Carcinogenesis, Vol. 20, No. 2, 343-346,
February 1999
© 1999 Oxford University Press
Short Communications |
5-Aza-2'-deoxycytidine is chemopreventive in a 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone-induced primary mouse lung tumor model
1 Departments of Pathology and
2 Surgery, Medical College of Ohio, Health Education Building, Room 202, Toledo, OH 43614 and
3 Chemoprevention Branch, National Cancer Institute, Rockville, MD 20892, USA
Carcinogenesis is a multistep process in which many alterations in both genetic and epigenetic controls lead to a growth advantage for neoplastic cells. Hypermethylation has been established as the basis of genomic imprinting, but recent studies have also shown that alterations in genomic methylation patterns may contribute to tumorigenesis. The chemical 5-aza-2'-deoxycytidine (5-aza-dC) has been used both in vitro and in vivo to inhibit DNA methylation. In this study, we investigated the chemopreventive efficacy of 5-aza-dC in a well-established primary mouse lung tumor model. Five-week-old male (C3H/HeJxA/J) F1 hybrid mice were treated for 24 consecutive weeks with 5-aza-dC, three times per week i.p. Lung tumors were induced with two consecutive weekly doses of 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone starting 1 week after initial treatment with 5-aza-dC. We demonstrated that 5-aza-dC exhibits a chemopreventive effect in this primary mouse lung tumor model which, like human lung adenocarcinomas, harbors an activating K-ras mutation. Treatment with 5-aza-dC resulted in a 23% reduction in tumor incidence, as well as a 42% reduction in tumor multiplicity. This work supports further investigation of methylation inhibitors likes 5-aza-dC for early intervention, prevention and treatment of lung cancer.
Abbreviations: 5-aza-dC, 5-aza-2'-deoxycytidine; C3A F1, (C3H/HeJxA/J) F1; LOH, loss of heterozygosity; MTase, methyltransferase; MTD, maximum tolerated dose; NNK, 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone; PBS, phosphate-buffered saline.
4 To whom correspondence should be addressed Email: myou{at}mco.edu
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