Transgenic tumor models for carcinogen identification: the heterozygous Trp53-deficient and RasH2 mouse lines.
Genetically altered mouse models (GAMM) for human cancers have been critical to the investigation and characterization of oncogene and tumor suppressor gene expression and function and the associated cancer phenotype. Similarly, several of the mouse models with defined genetic alterations have shown promise for identification of potential human carcinogens and investigation of mechanisms of carcinogen-gene interactions and tumorigenesis. In particular, both the B6.129N5-Trp53 mouse, heterozygous for a p53 null allele, and the CB6F1-RasH2 mouse, hemizygous for the human H-ras transgene, have been extensively investigated. Using 26-week exposure protocols at or approaching the maximum tolerated dose, the summary results to date indicate the potential for GAMM to identify and, possibly, classify chemicals of potential risk to humans using short-term carcinogenicity experiments. This IWGT session focused on: (1) the development of recommendations for genetic/molecular characterization required in animals, tissues, and tumors before and after treatment for identification of presumptive human carcinogens based on the current state of knowledge, (2) identification of data gaps in our current state of knowledge, and (3) development of recommendations for research strategies for further development of our knowledge base of these particular models. By optimization of protocols and identification of significant outcomes and responses to chemical exposure in appropriate short-term mechanism-based genetically altered rodent models, strategies for prevention and intervention may be developed and employed to the benefit of public health.
Storer
R D
RD
Department of Genetic and Cellular Toxicology, Merck Research Laboratories, WP45-311, West Point, PA 19486, USA. richard_storer@merck.com
French
J E
JE
Donehower
L A
LA
Gulezian
D
D
Mitsumori
K
K
Recio
L
L
Schiestl
R H
RH
Sistare
F D
FD
Tamaoki
N
N
Usui
T
T
van Steeg
H
H
D000818:Animals; D001681:Biological Assay / Q000592:standards*; D015197:Carcinogenicity Tests / Q000592:standards; D004195:Disease Models, Animal; D016147:Genes, Tumor Suppressor; D051379:Mice; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D018631:ras Proteins