Toxicity and adverse effects of Tamoxifen and other anti-estrogen drugs
Introduction
Breast cancer is the second most common cancer worldwide and the leading cause of cancer death in women (Siegel et al., 2012). The National Cancer Institute reports that women born now have a 12% chance of developing breast cancer based on statistics obtained from 1975 to 2009 (Howlader et al., 2012). Unfortunately, the incidence rates of breast cancer are increasing. While this may be due to significant advances in diagnostics and detection, it highlights the need for improved therapy for this malignancy.
The heterogeneity of breast cancers poses a formidable challenge in diagnosis and treatment (Polyak, 2011). Breast tumors can be classified into different subgroups according to their molecular expression profiles. For example, triple negative breast cancer which does not express human epidermal growth factor receptor 2 (HER2), progesterone receptor (PR), or estrogen receptor (ER), do not respond to hormonal therapies and thus are associated with poor prognosis. On the other hand, HER2 positive breast cancers respond to Herceptin, a monoclonal antibody. Thus, breast cancer is a heterogeneous disease characterized by distinct pathological types with distinct outcomes (Polyak, 2011, Aziz et al., 2012, Nowsheen et al., 2012, Yang et al., 2012). In addition, breast tumors have diverse genetic mutations affecting a variety of signaling pathways. This often leads to failure to respond to or resistance to therapies (Ellis and Offit, 2012, McCarthy, 2012).
Breast cancer in men rarely occurs, but it poses the same problems as it does for women. Male breast cancer makes up 1% of all breast cancer cases, and 1.5% of all cancers in men (Vetto et al., 1999). Due to the infrequency of male breast cancer and its small relevance to men, it's not uncommon that the disease is detected later in life at more progressive stages. Several conditions such as undescended testes, orchitis, testicular injury, late puberty, Kleinfelter's syndrome, and ionizing radiation contribute to a man's risk (Güth et al., 2011, Kantarjian et al., 2011). Other potential indicators of male breast cancer are gynecomastia, inflammatory lesions, chest wall malignancies (sarcomas), and metastases to the breast (Donegan & Redlich, 1996). Androgen deficiency may prompt the onset of this disease because androgen is primarily produced in the testes. Breast cancer in men are histologically no different than in women, and male breast cancer can be estrogen positive or negative as well (Thomas et al., 1992, Stratton et al., 1994). Tumors in men are regulated in 80– 90% of all cases by estrogen, in 7% by progesterone, and 50% by androgen; therefore, the prognosis for women and men is similar when characteristics such as tumor size, grade, and axillary lymph nodes are considered (Willsher et al., 1997, Osborne, 1998). Breast cancer can be hereditary as well. Mutations in certain genes predispose an individual to the disease. Lifestyle choices and epigenetics also play critical roles in breast cancer as discussed below.
This review focuses on one of the most extensively used drugs for the treatment of breast cancer, the drug Tamoxifen (TAM). Dr. Dora Richardson at Imperial Chemical Industries PLC (ICI) Pharmaceuticals Division synthesized the drug, ICI 46,474 that later became known as TAM (Jordan, 1988). Despite the current use of TAM, it was originally designed as a contraceptive in the 1960s after scientists discovered its anti-fertility effects in rats (Jordan, 2003). When rats were supplemented with TAM after coitus, it prevented a gametic union. However, the differences in rat and human ovulation and implantation were significant enough that when tested in women, it induced ovulation. Following this elusive discovery, Dr. Arthur Walpole, who is mostly attributed with the discovery of TAM in 1962, and his colleague Dr. Michael Harper, both from ICI Ltd. Pharmaceuticals Division, began exploring the drug's chemical structures. They found that the cis isomer, ICI 47,699 is an estrogen, whereas the trans isomer, ICI 46,474, can be used as an antiestrogen. This finding prompted Dr. Walpole to push for clinical testing at the Christie Hospital and Holt Radium Institute in Manchester (Jordan, 1988). Mary Cole and her team led the pioneering clinical trials of ICI 46,747 to treat advanced breast cancer at the Christie Hospital. From their results came the notion that antiestrogens can be potential agents for treating breast cancer. In 1973 at the Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts, the first experiments gauging the efficacy of ICI 46,747 took place using DMBA-induced rat mammary carcinoma model. Rob Nicholson from Tenovus Institute for Cancer Research in Cardiff, Wales, took the same approach of testing DMBA-induced rat mammary carcinoma for anticancer activities using ICI 46,474. Both research supported the positive effects of the drug in vivo (Jordan, 1988).
Section snippets
Factors controlling the risk for breast cancer
A variety of factors affect an individual's risk of breast cancer, including demographic, environmental, health and lifestyle choices.
Treatment of breast cancer
As mentioned above, the significant heterogeneity prevalent in breast cancer poses a formidable challenge to effective treatment for the disease. Breast cancer patients would benefit tremendously from individualized medicine or individual therapeutic regiments designed to treat their particular types of cancer. With the advent of whole genome and whole exome sequencing (sequencing only of the coding genome regions), the exact mutations responsible for the cancer in that individual can be
Breast cancer outlook and prevention
According to the Centers for Disease Control and Prevention, cancer is the second leading cause of death in women following heart disease, making breast cancer the most common type of cancer regardless of race or ethnicity (Prevention, 2012). The treatment and methods for discovering breast cancer have improved gradually throughout the past decades. Accompanying the progress of medicine and technology are the push for achieving a healthy lifestyle and the vast support for breast cancer
Conclusion
With emerging research, as we realize the complexity resulting from the variety of biologically distinct subtypes, conducting well-designed clinical trials to assess the treatment modalities becomes increasingly important. Though it is unlikely that there will be many circumstances where single-modality treatment will be successful, some anti-estrogen agents such as TAM have had success. Since agents may show efficacy in only a small patient population, personalized medicine and the use of
Conflict of interest
All authors declare not any actual or potential conflict of interest.
Submission declaration
All authors declare that by submission of this article that that the work described has not been published previously and that it is not under consideration for publication elsewhere. This publication is approved by all authors and if accepted, it will not be published elsewhere in the same form, in English or in any other language, without the written consent of the copyright-holder.
Acknowledgments
This work was supported by funds provided to Dr. Georgakilas by an EU grant MC-CIG-303514 and COST Action CM1201 ‘Biomimetic Radical Chemistry’. We apologize to investigators whose meritorious work could not be cited due to space constraints.
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These authors contributed equally to the manuscript.