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Metastatic breast cancer (MBC) is almost always incurable and median survival is 18-24 months.Although the combination of adriamycin (ADR) and docetaxel (DOC) has demonstrated higher efficacy against MBC,severe myelosuppression and cardiotoxicity have been dose-limiting factors.The purpose of this study was to devise an optimal dosing-schedule for this combination which lessens the severity of adverse effects and enhances antitumor effects.(I) Dosing-sequence : Mice were assigned to a simultaneous dosing group (ADR/DOC ; regimen commonly used in clinical practice) in which both drugs were administered simultaneously and 2 intermittent dosing groups (ADR-DOC and DOC-ADR) in which the second drug was administered 12 hours after the first one.In the DOC-ADR group,as compared to the ADR/DOC group,in addition to there being significantly less leukopenia and toxic death,the tumor growth inhibition rate was significantly higher.(II) Dosing-interval : When dosing intervals were varied in the 6-24 hour range in the DOC-ADR group,on day 21,body weights were markedly lower for doing intervals of 6 and 24 hours than they were for a dosing interval of 12 hours.(III) Dosing-time : For a group treated with ADR and one treated with DOC,adverse effects were least when the dosing times were 21 : 00 and 9 : 00,respectively.In a DOC (9 : 00)-ADR (21 : 00) group in which DOC was administered at 9 : 00 followed by ADR at 21 : 00 both body weight loss and leukopenia were significantly reduced as compared with a DOC (21 : 00)-ADR (9 : 00) group in which DOC was administered at 21 : 00 followed by ADR at 9 : 00.These findings show that the therapeutic index of combination chemotherapy can be improved by choosing an optimal dosing-schedule.

Optimization of Combination Chemotherapy with Anti-Tumor Drugs Based on Experimental Animal Study