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The utility of the K6/ODC transgenic mouse as an alternative short term dermal model for carcinogenicity testing of

T J Miller1, R Honchel, P Espandiari

  • 1Division 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

Regulatory Toxicology and Pharmacology : RTP
|December 11, 2007
PubMed

Insights

The K6/ODC mouse model showed progressive adverse health and failed to develop tumors in response to oncogenic DNA. This suggests it may not be suitable for carcinogenicity testing of vaccines.

Area of Science:

  • Toxicology and Carcinogenesis
  • Transgenic Animal Models
  • Vaccine Safety Assessment

Background:

  • Transgenic rodents offer potential advantages over traditional models in cancer research.
  • Developing and validating new animal models is crucial for evolving regulatory perspectives.
  • The K6/ODC transgenic mouse is known to develop epidermal tumors upon exposure to genotoxic carcinogens.

Purpose of the Study:

  • To evaluate the K6/ODC mouse model's fitness and health robustness over 36 weeks.
  • To determine the oncogenic risk of residual DNA in vaccines derived from neoplastic cell substrates.
  • To assess the suitability of K6/ODC mice for pharmaceutical carcinogenicity testing.

Main Methods:

  • K6/ODC and C57BL/6 mice were treated with T24-H-ras expression plasmid, carrier vector DNA, or saline.
  • Treatments were administered topically or via subcutaneous injection.
  • A positive control group of K6/ODC mice received 7,12-dimethylbenz-[a]anthracene (DMBA) for comparison.

Main Results:

  • Only DMBA-treated K6/ODC mice developed papillomas; H-ras plasmid treatment did not induce tumors.
  • K6/ODC mice exhibited severe adverse health effects, including dehydration, dermal eczema, and loss of mobility.
  • Microscopic examination revealed significant pathology in K6/ODC mice, including hyperplasia, atrophy, and organ infiltration, but not in C57BL/6 mice.

Conclusions:

  • The K6/ODC mouse model demonstrated progressive adverse health and decreased survival.
  • The model's failure to develop tumors in response to the H-ras plasmid challenges its utility.
  • K6/ODC mice appear inappropriate for detecting oncogenic DNA and for pharmaceutical carcinogenicity testing.

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