Importance of DNA repair in carcinogenesis: evidence from transgenic and gene targeting studies

We have generated transgenic mice by introducing copies of the E. coli O-6- methylguanine-DNA methyltransferase gene, ada. Liver extracts from homozygo tes demonstrate about three times the control enzyme activity and increase up to about eight-fold can be induced by treatment with zinc, since the met al-responsive metallothionein promoter is attached to the ada gene. Further more, studies of liver carcinogenesis in our transgenic mice demonstrated s ignificantly reduced rates of development of hepatocellular tumors after tr eatment with dimethylnitrosamine or diethylnitrosamine. It is well known that xeroderma pigmentosum (XP) patients are deficient in DNA repair. The availability of XPA (XP group A complementing) knockout mic e has enabled us to investigate the functional role of the XPA nucleotide e xcision repair gene in carcinogenesis in vivo, first using the mouse skin a s a model system. XPA-/- mice demonstrated skin ulcers 5-7 days after 7,12- dimethylbenz[a]anthracene (DMBA) treatment and papilloma development within 4 weeks prior to promotion, skin tumor incidence being also much higher th an in heterozygous and wild-type mice. Experiments targeting the lung, live r and tongue have also been conducted to answer the question of whether the internal organs of these mice are also susceptible to chemical carcinogens . For lung carcinogenesis, mice were instilled intratracheally with a small dose of benzo[a]pyrene. The pulmonary tumor incidence in XPA-/- mice was s ignificantly higher than in XPA+/- and XPA+/+ mice. XPA-/- mice were also f ound to be have enhanced sensitivity to aflatoxin B-1 regarding liver tumor induction, In addition, administration of 4-nitroquinoline-1-oxide in drin king water for 50 weeks resulted in tongue tumors only in XPA-/- mice. Thes e studies, thus, provided convincing evidence that XPA mice are also sensit ive to carcinogenesis in organs other than the skin. (C) 2001 Elsevier Scie nce B.V. All rights reserved.