Dose schedule evaluation of metoclopramide as a potentiator of cisplatin and carboplatin treatments of xenografted squamous cell carcinomas of the head and neck.
The potentiating effect of metoclopramide on the tumor growth inhibition of cisplatin has been studied on human squamous cell carcinomas xenografted to nude mice. In this system, the optimal time interval for intraperitoneal administration of metoclopramide was 8 h after intraperitoneal administration of cisplatin. The optimal single dose level of metoclopramide in this study was 2 mg/kg. Metoclopramide enhanced the cytotoxic effect of cisplatin at all cisplatin doses tested between 2.5 and 7.5 mg/kg body weight. Under experimental conditions that gave optimal sensitization of cisplatin-induced cytotoxicity, there was no potentiation of the cytotoxic effect with metoclopramide in combination with carboplatin. There is great similarity in the cytotoxic action of cisplatin and carboplatin, with the main difference being a much slower rate of formation of DNA crosslink formation following carboplatin exposure. Hence the data reported here support an important role for the kinetics of formation and reparability of DNA damage as part of the mechanism of metoclopramide sensitization of platinum-containing drugs.
Lybak
S
S
Department of Oto-rhino-laryngology, University Hospital of Lund, Sweden.
Wennerberg
J
J
Kjellén
E
E
Pero
R W
RW
D000818:Animals; D016190:Carboplatin / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D008787:Metoclopramide / Q000008:administration & dosage* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous
D016190:Carboplatin; D008787:Metoclopramide; D002945:Cisplatin