Carcinogenesis Advance Access published online on December 9, 2004
Carcinogenesis, doi:10.1093/carcin/bgh338
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1 Division of Cancer Prevention, National Cancer Institute, Bethesda, MD
* To whom correspondence should be addressed. Various aspects of the chemopreventive and chemotherapeutic properties of the RXR receptor agonist targretin (LCD 1069) were examined in the methylnitrosourea (MNU)-induced model of mammary cancer. The administration of targretin at dose levels of 60, 20, or 6.7 mg/kg BW/day by gavage decreased the number of mammary tumors by 96, 85, and 78%, respectively. When targretin was administered in the diet at 92 and 275 mg/kg diet, cancer multiplicities were reduced by 78 and 92%, respectively. A wider range of dietary doses of targretin at 15, 50, and 150 mg/kg diet reduced the number of mammary tumors by 38, 55, and 70%, respectively. Treatment of rats with different regimens of targretin (250 mg/kg diet) yielded cancer multiplicities of 4.3 for non-treated rats, 0.5 for rats treated continuously with targretin, 2.1 for rats treated with targretin for 8 weeks followed by 10 weeks of control diet, and 1.6 for rats treated with targretin alternating 3 days on and 4 days off. Targretin was also examined as a therapeutic agent by treating rats with at least one palpable mammary tumor for five weeks. A high dose of targretin, 272 mg/kg diet, caused partial or complete regression of approximately 65% of the cancers over this time period. In contrast, in animals treated with 15 mg targretin/kg diet, only one of 12 cancers had a significant regression. Finally, the effect of a limited exposure to targretin (7 days) on cell proliferation and apoptosis in small mammary tumors was determined. Targretin at 150 mg/kg diet strongly decreased proliferation (75%) and increased apoptosis (300%), while a lower dose of targretin, 15 mg/kg diet (which still prevented 30% of cancers), had no effect on apoptosis but did decrease cell proliferation. Determination of serum IGF1 levels showed that treatment of rats with highly effective doses of targretin at 272 mg/kg diet or at 60 or 20 mg/Kg BW/day by gavage caused significantly decreased serum IGF1 levels.
Received August 5, 2004
Revised November 3, 2004
Accepted November 9, 2004
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Efficacy of targretin on methylnitrosourea-induced mammary cancers: prevention and therapy dose response curves and effects on proliferation and apoptosis
2 Department of Surgical Oncology, University of Illinois at Chicago, Chicago, IL
3 Department of Surgery, University of Alabama at Birmingham, Birmingham, AL; Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL
Ronald A. Lubet, E-mail: lubetr{at}mail.nih.gov
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