The utility of the K6/ODC transgenic mouse as an alternative short term dermal model for carcinogenicity testing of pharmaceuticals
| Autor: | Jun Zhang, Alan Knapton, Frank D. Sistare, Ronald Honchel, Joseph P. Hanig, Terry J. Miller, Parvaneh Espandiari |
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| Rok vydání: | 2007 |
| Předmět: |
Genetically modified mouse
Male medicine.medical_specialty Skin Neoplasms genetic structures Drug-Related Side Effects and Adverse Reactions Carcinogenicity Tests Transgene 9 10-Dimethyl-1 2-benzanthracene Drug Evaluation Preclinical DMBA Spleen Mice Transgenic Biology Toxicology medicine.disease_cause Kidney Ornithine Decarboxylase Transfection Sarcoma Viruses Murine Subcutaneous injection Mice Internal medicine medicine Animals Carcinogen Keratin-6 General Medicine Mice Inbred C57BL Disease Models Animal medicine.anatomical_structure Endocrinology Liver Cancer research Carcinogens Neoplastic cell Carcinogenesis |
| Zdroj: | Regulatory toxicology and pharmacology : RTP. 50(1) |
| ISSN: | 0273-2300 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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