Background: We have revealed in a pre-clinical study that the combination of adriamycin (ADR) and docetaxel (DOC) in which ADR was administered 12 h after DOC injection not only significantly reduced leukopenia and toxic death but also significantly increased the antitumor effect compared with the dosing schedule without an interval between each injection used commonly in clinical practice. The purpose of this study was to clarify in mice whether the toxic death caused by ADR was reduced by administering ADR after DOC injection when the doses and dosing-interval of ADR and DOC were changed.
Methods: ADR alone or a combination of ADR and DOC (ADR/DOC group in which both drugs were administered simultaneously or DOC-ADR group in which ADR was administered after DOC injection) was administered every 7 days in mice.
Results: When dosing intervals (0-24 h) were changed, there were no differences in survival rate among the 6, 12, and 24-h interval groups, although these groups showed significantly higher survival rate compared with the ADR/DOC group. When the dose of ADR (2.5-15 mg/kg) was changed, the survival rate was higher in all the DOC-ADR groups than the ADR alone groups. When the dose of DOC (3.125-12.5 mg/kg) was changed, DOC caused a dose-dependent reduction in toxic death. Although there was no striking difference in adverse effects between the ADR alone and DOC-ADR groups, the DOC-ADR group showed markedly attenuated increases in CPK-MB activity compared with the ADR alone group.
Conclusions: We conclude that pre-administration of DOC may protect against ADR-induced toxic death and cardiotoxicity.