Influence of dosing schedules on toxicity and antitumour effects of combined cisplatin and docetaxel treatment in mice.
OBJECTIVE
The combination of cisplatin and docetaxel shows a better cure rate against non-small-cell lung cancer than other drug combinations in clinical studies; however, severe myelosuppression and nephrotoxicity are dose-limiting factors. The purpose of this study was to establish a suitable dosing schedule to reduce adverse effects and improve the antitumour effects.


METHODS
Cisplatin and docetaxel were administered i.p. to male ICR mice simultaneously, or sequentially with either cisplatin or docetaxel first followed by the second drug 12 h later (docetaxel-cisplatin and cisplatin-docetaxel groups). Antitumour effects of these schedules were also tested in C57BL/6N mice bearing Lewis lung carcinomas.


RESULTS
The simultaneous docetaxel/cisplatin group showed the lowest survival rate and the highest blood urea nitrogen (BUN) concentration. Cisplatin concentrations in the plasma and kidney were higher in the simultaneous dosing group than the sequential dosing groups. Antitumour effect was the greatest in the docetaxel-cisplatin group.


CONCLUSIONS
The docetaxel-cisplatin regimen inhibited tumour growth the best and reduced mortality and nephrotoxicity.
Kodama
Ayumi
A
Clinical Pharmacokinetics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
To
Hideto
H
Kinoshita
Tomohiro
T
Ieiri
Ichiro
I
Higuchi
Shun
S
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity*; D001806:Blood Urea Nitrogen; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000401:mortality; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009368:Neoplasm Transplantation; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage
D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin