17α-Ethynyl-5α-androstane-3α, 17β-diol Treatment of MNU-Induced Mammary Cancer in Rats

Clarence N Ahlem,Rajkumar Lakshmanaswamy,Richard J Trauger,Steven K White,Christopher L Reading,James M Frincke

doi:10.4061/2011/618757

Clarence N Ahlem, Rajkumar Lakshmanaswamy + Show 4 more

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https://doi.org/10.4061/2011/618757

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Abstract

N-methyl-N-nitrosourea (MNU) induces estrogen-dependent mammary tumors in female Lewis rats. We explored the antineoplastic activity of a synthetic androstane derivative, 17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235), as a single agent or in combination with docetaxel compared to tamoxifen, anastrazole, and docetaxel monotherapies against MNU-induced mammary tumors in female Lewis rats. Treatment with HE3235 alone rapidly reduced tumor burden, similar in effect to tamoxifen and anastrozole. The combination of HE3235 with docetaxel was more effective than any single agent, although without apparent toxicity. Only HE3235 or HE3235 plus docetaxel continued to suppress tumor growth after cessation of treatment. HE3235 treatment increased immunohistochemical markers of apoptosis and expression of proapoptotic genes and estrogen receptor beta and decreased expression of antiapoptotic genes, androgen receptor, and estrogen receptor alpha. These data warrant clinical investigation of HE3235 for breast cancer treatment.

Highlights

Breast cancer is one of the most common cancers among women, and the incidence of breast cancer is increasing worldwide [1]
No animals treated with the combination of HE3235 plus docetaxel were sacrificed because of tumor burden (P = .0149 versus docetaxel alone); one animal was sacrificed in each of the groups treated with high or low-dose HE3235 monotherapy or tamoxifen (P = .073 versus docetaxel alone); six were sacrificed in the docetaxel group and seven in the anastrozole group; all animals were sacrificed in the vehicle group (Figure 1)
The cytoreductive activity of all active treatment groups was similar for the first two weeks of therapy, but the tumor ablative activity of low-dose HE3235, docetaxel, and anastrazole waned during the second half of the treatment period

Summary

Introduction

Breast cancer is one of the most common cancers among women, and the incidence of breast cancer is increasing worldwide [1]. 200,000 women are diagnosed with breast cancer annually, with an associated mortality of 40,000 in the United States [2]. There are few treatments for hormone-dependent breast cancer, with tamoxifen and anastrazole being the most widely used therapies [3]. These treatments can be associated with significant morbidity [4], and development of resistance is common [5, 6]. The carcinogen N-methyl-N-nitrosourea (MNU) induces hormone-dependent mammary tumors in rats. This model has previously been used to develop tamoxifen therapy in women with breast cancer [7], and is considered to be appropriate for studies of novel compounds potentially useful for the treatment of breast cancer. The model provides an opportunity to examine cause-and-effect relationships of the in situ environment fully impacted by systemic factors [9]

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