RELATIONSHIP BETWEEN THE TUMOR-TISSUE PHARMACOKINETICS AND THE ANTIPROLIFERATIVE EFFECTS OF ANTHRACYCLINES AND THEIR METABOLITES

The intrinsic activity of anthracyclines and their metabolites was mea sured in order to determine whether the tumour exposure to the compoun ds reflects the difference in their ability to inhibit tumour growth. (Dox), 4'-epidoxorubicin (Epi-Dox), daunorubicin (Dauno), N-1-leucyl-d oxormbicin (Leu-Dox) and their metabolites were analysed for their ant iproliferative effects in three human malignant cell lines: MCF7, RPMI 8226 and A2780. The antitumour efficacy of equitoxic, maximum tolerat ed doses of the parent drugs was assessed in nude mice bearing subcuta neous (s.c.) well-established A2780 human ovarian cancer xenografts. T he same doses were given to tumour-bearing mice to determine the distr ibution of the anthracyclines and their metabolites in A2780 tumour ti ssue during the first 48 h after injection. In vitro antiproliferative effects of the anthracyclines and their metabolites revealed a compar able activity for the parent drugs and daunorubicinol, whereas the oth er metabolites were at least 10-fold less active. The growth inhibitio n obtained in A2780 xenografts was 87% for Dox, 82% for Epi-Dox, 74% f or Dauno and 97% for Leu-Dox. In vivo, the exposure of tumour tissue t o the drug, calculated as the area under the concentration-time curve (AUC), was related to the extent of growth inhibition after correction of the AUC values for the intrinsic activity of the anthracycline. Fo r each of the anthracyclines, the sum of the corrected AUC values (nmo l/g/min) of the active compounds was calculated as 8812 for Dauno; 932 0 for Epi-Dox; 10 986 for Dox and 15 163 for Leu-Dox. The sequence of increasing AUC values corresponded with the sequence of increasing gro wth inhibition by the four anthracyclines observed in A2780 xenografts . Copyright (C) 1996 Elsevier Science Ltd