Effects of gefitinib (Iressa) on mammary cancers: preventive studies with varied dosages, combinations with vorozole or targretin, and biomarker changes
ABSTRACT The ability of the epidermal growth factor receptor inhibitor gefitinib (Iressa) to prevent/treat methylnitrosourea (MNU)-induced mammary cancers and to modulate biomarkers in female Sprague-Dawley rats was examined. Rats were given a single dose of MNU (75 mg/kg body weight) at 50 days of age. In the prevention studies, continual treatment with Iressa at 10, 3, or 1 mg/kg body weight per day beginning 5 days after MNU reduced tumor multiplicity by 93%, 43%, and 20%, respectively. Treatment of rats bearing small palpable cancers with Iressa (10 mg/kg body weight per day) resulted in the complete regression of 70% of the tumors. Short-term treatment of tumor-bearing rats with Iressa caused decreases in cell proliferation and phosphorylated epidermal growth factor receptor and increases in apoptosis. To examine treatment regimens that might decrease the skin toxicity associated with Iressa, both intermittent treatments and combinations of lower doses of Iressa with other effective agents were evaluated. Treatment with Iressa (10 mg/kg body weight per day) continually or intermittently (either "3 weeks on/3 weeks off" or "4 days on/3 days off") reduced cancer multiplicity by 91%, 24%, and 68%, respectively. However, all regimens reduced tumor weights >85%. Finally, combining suboptimal doses of Iressa with suboptimal doses of vorozole (an aromatase inhibitor) or targretin (a retinoid X receptor agonist) yielded greater chemopreventive efficacy than any of these agents given alone.
Article: Basic science (April 2006)Breast Cancer Online 07/2006; 9(08). DOI:10.1017/S1470903106005657
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ABSTRACT: The statins are highly effective in lowering cholesterol by inhibiting 3-hydroxy-3-methylglutaryl CoA reductase. Recently, there has been conflicting epidemiologic data indicating that statins decrease the incidence of certain types of cancer, including breast cancer. Atorvastatin and lovastatin, statins with different lipophicilities, were administered in diet either as single agents or in combination with suboptimal doses of tamoxifen or the retinoid X receptor agonist bexarotene were evaluated for prevention of estrogen receptor-positive mammary cancers induced in the rat with methylnitrosourea. Atorvastatin (125 or 500 mg/kg diet) alone did not significantly alter cancer incidence or multiplicity. Suboptimal doses of tamoxifen (0.4 mg/kg diet) or bexarotene (80 mg/kg diet) reduced cancer multiplicity from 3.8 (control) to 2.9 and 0.9, respectively. Combining atorvastatin (500 mg/kg diet) with either of these effective agents minimally altered their efficacy. Although this dose of atorvastatin did not decrease serum triglyceride levels in control rats, it significantly decreased triglyceride levels that had been increased in bexarotene-treated rats. Experiments done with a second statin, lovastatin (100 and 400 mg/kg diet), yielded similar results: (a) limited activity when administered alone, (b) no obvious synergy with bexarotene, and (c) an ability to decrease bexarotene-induced increases in serum triglycerides. Thus, the statins had minimal activity in this model of mammary cancer in which approximately half of the cancers are mutated in the Ha Ras oncogene. Similarly, atorvastatin failed to alter the development of estrogen receptor-negative mammary carcinomas in a new animal model using bitransgenic mice (MMTV-Neu(+/-)/p53KO(+/-)), whereas bexarotene (250 mg/kg diet) was effective.Cancer Prevention Research 03/2009; 2(2):161-7. DOI:10.1158/1940-6207.CAPR-08-0134 · 5.27 Impact Factor