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Chemical structures of tamoxifen and toremifene.
Source publication
A striking difference between two structurally related anti-estrogen medicines is that tamoxifen is strongly hepato-carcinogenic in the rat, whereas toremifene lacks such activity. To study the basis for this difference, the initiating potential of tamoxifen and toremifene were studied by measurement of rapid induction of hepatocellular altered foc...
Context in source publication
Context 1
... (TAM*) and toremifene (TOR) are structurally related polyphenylethylene anti-estrogens (Figure 1) used in the treatment of breast cancer. TAM is associated with cancer of the endometrium in treated patients, whereas evidence is inadequate for TOR (1), which was more recently introduced into medical use. ...
Citations
... Sex differences in treatments that antagonize sex hormones and sex hormone receptors. Anti-ER therapy was found to promote tumor development in a mouse model, however, several studies have demonstrated that anti-AR therapy inhibits liver tumorigenesis (Ahotupa et al., 1994;Williams et al., 1997;Ma et al., 2012;Tang et al., 2021). Anti-hormonal therapy primarily disrupts the interaction between hormones and hormone receptors, thereby modulating downstream targets. ...
... No clinical evidence was found over 20 years of Oxford overview analyses, that patients treated with tamoxifen developed liver cancer. By contrast, chlorine on the ethyl substitution at the double bond to produce toremifene resulted in no rat carcinogenesis (Williams et al. 1997). Toremifene is FDA approved to treat Stage IV breast cancer. ...
Following the discovery and approval of the oral contraceptive, the pharmaceutical industry sought new opportunities for the regulation of reproduction. The discovery of the first non-steroidal anti-oestrogen MER25, with antifertility properties in laboratory animals, started a search for ‘morning-after pills’. There were multiple options in the 1960s, however, one compound ICI 46,474 was investigated, but found to induce ovulation in subfertile women. A second option was to treat stage IV breast cancer. Although the patent for ICI 46,474 was awarded in the early 1960s in the UK and around the world, a patent in the USA was denied on the basis that the claims for breast cancer treatment were not supported by evidence. A trial at the Christie Hospital and Holt Radium Institute in Manchester, published in 1971, showed activity compared with alternatives: high-dose oestrogen or androgen treatment, but the US Patent Office was unswayed until 1985! The future of tamoxifen to be, was in the balance in 1972 but the project went forward as an orphan drug looking for applications and a translational research strategy was needed. Today, tamoxifen is known as the first targeted therapy in cancer with successful applications to treat all stages of breast cancer, male breast cancer, and the first medicine for the reduction of breast cancer incidence in high-risk pre- and post-menopausal women. This is the unlikely story of how an orphan medicine changed medical practice around the world, with millions of women’s lives extended.
... For example, the rodent hepatocarcinogen tamoxifen, which is DNA-reactive, 95 produced a rapid initiating effect in rat liver. 158 Promoting activity also suggests a potential for carcinogenic activity, 157 likely through epigenetic effects. In either case, it is possible to establish dose-effect data and no-effect levels to direct the design of chronic bioassays for risk assessment. ...
Chemicals with carcinogenic activity in either animals or humans produce increases in neoplasia through diverse mechanisms. One mechanism is reaction with nuclear DNA. Other mechanisms consist of epigenetic effects involving either interactions with regulatory macromolecules other than DNA or perturbation of cellular regulatory processes. The basis for distinguishing between carcinogens that have either DNA reactivity or an epigenetic activity as their primary mechanism of action is detailed in this review. In addition, important applications of information on these mechanisms of action to carcinogenicity testing and human risk assessment are discussed.
Gender disparity in hepatitis B virus (HBV)‐related diseases has been extensively documented. Epidemiological studies consistently reported that males have a higher prevalence of HBV infection and incidence of hepatocellular carcinoma (HCC). Further investigations have revealed that sex hormone‐related signal transductions play a significant role in gender disparity. Sex hormone axes showed significantly different responses to virus entry and replication. The sex hormones axes change the HBV‐specific immune responses and antitumor immunity. Additionally, Sex hormone axes showed different effects on the development of HBV‐related disease. But the role of sex hormones remains controversial, and researchers have not reached a consensus on the role of sex hormones and the use of hormone therapies in HCC treatment. In this review, we aim to summarize the experimental findings on sex hormones and provide a comprehensive understanding of their roles in the development of HCC and their implications for hormone‐related HCC treatment.
Carcinogenesis is a long, multi-step process that transforms normal cells into malignant cells. It occurs through several steps of initiation, promotion, and progression. By their mechanisms of action, chemical carcinogens may be genotoxic or nongenotoxic and may rely upon mutational or nonmutational/epigenetic effects. Epigenetic changes are heritable alterations in gene expression that occur without a change in the DNA sequence and encompass DNA methylation, histone modifications, and microRNA expression. They can be triggered by a wide array of chemical carcinogens. This chapter summarizes the knowledge of several selected chemical carcinogen-induced genetic and epigenetic changes and their roles in genome stability.
The approval of the oral contraceptive on June 23rd, 1960, by the Food and Drug Administration (FDA), changed Society forever. For the first time, a pill designed and tested by men, supported by influential women, allowed women to control their fertility. For the first time, the FDA approved a medicine to be taken by humans without a disease. The chance discovery of a new group of medicines called nonsteroidal antiestrogens, created an opportunity for the pharmaceutical industry. These compounds were postcoital antifertility agents in rats and mice. In the 1960s, the development of a “morning after pill” would have an enormous market. Numerous companies focused discovery efforts to evaluate the development of their patented nonsteroidal antiestrogens: Merrell (clomiphene), Upjohn (U-11,100A), and ICI Pharmaceutical Division (ICI46,474). However, the antifertility effects of antiestrogens in rats and mice does not mean that the new medicine will be an antifertility agent in women. In this case, clomiphene did exactly the opposite of what it was predicted to prevent. Clomiphene became the first medicine to induce ovulation in subfertile women. This article describes the twists and turns of drug discovery and development over the past half a century. The conclusion emphasizes the evolution of drug development over decades, based on fashions in medical research, and discoveries in clinical pharmacology. As a result, new uses for old molecules, that started life as “nonsteroidal antiestrogens”, have revolutionized women’s health as members of the new group of medicines called Selective Estrogen Receptor Modulators.
Background & aims:
Patients with cirrhosis are at high risk for hepatocellular carcinoma (HCC) and often have increased serum levels of estrogen. It is not clear how estrogen promotes hepatic growth. We investigated the effects of estrogen on hepatocyte proliferation during zebrafish development, liver regeneration, and carcinogenesis. We also studied human hepatocytes and liver tissues.
Methods:
Zebrafish were exposed to selective modifiers of estrogen signaling at larval and adult stages. Liver growth was assessed by gene expression, fluorescent imaging, and histologic analyses. We monitored liver regeneration after hepatocyte ablation and HCC development after administration of chemical carcinogens (dimethylbenzanthrazene). Proliferation of human hepatocytes was measured in a coculture system. We measured levels of G-protein-coupled estrogen receptor (GPER1) in HCC and nontumor liver tissues from 68 patients by immunohistochemistry.
Results:
Exposure to 17β-estradiol (E2) increased proliferation of hepatocytes and liver volume and mass in larval and adult zebrafish. Chemical genetic and epistasis experiments showed that GPER1 mediates the effects of E2 via the phosphoinositide 3-kinase-protein kinase B-mechanistic target of rapamycin pathway: gper1-knockout and mtor-knockout zebrafish did not increase liver growth in response to E2. HCC samples from patients had increased levels of GPER1 compared with nontumor tissue samples; estrogen promoted proliferation of human primary hepatocytes. Estrogen accelerated hepatocarcinogenesis specifically in male zebrafish. Chemical inhibition or genetic loss of GPER1 significantly reduced tumor development in the zebrafish.
Conclusions:
In an analysis of zebrafish and human liver cells and tissues, we found GPER1 to be a hepatic estrogen sensor that regulates liver growth during development, regeneration, and tumorigenesis. Inhibitors of GPER1 might be developed for liver cancer prevention or treatment.
Transcript profiling:
The accession number in the Gene Expression Omnibus is GSE92544.
Carcinogenesis is a multi-stage (1,2), multi-step (3,4), and multi-pathway (5) process. Certain chemicals may modulate this process at any step in a genetic and/or epigenetic manner. In animals, the stages of initiation, promotion, and progression can be operationally demonstrated (1,2). The rat liver has been extensively analyzed as a multistage model system for analysis of the stage(s) at which a compound can act to modify the carcinogenic process (6).
Predicting the outcome of life-time carcinogenicity studies in rats based on chronic (6-month) toxicity studies in this species is possible in some instances. This should reduce the number of such studies and hence have a significant impact on the total number of animals used in safety assessment of new medicines. From a regulatory perspective, this should be sufficient to grant a waiver for a carcinogenicity study in those cases where there is confidence in the outcome of the prediction. Pharmacological properties are a frequent key factor for the carcinogenic mode of action of some pharmaceuticals, but data-analysis on a large dataset has never been formally conducted. We have conducted an analysis of a dataset based on the perspective of the pharmacology of 255 compounds from industrial and regulatory sources. It is proposed that a pharmacological, class-specific, model may consist of an overall causal relationship between the pharmacological class and the histopathology findings in rats after 6 months treatment, leading to carcinogenicity outcome after 2 years. Knowledge of the intended drug target and pathway pharmacology should enhance the prediction of either positive or negative outcomes of rat carcinogenicity studies. The goal of this analysis is to review the pharmacological properties of compounds together with the histopathology findings from the chronic toxicity study in rodents in order to introduce an integrated approach to estimate the risk of human carcinogenicity of pharmaceuticals. This approach would allow scientists to define conditions under which 2-year rat carcinogenicity studies will or will not add value to such an assessment. We have demonstrated the possibility of a regulatory waiver for a carcinogenicity study in rats, as currently discussed in the International Council for Harmonization (ICH) - formerly known as the International Conference on Harmonization (ICH), by applying the proposed prediction approach in a number of case studies.
One of the major reasons for terminating a clinical trial is the liver toxicity induced by chemotherapy. Tamoxifen (TAM) is an anti-estrogen used in the treatment and prevention of hormone-dependent breast cancer. Tamoxifen therapy may cause hepatic injury. The seeds of Nigella sativa, which contain the active ingredient thymoquinone (TQ), have been used in folk medicine for diverse ailments. TQ is reported to possess anticancer and hepatoprotective effects. In this study, the protective effects of TQ against TAM-induced hepatotoxicity in female rats were evaluated. Four groups of rats were used: control; TAM; TQ; TAM+TQ. TAM (45 mg·(kg body mass)(-1)·day(-1), by intraperitoneal injection (i.p.), for 10 consecutive days) resulted in elevated serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, total bilirubin, and gamma glutamyl transferase, as well as depletion of reduced glutathione in the liver and accumulation of lipid peroxides. Also, TAM treatment inhibited the hepatic activity of superoxide dismutase. Further, it raised the levels of tumor necrosis factor alpha in the liver and induced histopathological changes. Pretreatment with TQ (50 mg·(kg body mass)(-1)·day(-1); orally, for 20 consecutive days, starting 10 days before TAM injection) significantly prevented the elevation in serum activity of the assessed enzymes. TQ significantly inhibited TAM-induced hepatic GSH depletion and LPO accumulation. Consistently, TQ normalized the activity of SOD, inhibited the rise in TNF-α and ameliorated the histopathological changes. In conclusion, TQ protects against TAM-induced hepatotoxicity.
