Table 6.

Carcinogens strongly induce tumorigenesis in Pim mouse models.

Mouse model and phenotype	Carcinogen: dose and time of treatment	Carcinogen action	Phenotype	Increased levels of oncogenes or K-ras mutation
Eμ-pim1: 10% mice developed T-cell lymphoma, at 34 weeks	ENU 200, 60, 15, 4.1, or 0.1 mg/kg, 15 days after birth	Small alkyl DNA adducts	T-cell lymphomas: latency of 17 weeks for the highest dose and 34 weeks for the lowest doses Penetrance: 100–70% for the three highest doses and 20% for 4–0.1 mg 7 kg dose	Enhanced expression of c-myc without rearrangement or amplifications. Incidence of mutations: 4.5% N-ras mutations, 9% K-ras mutations (23, 76)
	ENU 50 mg/kg in combination with dietary administration of 4-HPR, DFMO as chemopreventive agents	Small alkyl DNA adducts	Infiltrative metastatic lymphomas. Only 4-HPR induces a dose-related delay in tumor progression	n.d. (79)
	Diet of 0.03% PhiP for 7 months or 0.03% IQ for 6 months	Carcinogenic or mutagenic, respectively	Lymphoblastic lymphoma in 80% of the females and 27% of the males, 28.5 weeks after treatment	n.d. (80, 81)
	25 and 100 mg/kg AAF, 1 and 3 mg/kg NDEA, 100 and 300 mg/kg 1,2-DCE, and 50 and 100 mg/kg BEN	Genotoxic procarcinogens	Pleomorphic, lymphocytic lymphomas, and leukemias. Small but significant increase in incidence of malignant lymphomas in males treated with a high dose of 2-AAF (3.4-fold), the females treated with high and low doses of NDEA (2.5-fold), and females treated with a high dose of 1,2-DCE (1.8-fold)	n.d. (82)
	4.3, 13, or 39 mg/kg oral administration of B[a]P for 13 weeks and topical administration of 10 μg TPA twice a week; 7 weeks interruption and 35 weeks of 3 μg treatment. 220 μg total TPA dose/mouse	B[a]P requires metabolism and generates bulky DNA adduct. TPA is a tumor promoter	Multicentric lymphoma and T-cell lymphomas with B[a]P B[a]P dose-dependent induction of lymphomas in males, starting at 25 days. Transgenic mice five time more sensitive that wild-type counterparts	75% Of mice had increased c-myc levels, and 12.5% of tumors harbored K-ras mutations (83)
	Total body X-irradiation	DNA strand breaks	Dose-dependent incidence of T-cell lymphomas: (4 × 1.5 Gy X-ray: 100%; 4 × 1.0 Gy X-ray: 90%; 4 × 0.5 Gy X-ray: 28%) 36 weeks after the last dose	75% Of mice had 5–20- fold expression of c-myc, and 16% mice have increased pim-1 levels (85, 86)
	Mitomycin c, cumulative dose of 2.67–6.55 mg/kg	DNA cross-linking agent	11–30% Of females developed T-cell lymphomas with no dose response effect	n.d. (84)
alb-pim3	DEN 10 mg/kg	Liver injury	81% Males developed hepatocellular carcinoma after DEN treatment for 10 months (versus 41% of wild-type mice)	n.d. (35)
AKR mice: spontaneous thymomas at >24 weeks old. MCF provirus integration: 17% pim1, 6.66% c-myc	NMU 50 mg/kg, 4-week-old mice	Methylating agent; G-A transition mutations	Thymomas between 12 and 24 weeks	Ecotropic-like provirus integration; 3.84% c-myc and 9.33% pim-1. 24% K-ras mutations (78)
	MMS 120 mg/kg, 4-week-old mice	Methylating agent: weak mutagen	Thymomas developed between 20 and 50 weeks in 100% of mice	MCF (mink cytopathic focus-forming) provirus integration 19.2% c-myc and 4% pim-1; no mutations in K-ras (77)

n.d., not determined.