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Suppression of Lung Tumor Formation by the Regulatory Subunit of Ribonucleotide Reductase

Division and Program of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida

Requests for reprints: Gerold Bepler, Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Medical Research Council-4W, Room 4046, 12902 Magnolia Drive, Tampa, FL 33612-9497. Phone: 813-903-6895; Fax: 813-903-6875; E-mail: beplerg{at}moffitt.usf.edu.

The nucleotide metabolism enzyme ribonucleotide reductase is composed of a regulatory subunit (RRM1) and a catalytic subunit (RRM2). The RRM1 locus has frequent loss of heterozygosity in lung cancers, ectopic expression of RRM1 suppresses proliferation of ras-transformed mouse fibroblasts, and high levels of RRM1 expression are associated with a significant survival benefit in patients with lung cancer. In RRM1 transgenic human lung and colon cancer cell lines, we observed induction of G₂ cell cycle arrest, apoptosis, and efficient DNA damage repair. We generated strains of RRM1 transgenic mice and found that carcinogen-induced lung tumor formation was significantly suppressed. The tumor suppression was more pronounced in strains with high levels of RRM1 expression than in those with low levels of expression. DNA damage repair capacity in transgenic animals was determined, and RRM1 transgenic animals repaired chemically induced DNA damage with greater efficiency than control animals. We conclude that the regulatory subunit of ribonucleotide reductase has tumor suppressor activity that is mediated through efficient DNA damage repair. (Cancer Res 2006; 66(13): 6497-502)

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