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.
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ABSTRACT: EGFR inhibitors are employed in therapy of lung and pancreatic cancers, and effectively prevent cancers in multiple animal models. Although daily dosing with erlotinib is effective, weekly dosing may reduce toxicity and have advantages, particularly for prevention. We tested alternative dosing regimens for preventive/therapeutic efficacy in a rat mammary cancer model. For prevention, erlotinib was administered by gavage beginning 5 days after MNU. For therapy and biomarker studies, rats with palpable mammary cancers were treated for six weeks or for 6 days, respectively. Prevention. Experiment A. Erlotinib (6 mg/Kg BW/day, i.g.): daily (7x/week); one day on/one day off; and two days on/two days off. All regimens decreased tumor incidence, increased tumor latency, and decreased cancer multiplicity vs controls (P<.01). However, intermittent dosing was less effective than daily dosing (P<.05). Experiment B. Erlotinib (6 mg/kg BW/day) daily or two days on/two days off; or 1x/week at 42 mg/kg BW. All regimens reduced cancer incidence and multiplicity vs controls (P<.01). Interestingly, daily and weekly dosing were equally effective (P>0.5). Experiment C. Erlotinib administered at 42 or 21 mg/kg BW, 1x/week, decreased tumor incidence and multiplicity (P<.01). Pharmacokinetics. Erlotinib had a serum half-life of ≤8 hours, and weekly treatment yielded effective serum levels for <48 hours. Therapy. Daily or weekly treatment of cancer bearing rats reduced mammary tumor size 25-35%, while control cancers increased >250%. Biomarkers. Levels of phosphorylated ERK were strongly decreased in rats treated daily/weekly with erlotinib. Thus, altering the dosing of erlotinib retained most of its preventive and therapeutic efficacy.Cancer Prevention Research 03/2013; 6(5). DOI:10.1158/1940-6207.CAPR-12-0322 · 5.27 Impact Factor
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ABSTRACT: Activation of receptor tyrosine kinases (RTK) plays a key role in the prognosis of mammary cancer. Lapatinib is a small molecule dual RTK inhibitor that targets epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Identifying the protein targets involved in the effects of lapatinib and other RTK inhibitors might help determine why preventive efficacy varies. In this study, female Sprague-Dawley rats were given methylnitrosourea (MNU) by intravenous injection resulting in the development of multiple estrogen receptor-positive tumors. Treatment with lapatinib beginning 5 days after MNU was highly effective in preventing cancer development. In addition, we treated rats with palpable mammary tumors with lapatinib daily. In these tumor-bearing animals, treatment continued for 42 days and therapeutic results were obtained. Some rats bearing cancers were treated for 5 days, and the resulting lesions were examined for biomarker modulation. Lapatinib effectively suppressed the abundance of HER2, phosphorylated HER2 (Tyr1221/1222), and phosphorylated EGFR (Tyr1173, Tyr1110) compared with tumors from untreated rats. Protein array analyses allowed parallel determination of the effect of lapatinib on the relative levels of protein phosphorylation and proteins associated with apoptosis. These results combined with immunoreactivity data indicated that, in addition to EGFR and HER2, lapatinib treatment was associated with changes in a number of other signaling molecules, including IGF-1R, Akt, and downstream targets such as GSK3, p27, p53, and cyclin D1 presumably leading to impaired proliferation, apoptosis, or cell-cycle arrest.Cancer Prevention Research 08/2011; 4(8):1190-7. DOI:10.1158/1940-6207.CAPR-10-0330 · 5.27 Impact Factor
Chapter: RetinoidsBurger's Medicinal Chemistry, Drug Discovery and Development, 09/2010; , ISBN: 9780471266945