title: The rasH2 mouse model for assessing carcinogenic potential of pharmaceuticals.
abstract: A factor limiting widespread use of the transgenic rasH2 mouse model for carcinogenicity testing of pharmaceuticals is the paucity of published data on actual drug candidates in rasH2 mice. This report addresses this gap by highlighting rasH2 mouse study data for 10 pharmaceutical candidates. These results were compared with findings in the 2-year studies in Sprague-Dawley rats for the same 10 compounds. In the 6-month rasH2 studies, only 2 of the 10 compounds tested positive for carcinogenicity and these correlated with positive findings in the companion 2-year rat studies. One compound, sunitinib, produced gastroduodenal carcinoma in both sexes and increased hemangiosarcoma in spleen and uterus in female rasH2 mice; in rats it produced gastroduodenal carcinoma and increased pheochromocytoma (males only). The second compound, bazedoxifene, produced ovarian granulosa cell neoplasms in rasH2 mice and rats, and renal tubular neoplasms associated with increased chronic progressive nephropathy only in rats. The higher percentage of carcinogenicity positive rat bioassays could be attributed to rat-specific phenomena with little or low relevance to man. Thus, this article confirms previous reports that rasH2 mice develop rodent-specific neoplasms less frequently than rats and positive findings, when present, are accompanied by similar positive results in the rat.
authors: 1Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut, USA.
authors: Prashant R
authors: PR
authors: Nambiar
authors: Daniel
authors: D
authors: Morton
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015197:Carcinogenicity Tests / Q000379:methods* / Q000592:standards; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D011905:Genes, ras; D007211:Indoles / Q000633:toxicity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics; D011758:Pyrroles / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077210:Sunitinib
chemical_list: D007211:Indoles; D011758:Pyrroles; C447119:bazedoxifene; D000077210:Sunitinib
keywords: carcinogenicity; drug; mice; neoplasia.; ras; rasH2