Relationship between the tumour tissue pharmacokinetics and the antiproliferative effects of anthracyclines and their metabolites.

The intrinsic activity of anthracyclines and their metabolites was measured in order to determine whether the tumour exposure to the compounds reflects the difference in their ability to inhibit tumour growth. (Dox), 4'-epidoxorubicin (Epi-Dox), daunorubicin (Dauno), N-1-leucyl-doxorubicin (Leu-Dox) and their metabolites were analysed for their antiproliferative effects in three human malignant cell lines: MCF7, RPMI 8226 and A2780. The antitumour efficacy of equitoxic, maximum tolerated doses of the present drugs was assessed in nude mice bearing subcutaneous (s.c.) well-established A2780 doses of the parent drugs was assessed in nude mice bearing subcutaneous (s.c.) well-established A2780 human ovarian cancer xenografts. The same doses were given to tumour-bearing mice to determine the distribution of the anthracyclines and their metabolites in A2780 tumour tissue during the first 48 h after injection. In vitro antiproliferative effects of the anthracyclines and their metabolites revealed a comparable activity for the parent drugs and daunorubicinol, whereas the other metabolites were at least 10-fold less active. The growth inhibition obtained in A2780 xenografts was 87% for Dox, 82% for Epi-Dox, 74% for Dauno and 97% for Leu-Dox. In vivo, the exposure of tumour tissue to 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. For each of the anthracyclines, the sum of the corrected AUC values (nmol/g/min) of the active compounds was calculated as 8812 for Dauno; 9320 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 growth inhibition by the four anthracyclines observed in A2780 xenografts.