Short-term carcinogenesis bioassay of genotoxic procarcinogens in PIM transgenic mice.
E mu-pim-1 transgenic mice, which overexpress the pim-1 oncogene in lymphoid tissues, have shown increased susceptibility to induction of T cell lymphomas by N-ethyl-N-nitrosourea, a direct-acting chemical carcinogen (Nature, 340, 61-63, 1989). We sought to further evaluate E mu-pim-1 transgenic mice as a potential test animal for a short-term carcinogenesis bioassay. We chose to test four genotoxic procarcinogens; 2-acetylaminofluorene (2-AAF), N-nitro-sodiethylamine (NDEA), 1,2-dichloroethane (1,2-DCE) and benzene (BEN). These compounds require metabolic activation and, with the exception of benzene, are not mouse lymphomagens. Compounds were administered by gavage daily for 38 (NDEA and 2-AAF) or 40 (BEN and 1,2-DCE) weeks to groups of 25-29 male and female PIM mice at 1 and 3 mg/kg for NDEA, 50 and 100 mg/kg for BEN, 25-100 mg/kg for 2-AAF and 100-300 mg/kg for 1,2-DCE. Small but statistically significant increases in the incidence of malignant lymphoma were seen for three of the four carcinogens tested; in high dose males treated with 2-AAF, high and low dose females treated with NDEA and high dose females treated with 1,2-DCE. Results for BEN, the only mouse lymphomagen tested, did not show a statistically significant increase in the incidence of malignant lymphomas in transgenic mice within the 40 week duration of the study. NDEA also produced a high incidence (> 70%) of hepatic hemangiosarcomas in both sexes at the low and high dose levels. These results demonstrate that over-expression of the pim-1 oncogene in lymphoid tissue can confer susceptibility of this tissue to chemical carcinogenesis by genotoxic procarcinogens. However, whereas potent genotoxic carcinogens produced only small increases in the incidence of lymphoma and since BEN, a mouse lymphomagen, was negative, PIM transgenic mice may lack sufficient sensitivity to established carcinogens to justify their routine use in a short-term carcinogenesis screening assay.
Department of Genetic Toxicology (WP45-311), Merck Research Laboratories, West Point, PA 19486.
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Storer
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Cartwright
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Cook
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Soper
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Nichols
D015073:2-Acetylaminofluorene / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D001554:Benzene / Q000493:pharmacokinetics / Q000633:toxicity; D001711:Biotransformation; D001835:Body Weight / Q000187:drug effects; D015197:Carcinogenicity Tests / Q000379:methods*; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity*; D004052:Diethylnitrosamine / Q000493:pharmacokinetics / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005025:Ethylene Dichlorides / Q000493:pharmacokinetics / Q000633:toxicity; D005260:Female; D006394:Hemangiosarcoma / Q000139:chemically induced; D008223:Lymphoma / Q000139:chemically induced; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic / Q000502:physiology*; D009857:Oncogenes; D011355:Prodrugs / Q000493:pharmacokinetics / Q000633:toxicity*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051573:Proto-Oncogene Proteins c-pim-1; D013274:Stomach Neoplasms / Q000139:chemically induced
D002273:Carcinogens; D005025:Ethylene Dichlorides; D011355:Prodrugs; D011518:Proto-Oncogene Proteins; D004052:Diethylnitrosamine; C024565:ethylene dichloride; D015073:2-Acetylaminofluorene; C496636:Pim1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; D001554:Benzene