Arzoxifene, a new selective estrogen receptor modulator with strong breast antiestrogen activity and absence of uterine agonist activity, was explored as a potential chemoprevention agent. We performed a multi-institutional evaluation of arzoxifene in women with newly diagnosed ductal carcinoma in situ or T1/T2 invasive cancer.
In a Phase IA trial, 50 pre- or postmenopausal women were randomized to 10, 20, or 50 mg of arzoxifene daily in the interval between biopsy and re-excision or were enrolled as no-treatment controls. In a Phase IB trial, 76 postmenopausal women were randomized to 20 mg of arzoxifene versus matched placebo. Serum specimens collected at entry and at re-excision were assayed for various hormones and growth factors. Tissue from biopsies (estrogen receptor + and/or progesterone receptor +) and re-excision specimens was evaluated immunohistochemically for proliferation (Ki-67 by MIB-1 and proliferating cell nuclear antigen) and other biomarkers.
In both trials, increases in serum sex hormone binding globulin were noted, as were decreases in insulin-like growth factor (IGF)-I and the IGF-I:IGF binding protein-3 ratio (P < 0.007 versus control/placebo). For 45 evaluable women in Phase IA, decreases in proliferation indices were more prevalent for arzoxifene (particularly 20 mg) than for controls. For 58 evaluable women in Phase IB, a decrease in estrogen receptor expression for arzoxifene was observed compared with no change with placebo (P = 0.0068). However, decreases in proliferation indices for arzoxifene were not statistically different from placebo, perhaps due to a confounding effect of stopping hormone replacement therapy before entry.
Given the favorable side effect profile and the biomarker modulations reported here, arzoxifene remains a reasonable candidate for additional study as a breast cancer chemoprevention agent.
"A phase 1 clinical trial of arzoxifene determined that daily oral dosing was safe and well tolerated; and combined with all previous studies, this suggests that arzoxifene may be useful in the treatment of metastatic breast cancer (Munster et al., 2001; Fabian et al., 2004). A phase 2 clinical trial determined that arzoxifene is effective in treating tamoxifen-sensitive and tamoxifen-refractory patients with advanced or metastatic breast cancer (Chan, 2002; Baselga et al., 2003; Buzdar et al., 2003). "
[Show abstract][Hide abstract] ABSTRACT: Nuclear receptors are ligand-activated transcription factors and include the receptors for steroid hormones, lipophilic vitamins, sterols, and bile acids. These receptors serve as targets for development of myriad drugs that target a range of disorders. Classically defined ligands that bind to the ligand-binding domain of nuclear receptors, whether they are endogenous or synthetic, either activate receptor activity (agonists) or block activation (antagonists) and due to the ability to alter activity of the receptors are often termed receptor "modulators." The complex pharmacology of nuclear receptors has provided a class of ligands distinct from these simple modulators where ligands display agonist/partial agonist/antagonist function in a tissue or gene selective manner. This class of ligands is defined as selective modulators. Here, we review the development and pharmacology of a range of selective nuclear receptor modulators.
"Effective to prevent ERpositive and ER-negative mammary tumors especially in combination with LG100268   Phase III trial (200 patients) inferior to tamoxifen  Phase I trials (50 and 76 women) low toxicity and favorable biomarker profile  "
[Show abstract][Hide abstract] ABSTRACT: Selective estrogen receptor modulators (SERMs) are structurally different compounds that interact with intracellular estrogen receptors in target organs as estrogen receptor agonists or antagonists. These drugs have been intensively studied over the past decade and have proven to be a highly versatile group for the treatment of different conditions associated with postmenopausal women’s health, including hormone responsive cancer and osteoporosis. Tamoxifen, a failed contraceptive is currently used to treat all stages of breast cancer, chemoprevention in women at high risk for breast cancer and also has beneficial effects on bone mineral density and serum lipids in postmenopausal women. Raloxifene, a failed breast cancer drug, is the only SERM approved internationally for the prevention and treatment of postmenopausal osteoporosis and vertebral fractures. However, although these SERMs have many benefits, they also have some potentially serious adverse effects, such as thromboembolic disorders and, in the case of tamoxifen, uterine cancer. These adverse effects represent a major concern given that long-term therapy is required to prevent osteoporosis or prevent and treat breast cancer.
The search for the ‘ideal’ SERM, which would have estrogenic effects on bone and serum lipids, neutral effects on the uterus, and antiestrogenic effects on breast tissue, but none of the adverse effects associated with current therapies, is currently under way. Ospemifene, lasofoxifene, bazedoxifene and arzoxifene, which are new SERM molecules with potentially greater efficacy and potency than previous SERMs, have been investigated for use in the treatment and prevention of osteoporosis. These drugs have been shown to be comparably effective to conventional hormone replacement therapy in animal models, with potential indications for an improved safety profile. Clinical efficacy data from ongoing phase III trials are available or are awaited for each SERM so that a true understanding of the therapeutic potential of these compounds can be obtained.
In this article, we describe the discovery and development of the group of medicines called SERMs. The newer SERMs in late development: ospemifene, lasofoxifene, bazedoxifene, are arzoxifene are described in detail.
"However, it increased the risk of endometrial cancer and venous thrombo-embolism in these patients (Nelson et al., 2009). Another clinical trial with arzoxifene, a potent antiestrogenic agent, showed decreased expression of estrogen receptor, although no significant reduction of proliferation was observed (Fabian et al., 2004). Administration of a-difluoromethylornithine, an irreversible inhibitor of polyamine synthesis, among high-risk women in a randomized phase II trial showed no difference in cytology results, expression of proliferation and transcription markers, and the study concluded that the dose of adifluoromethylornithine was too low to affect polyamine synthesis (Fabian et al., 2002). "
[Show abstract][Hide abstract] ABSTRACT: Many chemopreventives that show efficacy in vitro show little/no response or require bolus doses in animal models and clinical trials because of limited bioavailability. Ellagic acid has been tested in various animal models with mixed results. We report the efficacy of ellagic acid delivered by a subcutaneous implant compared with a dietary route against estrogen-induced mammary tumors. Ellagic acid delayed the first tumor appearance by 2 and 3 weeks by implant and diet routes, respectively. The tumor incidence was 75% and 69% by the implant and dietary routes when the control group had 100% palpable tumors by 26 weeks. Ellagic acid also significantly reduced the tumor burden by both implant (855±242 mm; P=0.0375) and dietary (599±169 mm; P=0.0133) routes compared with control (1522±299 mm). Similar reductions were observed in tumor multiplicity (4.8±0.5; P=0.0042 and 4.5±0.4; P=0.0031 tumors/rat with implant and diet, respectively, vs. 8.9±1.2 in control). The total amount of ellagic acid administered by implant was 5.92±3.48 whereas it was 800±40 mg/rat through diet. Thus, over 130-fold dose reduction produced similar biological responses when delivered by implant. The anticarcinogenicity effects corroborated the observed reduction in levels of pituitary prolactin. This novel approach opens new avenues to test agents individually or as mixtures for their chemopreventive potential that are discontinued, either due to lack of bioavailability or toxicity potentially associated with high doses or due to lack of availability of sufficient quantities.
European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP) 07/2011; 20(6):484-91. DOI:10.1097/CEJ.0b013e3283498e00 · 3.03 Impact Factor
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