-bearing nude mice, comparable levels of DOX were found in plasma, whereas differences were seen in tumour tissue concentrations. Thus, in animals carrying highly sensitive (LOX) and resistant (THX) melanomas, higher tumour concentrations of free DOX were observed in the Leu-DOX treated group from 24 up to 240 h after drug injection. Notably, the difference in drug-induced tumour growth inhibition correlated with differences in tumour exposure to free DOX, assessed as area under the curve (AUC) calculated over the first 48 h. In conclusion, the results confirm the prodrug nature of Leu-DOX and provide a possible explanation for its increased antitumour efficacy.
Breistøl
K
K
Department of Tumour Biology, Norwegian Radium Hospital, Montebello, Oslo, Norway.
Hendriks
H R
HR
Fodstad
O
O
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011355:Prodrugs; C073409:N-leucyldoxorubicin; D004317:Doxorubicin