Transgenic human O6-alkylguanine-DNA alkyltransferase decreases incidence and increases latency of MNU-induced thymic lymphomas in Ttg-1 transgenic mice (Meeting abstract).

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Transgenic human O6-alkylguanine-DNA alkyltransferase decreases incidence and increases latency of MNU-induced thymic lymphomas in Ttg-1 transgenic mice (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 36:A1122 1995. Unique Identifier : AIDSLINE ICDB/95608899
Allay E; McGuire EA; Koc ON; Marko DA; Pincus E; Gerson SL; Cancer Research Center, Case Western Reserve Univ. Sch of Med,; Cleveland, OH 44106

Abstract: Overexpression of alkyltransferase in thymus of MGMT transgenic mice prevents MNU-induced thymic lymphomas. Spontaneous lymphomas occur in transgenic mice expressing Ttg-1, the oncogene at [t(11:14)(p15:q11)] identified in 14% of patients with T-ALL. To better understand the role of DNA repair in chemical- and oncogene-activated carcinogenesis, we bred MGMT to Ttg-1 mice. F1 progeny of the cross received 50 mg/kg MNU at 6 wk of age. MNU increases the incidence of lymphomas in Ttg-1 mice from 50% to 75% and decreases median latency from 273 to 128 days over spontaneous rates. A protective effect of MGMT is seen in +/+ mice (+ = transgene; MGMT/Ttg); increased repair of O6mG adducts reduces lymphoma incidence to spontaneous rates in Ttg-1 mice and increases latency closer to that of untreated Ttg-1 mice (46% incidence of lymphomas, median latency = 193 days). Lymphoma phenotype of MNU-induced tumors was CD4+CD8+, while spontaneous tumors were either CD4-CD8+ or CD4+CD8+. 30% of MNU-induced lymphomas in -/- mice contained an activating G to A point mutation in codon 12 of K-ras, whereas 60% of Ttg-1 mice (-/+) carried the K-ras mutation. Thus, we noted cooperation between chemical and oncogene activated carcinogenesis that could be blocked by increased alkyltransferase-mediated DNA repair. This repair appears to prevent potential activating point mutations, reducing the incidence of (MNU)-induced lymphomas to levels similar to untreated, oncogene initiated mice.

Keywords: Animal Carcinogens CD4-CD8 Ratio DNA Repair DNA-Binding Proteins/*GENETICS Immunophenotyping Lymphoma/CHEMICALLY INDUCED/*GENETICS/IMMUNOLOGY Metalloproteins/*GENETICS Methylnitrosourea Methyltransferases/*GENETICS Mice Mice, Transgenic Mutation Proto-Oncogene Protein p21(ras)/GENETICS Thymus Neoplasms/CHEMICALLY INDUCED/*GENETICS/IMMUNOLOGY ABSTRACT
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