title: DNA Alkylating Agent Protects Against Spontaneous Hepatocellular Carcinoma Regardless of O6-Methylguanine-DNA Methyltransferase Status.
abstract: Hepatocellular carcinoma is increasingly important in the United States as the incidence rate rose over the last 30 years. C3HeB/FeJ mice serve as a unique model to study hepatocellular carcinoma tumorigenesis because they mimic human hepatocellular carcinoma with delayed onset, male gender bias, approximately 50% incidence, and susceptibility to tumorigenesis is mediated through multiple genetic loci. Because a human O(6)-methylguanine-DNA methyltransferase (hMGMT) transgene reduces spontaneous tumorigenesis in this model, we hypothesized that hMGMT would also protect from methylation-induced hepatocarcinogenesis. To test this hypothesis, wild-type and hMGMT transgenic C3HeB/FeJ male mice were treated with two monofunctional alkylating agents: diethylnitrosamine (DEN; 0.025 μmol/g body weight) on day 12 of life with evaluation for glucose-6-phosphatase-deficient (G6PD) foci at 16, 24, and 32 weeks or N-methyl-N-nitrosurea (MNU; 25 mg MNU/kg body weight) once monthly for 7 months starting at 3 months of age with evaluation for liver tumors at 12 to 15 months of age. No difference in abundance or size of G6PD foci was measured with DEN treatment. In contrast, it was unexpectedly found that MNU reduces liver tumor prevalence in wild-type and hMGMT transgenic mice despite increased tumor prevalence in other tissues. hMGMT and MNU protections were additive, suggesting that MNU protects through a different mechanism, perhaps through the cytotoxic N7-alkylguanine and N3-alkyladenine lesions which have low mutagenic potential compared with O(6)-alkylguanine lesions. Together, these results suggest that targeting the repair of cytotoxic lesions may be a good preventative for patients at high risk of developing hepatocellular carcinoma.
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Maryanne C S
authors.initials: MC
authors.lastname: Herzig
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Zavadil
authors.affiliation: Saddleback College, Mission Viejo, California.
authors.forename: Karah
authors.initials: K
authors.lastname: Street
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Kim
authors.initials: K
authors.lastname: Hildreth
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Norman R
authors.initials: NR
authors.lastname: Drinkwater
authors.affiliation: Transgenic Mouse Facility, Duke University Medical Center, Durham, North Carolina.
authors.forename: Traci
authors.initials: T
authors.lastname: Reddick
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Damon C
authors.initials: DC
authors.lastname: Herbert
authors.affiliation: Department of Laboratory Animal Resources, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Martha A
authors.initials: MA
authors.lastname: Hanes
authors.affiliation: Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: C Alex
authors.initials: CA
authors.lastname: McMahan
authors.affiliation: Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Reddick
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas. Barshop Center for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas. San Antonio Cancer Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas. South Texas Veteran's Health Care System, Audie Murphy Hospital, San Antonio, Texas. walter@uthscsa.edu.
authors.forename: Christi A
authors.initials: CA
authors.lastname: Walter
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D004052:Diethylnitrosamine / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008770:Methylnitrosourea / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000477:Alkylating Agents; D025521:Tumor Suppressor Proteins; D004052:Diethylnitrosamine; D008770:Methylnitrosourea; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes