Society of Toxicology Workshop on effects and mechanistic aspects of tamoxifen action in different cell systems
✍ Scribed by Eugenia Harnagea-Theophilus; Michael R. Miller
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- French
- Weight
- 37 KB
- Volume
- 78
- Category
- Article
- ISSN
- 0020-7136
No coin nor oath required. For personal study only.
✦ Synopsis
The 37th meeting of the Society of Toxicology (SOT) was held in Seattle March 1-5, 1998. The broad goals of the discipline of toxicological sciences include those aspects related to harmful effects resulting from exposure to drugs, relevant to risk assessment. The current report focuses on some harmful effects displayed by tamoxifen. These effects may be important in better understanding tamoxifen action.
Tamoxifen is an anti-estrogenic drug used in breast cancer treatment or prevention (in clinical trials). A series of studies presented at the SOT meeting described some deleterious effects of this widely used drug. One problem is that tamoxifen is not a pure anti-estrogen but it exhibits mixed estrogenic and anti-estrogenic actions. Although tamoxifen is administered to inhibit breast cancer cell proliferation, in some situations it actually increases breast cancer cell proliferation. Moreover, although tamoxifen is widely used to treat cancer of the breast, it is a genotoxic carcinogen for other organs (e.g., liver) in some species. Smith et al. reported on tamoxifen-induced hepatocarcinogenesis. The authors administered tamoxifen to various strains of rats to determine if all or only selected strains of rats develop liver tumors. The authors found that all rats developed liver tumors in response to tamoxifen, but strain-specific differences in tumor latency time were reported. Wistar and Lewis rats are more sensitive and develop tumors sooner than Fisher rats. Wistar and Lewis rats also displayed increases in the numbers of apoptotic hepatocytes earlier in time than Fisher rats. The authors proposed that sustained cell death by apoptosis plays a role in the mechanism of promotion in tamoxifen-induced liver tumors by eliciting compensatory hyperplasia. Cyclohexamide has also been shown to cause apoptosis but not necrosis in rat liver. Cyclohexamide, like tamoxifen, caused DNA synthesis and cell division in hepatocytes, indicating compensatory hyperplasia can occur in liver after apoptosis in the absence of necrosis. Edwards et al. presented other aspects of tamoxifen-induced liver cancer. These authors analyzed the correlation between liver adenomas and carcinomas induced by tamoxifen in several strains of rats and tumor estrogen receptor (ER) status. Long-term administration of tamoxifen lead to formation of pre-neoplastic foci that subsequently formed adenomas and carcinomas in all rats, regardless of strain or sex. This progression correlated with gradual depletion of ERs at the tumor site. When other agents (thioacetamide, dimethylnitrosoamine, aflatoxin) were used to induce rat liver tumors, ER depletion was also observed. These results suggest that a common mechanism for tumor formation may occur in liver, and that ER depletion can occur independently of the presence or absence of estrogenic activity of the tested carcinogen.
Other investigators, Styles et al., have evaluated genetic changes underlying tamoxifen-induction of liver tumors. Tamoxifen increased mutation frequency at the lacI gene locus in liver DNA of female F344 blue transgenic rats. The liver is the target organ for tamoxifen-induced carcinogenesis in these rats. The spectrum of these mutations is different from those induced by spontaneous mutation, indicating that tamoxifen may induce a specific mutation pattern. Establishment of a specific mutation pattern induced by tamoxifen in human liver may help as a diagnostic tool for determining early stages of tamoxifen-induced liver damage in patients taking tamoxifen or for determining the etiology of liver tumors. Besides genetic changes, other explanations for the mechanism of tamoxifen-induced hepatocarcinogenicity were proposed.
Custodio et al. proposed an alternative mechanism for tamoxifen-induced liver cancer, in which tamoxifen inhibited mitochondrial permeability transition (MPT) independently of ER binding. In these studies, MPT was induced by calcium in rat liver mitochondria in vitro. Pre-incubation with tamoxifen prevented the calcium-induced MPT and release of glutathione in a dose-dependent manner, suggesting an effect on the calcium uniporter. Alternative explanations of tamoxifen-induced liver and also endometrial carcinogenicity are offered by tamoxifen metabolism studies.
Tamoxifen is thought to be a pro-drug, which requires metabolic activation to exert both its anti-estrogenic and carcinogenic effects. In humans and rodents, tamoxifen is metabolized to various compounds and reactive intermediates. Various investigators researched which of the metabolites is responsible for the carcinogenic effects. One of the phenolic metabolites thought to be involved is 3, 4-dihydroxy-tamoxifen, which, in turn, forms an ortho-quinone reactive metabolite. Butterworth et al. have shown that 3, 4-dihydroxy-tamoxifen was as effective as tamoxifen at inducing micronuclei in the MCL5 cell line. When the 3, 4-dihydroxy-tamoxifen metabolite or its ortho-quinone were incubated with DNA, both compounds induced damage, with ortho-quinone being more potent. It was concluded that the 3, 4-dihydroxymetabolite is not one of the primary active metabolites responsible for tamoxifen-induced DNA adducts in vivo.