Overexpression of human O6-alkylguanine DNA alkyltransferase (AGT) prevents MNU induced lymphomas in heterozygous p53 deficient mice

Abstract

-alkylguanine DNA alkyltransferase (AGT) is a key mechanism in the prevention against MNU induced malignant transformation by removal of O 6 methyl guanine (O 6 mG) adducts. We asked whether heterozygous p53 de®cient mice (p53+/7) would be more susceptible to MNU induced lymphomas than wild type mice, and whether O 6 mG adducts were responsible for this susceptibility. To determine whether MGMT overexpression would be protective, p53+/7 mice were bred to human MGMT transgenic mice (MGMT+) and treated with 50 mg/kg MNU. MNU increased the incidence of thymic lymphomas in non-transgenic p53+/7 mice from 23% (n=13) to 68% (n=22) and decreased the mean latency from 433 to 106 days (P=0.01 compared to untreated mice). Wild type mice had an incidence of 30% (n=38) and a mean latency of 135 days after MNU. Overexpression of MGMT in the thymus of p53+/7 mice signi®cantly reduced the lymphoma incidence from 68 to 28% (n=17) and increased the latency from 106 to 167 days (P=0.003). Similarly, the lymphoma incidence in MGMT+/wild type mice decreased from 30 to 8% (n=12) and the latency increased to 297 days (P=0.2). Loss of the wild type allele was found in only 2/17 lymphomas occurring in p53+/7 mice and there were no signi®cant point mutations in exons 5 ± 8 of p53. Furthermore, there was no loss of p53 function in these mice. These data demonstrate that unrepaired O 6 mG lesions act cooperatively with the reduced p53 dose and lead to lymphomagenesis in p53+/7 mice, but AGT overexpression and rapid removal of O 6 mG adducts is protective. Oncogene (2001) 20, 5258 ± 5263.

Lung tumorigenesis associated with erb-B-2 and erb-B-3 overexpression in human erb-B-3 transgenic mice is enhanced by methylnitrosourea

“…We have found in other mouse MNU carcinogenesis studies (Dumenco et al, 1993;Qin et al, 1999a,b;Reese et al, 2001;Zhou et al, 2001) that predisposing oncogenic processes such as mismatch repair defects (Qin et al, 1999a,b), erb-B-2 over-expression (Zhou et al, 2001), or p53 mutation (Reese et al, 2001) increase the carcinogenicity of MNU. In these other studies, the thymus, mammary gland and colon, have been the tissue targets.…”

Carcinogenesis, cancer therapy and chemoprevention

“…10 Overexpression of MGMT reduces the risk of carcinogenesis. 44,45 Therefore, MGMT-deficient cells may preferentially undergo transformation. In turn, low levels of MGMT render cancer cells vulnerable to DNA-damaging drugs and can be exploited for therapy.…”

Live and let die: In vivo selection of gene-modified hematopoietic stem cells via MGMT-mediated chemoprotection

“…In practice, there is little evidence that such a chemoprotective strategy would promote leukemia in cells which overexpress MGMT. In fact, gene modified hematopoietic cells demonstrate a significant reduction in mutation frequency and chromosomal aberrations upon challenge with O 6 alkylating agents [ 31,[82][83][84] and mice transgenic for human MGMT show a decrease in cellular transformation frequency upon drug treatment [85][86][87][88][89]. Perhaps most compelling in this regard is the observation that there was no evidence of hematopoietic malignancy following an extended, dose escalating chemotherapeutic regimen in a canine large animal model which enabled selection of gene modified cells [ 62 ].…”