Effect of bexarotene and mushroom extract lsy16 on intestinal neoplasia in the Apc Min/+ mouse model
Authors: Carrie E. Merkel, Wen-Chi L. Chang, Renata A. Coudry, Tianyu Li, Harry S. Cooper, Ronald A. Lubet, Insu P. Lee, Vernon E. Steele, Margie L. Clapper
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

3943 

Previous studies by others have demonstrated the ability of bexarotene (Targretin), a selective retinoid X receptor (RXR) agonist, to inhibit both mammary and lung cancers in a variety of animal models. An extract (lsy16) isolated from the mushroom Agaricus blazei Murill Kyowa has also been shown to decrease the formation of chemically induced pulmonary adenomas and colonic aberrant crypt foci (ACF) significantly. The goal of the present study was to assess the chempreventive activity of bexarotene and mushroom extract lsy16 in the ApcMin/+ mouse model of spontaneous intestinal tumorigenesis. Male ApcMin/+ mice (65 days of age) were maintained on a modified AIN 76A diet and randomized to receive either bexarotene, lsy16 or control diet (n = 10 per group). Bexarotene (400, 600 or 800 ppm in the diet) was administered for the duration of the study (45 days). lsy16 extract (100, 200 or 400 mg/kg body weight) was administered in the drinking water on Days 1-14, with animals receiving untreated drinking water on Days 15-45. Body weights were obtained weekly. At the time of sacrifice (Day 45), small intestines were collected for gross lesion count and histopathological evaluation. Bexarotene was well tolerated by all mice except those receiving the highest dose (800 ppm), for which a 20% reduction in survival was observed. The body weights of the remaining bexarotene-treated animals were decreased significantly on Days 35 and 42 (p = 0.01; Wilcoxon test). However, after Bonferroni multi-comparison adjustment, only the body weights of animals receiving 600 ppm bexarotene remained significantly different from those of controls. All animals survived exposure to lsy16, and treatment had no effect on body weight (p = 0.55; Wilcoxon test). No significant difference was observed in the number of gross small intestinal lesions present in bexarotene-treated vs. control animals (mean ± SEM - control 15.6 ± 5.2; 400 ppm 21.8 ± 7.7; 600 ppm 26.2 ± 9.3; 800 ppm 19.6 ± 7.4; p = 0.48 by Wilcoxon test). Likewise, administration of lsy16 had no effect on the number of gross small intestinal lesions per animal (mean ± SEM - control 16.8 ± 6.3; 100 mg/kg 20.9 ± 7.9; 200 mg/kg 21.0 ± 8.5; 400 mg/kg 14.5 ± 5.5; p = 0.82 by Wilcoxon test). Histopathological analyses have confirmed the lack of effect of bexarotene on spontaneous intestinal tumorigenesis. Similar histopathological reviews of tissues from animals exposed to lsy16 remain in progress. The bexarotene data from the present study are consistent with recent findings from others, which indicate the inability of this agent to inhibit tumorigenesis in mouse models of urinary bladder, prostate and ovarian cancer. The contrasting activity of the lsy16 extract against chemically induced ACF and spontaneous ApcMin/+ intestinal adenomas suggests that this agent may not exhibit chemopreventive activity against intestinal cells with an existing Apc mutation. (Supported by NIH N01 CN43309.)