title: Metoclopramide enhances the effect of cisplatin on xenografted squamous cell carcinoma of the head and neck.
abstract: The chromatin-bound enzyme adenosine diphosphate ribosyl transferase is activated by DNA-damaging agents. Substances that inhibit the enzyme, such as benzamide analogues, are known to increase the cytotoxicity of ionising radiation and cytotoxic drugs. The purpose of the present study was to investigate whether the anti-emetic drug metoclopramide, a benzamide derivative (4-amino-N-2-(diethylaminoethyl)-5-chloro-2-methoxybenzamide; MCA), potentiates the effect of cisplatin (cis-diammine-dichloroplatinum; CDDP) on squamous cell carcinoma (SCC). For that purpose human SCC of the head and neck (i.e. tumour line AB and EH) xenografted to nude mice were used. Two administration schedules were tested: (a) MCA (2.0 mg kg-1 i.p.) one hour before CDDP (7.5 mg kg-1 i.p.); and (b) MCA (3 x 2.0 mg kg-1) given concomitant to, 24 and 48 hours after CDDP (7.5 mg kg-1) administration. Treatment efficacies were compared using the area under the growth curves (AUC), tumour volumes and specific growth delay (SGD). There was no mortality and no weight loss of significance in any treatment group. MCA alone did not induce any significant reduction in AUC, tumour volume or SGD with either treatment schedule. CDDP alone gave a significant reduction of tumour growth in tumour line AB but not in tumour line EH. In schedule (a) the addition of MCA did not give any additive effect. However, in schedule (b), for both tumour lines, MCA enhanced the effect of CDDP by significantly reducing the AUC (AB: P less than 0.0001; EH: P less than 0.001) and increasing SGD (AB: P less than 0.012; EH: P less than 0.001) when compared to the tumours given CDDP alone. These effects were observed at a MCA dose currently being administered to humans.
authors.affiliation: Department of Oncology, University of Lund, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Kjellén
authors.forename: J
authors.initials: J
authors.lastname: Wennerberg
authors.forename: R
authors.initials: R
authors.lastname: Pero
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008787:Metoclopramide / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous
chemical_list: D008787:Metoclopramide; D002945:Cisplatin