Tamoxifen carcinogenicity

The tamoxifen cation (48), which can be thought of as the ultimate tamoxifen carcinogen, has been the subject of a detailed study. Its lifetime is 125 p,s if the amine is neutral and 22 p,s if it is protonated in either case it only reacts at the CH group. This makes it a relatively long-lived electrophile by carbocation standards, approaching the lifetime of tfiaryhnethyl cations. The steric and electronic factors involved in the... 

Second Generation Second generation SERMs were developed with the objective of obtaining ER-targeted pharmaceuticals that lacked the utero-trophic and carcinogenic effects of tamoxifen. The most well characterized second generation SERM is... 

Andersson M, Storm HH, Mouridsen HT (1992) Carcinogenic effects of adjuvant tamoxifen treatment and radiotherapy for early breast cancer. Acta Oncol 31 259-263... 

Table 7.2 The Carcinogenic Effects of the Drug Tamoxifen in Rats...

Furthermore, animal studies have revealed that tamoxifen is also capable of causing liver tumors in rats exposed to the drug. Research showed that tamoxifen was genotoxic in vitro and was also a genotoxic carcinogen in vivo. It was further found that the drug formed adducts with DNA (on the N2 of guanine for example). 

The treatment of rats, both male and female, for two years with tamoxifen revealed a dose-related increase in malignant liver tumors (Table 7.2). Thus, the table indicates that liver carcinomas caused by tamoxifen show a dose-related increase in both sexes, with a similar incidence, and metastases showed a slight but similar incidence. Research by various groups on the mechanisms underlying the carcinogenicity of tamoxifen has been extremely important in assessing the risk from this important drug and has allowed it to continue to be used. 

The mechanism by which tamoxifen is carcinogenic is via metabolic activation to yield a reactive metabolite, which reacts with DNA. Study of the metabolism in different species has revealed the important metabolic pathways involved in both activation and detoxication. 

Greaves P, Goonetilleke R, Nunn G, et al. Two-year carcinogenicity study of tamoxifen in Alderley Park Wistar-derived rats. Cancer Res 1993 53(17) 3919-3924. 

Zhang F, Fan PW, Liu X, Shen L, van Breeman RB, Bolton JL (2000) Synthesis and reactivity of a potential carcinogenic metabolite of tamoxifen, 3, 4-dihydroxytamoxifen-o-quinone. Chem Res Toxicol 13 53-62... 

The correct choice = E. Tamoxifen forms a complex with the estrogen receptor. Procarbazine inhibits monoamine oxidase, an enzyme required to metabolize tyramine found in fermentative sources, such as cheese and some wines. X-irradiation is effective in eradicating leukemic cells which have found sanctuary in the CNS. Many anticancer drugs are mutagenic and carcinogenic, particularly the alkylating agents. 

Cho SD, Kim JH, Kim DY, Lee Y, Kang KS (2003) Prevalidation study for OECD enhanced test guideline 407 protocol by gavage for 4 weeks using propylthiouracil and tamoxifen. Toxicol Lett 144 195-204 Clemmesen J, Hjalgrim-Jensen S (1978) Is phenobarbital carcinogenic A follow-up of 8078 epileptics. Ecotoxicol Environ Saf 1 567-70... 

Toremifene (Fareston , chlorotamoxifen Figure 5.15) has been thoroughly investigated in the laboratory [269-272] and has antitumor activity in carcinogen-induced rat mammary cancer, but is less potent than tamoxifen [272-274]. Toremifene has been tested extensively in phase I—III clinical trials [275-278] and has been approved for use in postmenopausal women with metastatic breast cancer [279]. As predicted from the reduced potency in animal studies, the dose required for activity is 60 mg of toremifene daily (tamoxifen is used at 20 mg daily). The side-effects are similar to those of tamoxifen and, as with tamoxifen, the responses are observed in ER-positive tumors. However, because adjuvant therapy with tamoxifen is standard throughout the world, issues of cross-resistance of tamoxifen and toremifene are important considerations for the use of toremifene in recurrent breast cancer. Laboratory studies by Osborne et al. [280] have demonstrated that toremifene-stimulated tumors can develop from MCF-7 breast cancer cells transplanted into athymic mice. Toremifene is cross-resistant with tamoxifen in tamoxifen-stimulated breast cancer in the laboratory [281]. Similarly, cross-over clinical trials demonstrate that there is little possibility of a second response to toremifene after tamoxifen failure [282, 283]. 

The interesting property of toremifene is the reduced liver carcinogenicity in the rat [284, 285], Toremifene produces fewer DNA adducts than tamoxifen [284] however, there are reports of DNA damage [286] and the drug can still act as an... 

Idoxifene inhibits the growth of carcinogen-induced rat mammary tumors [293] and MCF-7 tumors grown in athymic mice [294, 295]. When compared to tamoxifen, idoxifene appears to have more antagonistic and less agonistic effects on ER in laboratory studies. Also, idoxifene has been reported to develop acquired antiestrogen resistance more slowly than tamoxifen [294]. However, there appears to be crossresistance in laboratory models of tamoxifen-stimulated growth [281]. 

The triphenylethylene drug tamoxifen is a strong liver carcinogen in the rat. Carcinogenesis, 14, 315-317. 

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