Modulation of oral squamous cell carcinoma incidence in rats via diet and a novel calcium channel antagonist.
An unexpected dose related increase in oral squamous cell carcinomas was observed in a standard 2-year carcinogenicity study with a novel calcium channel blocker, in which Wistar rats received daily doses of 0, 1.5, 7, 20, or 40 mg/kg of the compound mixed with a standard diet containing fibers from barley. This finding was associated with an increased incidence of severe (destructive) periodontitis and the formation of oro-nasal fistulae at the 2 highest doses. Five assays of the compound for genotoxicity were negative indicating that a genotoxic effect was highly improbable. To investigate the underlying pathogenic mechanisms a second 2-year study in the same strain of rats was initiated and the influence of the diet and/or a possible local irritancy by the drug was assessed. In this second study the compound was administered by oral gavage at daily doses of 0, 7, or 40 mg/kg (later reduced to 20 mg/kg due to systemic intolerance) to rats maintained either on the standard diet or on a low fiber diet assumed to be less aggressive in terms of inducing periodontal lesions. Dose dependent gingival overgrowth (a class-related effect) was observed in the incisor and molar teeth area of all treated groups but was independent of the diet used. No oral tumors were found in the standard diet or low fiber diet controls and all treatment groups fed the low fiber diet, whereas in the high-dose group fed the standard diet a total of 8 oral squamous cell carcinomas were detected in association with an increased incidence of severe periodontitis. These results indicate that the increased incidence of squamous cell carcinomas observed upon chronic administration of the compound is not due to a direct tumorigenic effect of the drug. Tumor formation is attributable to severe periodontal disease favored by the diet and class related gingival overgrowth.
Lenz
Barbara
B
Non-Clinical Development--Drug Safety, Hoffmann-La Roche Ltd. Basel Switzerland. barbara.lenz@roche.com
Crameri
Flavio M
FM
Eichler
David A
DA
Schläppi
Bernhard
B
Wiltshire
Hugh R
HR
Wood
John
J
Seymour
Robin A
RA
D000284:Administration, Oral; D000818:Animals; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000633:toxicity*; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D004032:Diet; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D020748:Mibefradil / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D015394:Molecular Structure; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D036401:Toxicity Tests, Chronic
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020748:Mibefradil