The Combination of the Rexinoid, LG100268, and a Selective Estrogen Receptor Modulator, Either Arzoxifene or Acolbifene, Synergizes in the Prevention and Treatment of Mammary Tumors in an Estrogen Receptor–Negative Model of Breast Cancer

Abstract

Purpose: We tested whether a selective estrogen receptor modulator (SERM) and a rexinoid are active for prevention and treatment in the mouse mammary tumor virus-neu mouse model of estrogen receptor^negative breast cancer. Experimental Design: For prevention, mice were fed a powdered control diet, the SERM arzoxifene (Arz, 20 mg/kg diet), the rexinoid LG100268 (268, 30 mg/kg diet), or the combination for 60 weeks. In a second prevention study, mice were fed Arz (6 mg/kg diet), 268 (30 mg/kg diet), the combination of Arz and 268, the SERM acolbifene (Acol, 3 mg/kg diet), or the combination of Acol and 268 for 52 weeks. For the treatment studies, mice with tumors were fed combinations of a SERM and 268 for 4 weeks. Results: The rexinoid 268 and the SERMs Arz and Acol, as individual drugs, delayed the development of estrogen receptor^negative tumors. Moreover, the combination of a SERM and 268 was strikingly synergistic, as no tumors developed in any mouse fed the combination of 268 and a SERM. Moreover, this drug combination also induced significant tumor regression when used therapeutically. These drugs did not inhibit transgene expression in vitro or in vivo, and the combination of Arz and 268 inhibited proliferation and induced apoptosis in the tumors. Conclusion: The combination of a rexinoid and SERM should be considered for future clinical trials.Despite the development of selective estrogen receptor (ER) modulators (SERMs), aromatase inhibitors, and the monoclonal antibody trastuzumab (Herceptin), breast cancer still claims >40,000 lives in the U.S. each year (1). Because of the genetic and epigenetic complexities of an invasive cancer, arresting or reversing carcinogenesis at its earliest stages offers an attractive alternative to treating advanced disease (2, 3). However, the realities of the clinic mean that new drugs and new drug combinations are desperately needed for both the prevention and treatment of breast cancer.A number of drugs have been shown to prevent or treat ER+ breast cancer. SERMs such as tamoxifen and raloxifene are effective in women for both prevention (4 -8) and treatment (9). Newer SERMs such as acolbifene (Acol, EM-652) and its prodrug (EM-800) have been used to prevent the development of and to treat established mammary tumors in animal models (10 -12), and caused the disappearance of 60% of human breast cancer tumors in nude mice (13). Acol also showed positive responses in women who failed tamoxifen treatment (14), suggesting the superiority of Acol over tamoxifen in a series of preclinical studies (15). The SERM arzoxifene (Arz) also prevented mammary carcinogenesis in rats (16) and decreased ER expression in humans in a phase 1 chemoprevention trial (17).In addition to the SERMs, retinoids, such as 9-cis-retinoic acid (18,19), or rexinoids [selective ligands for the retinoid X receptors (RXRs)], such as LGD1069 (bexarotene, Targretin; refs. 20, 21) and LG100268 (268; refs. 22, 23), have been reported to prevent and treat mammary tumors in animal models of ER+ breast ...

Structural modulation of reactivity/activity in design of improved benzothiophene selective estrogen receptor modulators: induction of chemopreventive mechanisms

“…In ER(À) MCF-7 cells, DMA showed significant induction of NQO1, which is compatible with its ability to induce NQO1 via ER-independent activation of the ARE. The chemopreventive properties of arzoxifene toward ER(À) breast cancer have previously been reported in a mouse model (33).…”

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

“…In contrast, the rexinoid LG100268 (LG268, see Fig 1A for structure) has been reported to have adverse effects on both TG and T4 levels in rodent studies (12,13). Despite these undesirable actions, LG268 is well tolerated in both rats and mice and has been an extremely potent and useful agent for both prevention and treatment of experimental breast and lung cancer (14)(15)(16)(17)(18)(19)(20).…”

A New Rexinoid, NRX194204, Prevents Carcinogenesis in Both the Lung and Mammary Gland

“…We and others have reported that the rexinoids bexarotene and 268 do not reduce neu transgene expression in vitro or in vivo (12,20) and 4204 also did not inhibit ErbB2 expression in E18-14C-27 cells (data not shown) or in regressing tumors from mice treated with a 60 mg/kg diet of 4204 for 1 to 2 weeks in the treatment studies (Fig. 4B).…”

“…Active tumor growth was defined as a >50% increase in tumor volume. Further details of the ER-experiments, including evaluation of transgene expression and terminal nucleotidyl transferase -mediated nick end labeling staining, have been previously reported (20). Animal studies have been done in compliance with standards maintained by , and either the amount of interleukin 6 released into the media was measured using an ELISA (C) or cell lysates were immunoblotted with cyclooxygenase-2 antibodies (D).…”