Carcinogenesis Advance Access published online on December 9, 2004
Carcinogenesis, doi:10.1093/carcin/bgh352
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1 Division of Cancer Prevention, National Cancer Institute, Bethesda, MD
* To whom correspondence should be addressed. The administration of OH-BBN to male B6D2F1 mice yielded a high incidence of large palpable urinary bladder cancers that were characterized for expression of certain cancer related genes (FHIT, survivin and COX-2). FHIT was expressed at high levels in normal bladder epithelium, but was minimally expressed in cancers. The antiapoptotic protein survivin was not expressed in normal bladder epithelium, but was variably expressed in bladder cancers. Finally, COX-2 was minimally expressed in both normal bladder and cancer cells. Based on previous positive results, we further explored the chemopreventive effects of the NSAID indomethacin. Continual indomethacin treatment (20 mg/kg diet) was initiated either prior to or following OH-BBN dosing for 12 weeks. Palpable bladder masses developed in 32% of carcinogen-treated only mice by 8 months, while mice administered indomethacin either prior to or after OH-BBN developed palpable masses in 3 and 6% of the animals. In Experiment II, mice were treated with indomethacin beginning 1 week after OH-BBN either for 12 weeks or for 28 weeks. Continual treatment resulted in a 77% decrease in palpable bladder masses and an 82% decrease in all cancers (palpable and microscopic), while limited treatment decreased palpable masses by 48% but failed to decrease the number of bladder cancers (palpable plus microscopic). In Experiment III, OH-BBN treated mice were followed for 14 months. Palpable masses developed in 66% of control mice, while 26% of mice treated with indomethacin continually from one week after OH-BBN developed palpable masses. A separate group treated with indomethacin beginning when 5% of the mice had palpable bladder masses continued to develop new masses for an additional 4 weeks. By 6 weeks after beginning indomethacin treatment, however, these animals showed a profound decrease in the development of additional masses.
Received May 27, 2004
Revised September 21, 2004
Accepted November 26, 2004
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
4-hydroxybutyl(butyl)nitrosamine (OH-BBN)-induced urinary bladder cancers in mice: characterization of FHIT, survivin and COX-2 expression and chemopreventive effects of indomethacin
2 Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
3 Cancer Center, University of Massachusetts Medical School, Worcester, MA
4 Department of Surgery, University of Alabama at Birmingham, Birmingham, AL; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
Ronald A. Lubet, E-mail: rl57{at}nih.gov
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