title: The utility of the K6/ODC transgenic mouse as an alternative short term dermal model for carcinogenicity testing of pharmaceuticals.
abstract: The use of transgenic rodents may overcome many limitations of traditional cancer studies. Regulatory perspectives continue to evolve as new models are developed and validated. The transgenic mouse, K6/ODC, develops epidermal tumors when exposed to genotoxic carcinogens. In this study, K6/ODC mice were evaluated for model fitness and health robustness in a 36-week study to determine oncogenic risk of residual DNA in vaccines from neoplastic cell substrates. K6/ODC and C57BL/6 mice were treated with T24-H-ras expression plasmid, carrier vector DNA, or saline topically or by subcutaneous injection. One group of K6/ODC mice received 7,12-dimethylbenz-[a]anthracene [DMBA] dermally. Only DMBA-treated mice developed papillomas by six weeks, increasing in incidence to 25 weeks. By week 11, many K6/ODC mice showed severe dehydration and dermal eczema. By week 32, (6/8) surviving K6/ODC mice showed loss of mobility and balance. Microscopic evaluation of tissues revealed dermal/sebaceous gland hyperplasia, follicular dystrophy, splenic atrophy, and amyloid deposition/neutrophilic infiltration within liver, heart, and spleen, in all K6/ODC mice. Pathology was not detected in C57BL/6 mice. Progressive adverse health, decreased survival, and failure to develop papillomas to the H-ras plasmid suggest that K6/ODC mice may be an inappropriate alternative model for detection of oncogenic DNA and pharmaceutical carcinogenicity testing.
authors: Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993-0002, USA. terry.miller@fda.hhs.gov
authors: T J
authors: TJ
authors: Miller
authors: R
authors: R
authors: Honchel
authors: P
authors: P
authors: Espandiari
authors: A
authors: A
authors: Knapton
authors: J
authors: J
authors: Zhang
authors: F D
authors: FD
authors: Sistare
authors: J P
authors: JP
authors: Hanig
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000008:administration & dosage; D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods; D002273:Carcinogens / Q000008:administration & dosage; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D053553:Keratin-6 / Q000235:genetics*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009955:Ornithine Decarboxylase / Q000235:genetics*; D009053:Sarcoma Viruses, Murine / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000473:pathology; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D014162:Transfection
chemical_list: D002273:Carcinogens; D053553:Keratin-6; D015127:9,10-Dimethyl-1,2-benzanthracene; D009955:Ornithine Decarboxylase