Tamoxifen toxicity

Jordan. V.C. (1995) Tamoxifen Toxicities and drug resistance during the treatment and prevention breast cancer. Annu. Rev. Pharmacol. Toxkol., 35. I95-21I. 

Until recently, there was little evidence that the response or survival benefit from one endocrine therapy was clearly superior to that achieved with other therapies. Given this equality in efficacy, the choice of a particular endocrine therapy was based primarily on toxicity (Table 86-8). Based on these criteria, tamoxifen is the preferred initial agent when metastases are present. An exception to this occurs when the patient is receiving adjuvant tamoxifen at the time or within 1 year of occurrence of metastatic disease. 

Tamoxifen can be used in both premenopausal and postmenopausal women with metastatic breast cancer who have tumors that are hormone-receptor-positive. The toxicities of tamoxifen are described in the section on adjuvant endocrine therapy. The only additional toxicity that one might expect to find in the setting of metastatic breast cancer (specifically bone metastases) is a tumor flare or hypercalcemia, which occurs in approximately 5% of patients following the initiation of any SERM therapy and is not an indication to discontinue SERM therapy. It is generally accepted that this is a positive indication that the patient will respond to endocrine therapy. 

The use of triphenylethylene SERMs as Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration, which is likely due to the involvement of proteins with the ability to bind these compounds. For instance, toremifene is able to reverse MDR and to sensitize human renal cancer cells to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular a 1-acid glycoprotein (AAG), which may limit its tissue availability (Braybrooke et al. 2000). In agreement with this, Chatterjee and Harris (1990) have shown that tamoxifen and 4-OH-tamoxifen were similarly potent in reversing MDR in Chinese hamster ovary (CHO) cells with acquired resistance to adriamycin. However, the addition of AAG (0.5 to 2 mg/ml, the range found in vivo) to cell cultures decreased the effect of tamoxifen on reversing MDR, and at the highest AAG concentration there was a complete reversal of the effects of... 

Pavlidis NA, Petris C, Briassoulis E, Klouvas G, Psilas C, Rempapis J, Petroutsos G (1992) Clear evidence thatlong-term, low-dose tamoxifen treatment can induce ocular toxicity a prospective study of 63 patients. Cancer 69(12) 2961-2964... 

Gorin MB, Day R, Costantino JP, Fisher B, Redmond CK, Wickerham L, et al. (1998) Long-term tamoxifen citrate use and potential ocular toxicity. Am J Ophthalmol 126 338... 

Species Differences. Species differences in metabolism are amongst the principal reasons that there are species differences in toxicity. Differences in cytochrome P450 is one of the most common reasons for differences in metabolism. For example, Monostory et al. (1997) recently published a paper comparing the metabolism of panomifene (a tamoxifen analog) in four different species. These data serve to address that the rates of metabolism in the non-human species was most rapid in the dog and slowest in the mouse. Thus, one should not a priori make any assumptions about which species will have the more rapid metabolism. Of the seven metabolites, only one was produced in all four species. Both the rat and the dog produced the two metabolites (M5 and M6) produced by human microsomes. So how does one decide which species best represents humans One needs to consider the chemical structure of the metabolites and the rates at which they are produced. In this particular case, M5 and M6 were relatively minor metabolites in the dog, which produced three other metabolites in larger proportion. The rat produced the same metabolites at a higher proportion, with fewer other metabolites than the dog. Thus, in this particular instance, the rat, rather than the dog, was a better model. Table 18.8 offers a comparison of excretion patterns between three species for a simple inorganic compound. 

Tamoxifen administration is associated with few toxic side effects, most frequently hot flashes (in 10-20% of patients) and occasionally vaginal dryness or discharge. Mild nausea, exacerbation of bone pain, and hypercalcemia may occur. 

Wiseman H. Dietary phytoestrogens, oestrogens and tamoxifen mechanisms of action in modulation of breast cancer risk and in heart disease prevention. In Biomolecular Free Radical Toxicity Causes and Prevention (H Wiseman, P Goldfarb, TJ Ridgway, A Wiseman, editors) John Wiley, Chichester, pp. 170-208, 2000. 

The use of tamoxifen to prevent breast cancer has been reviewed (8). The merits of using tamoxifen to prevent mammary carcinoma in women who have never had the disease but are believed to be at high risk have been disputed (9), but it is clear that it would involve very long treatment and that one s view of the adverse effects might need to be revised for this class of users. The available data after 5,10, and 15 years of follow up confirmed an increase in the incidence of endometrial cancer and of thromboembolic complications and suggested ocular toxicity, but these effects were not common and should be more than balanced by the reduced risk of coronary heart disease and osteoporosis (8). 

An important synergistic reaction between radiation-related pulmonary fibrosis and tamoxifen has been described in 196 women followed for a minimum of 5 years, with a relative risk of 2.0 (39). However, others have shown that tamoxifen did not increase the pulmonary toxicity of agents such as carmustine and dacarbazine (40). 

In a prospective study even in low doses (for example 10 mg/day or lower) tamoxifen caused ocular toxicity if given for a sufficiently long period most of the changes were reversible but they justify very close monitoring (44). A related compound, MER-29 (triparanol), causes cataract and has various other adverse reactions in common with tamoxifen. 

Montes A, Powles TJ, O Brien ME, Ashley SE, Luckit J, Treleaven J. A toxic interaction between mitomycin C and tamoxifen causing the haemolytic uraemic syndrome. Eur J Cancer 1993 29A(13) 1854-7. 

Tamoxifen is a competitive partial agonist inhibitor of estradiol at the estrogen receptor and is extensively used in the palliative treatment of advanced breast cancer in postmenopausal women. It is a nonsteroidal agent (see structure below) that is given orally. Peak plasma levels are reached in a few hours. Tamoxifen has an initial half-life of 7-14 hours in the circulation and is predominantly excreted by the liver. It is used in doses of 10-20 mg twice daily. Hot flushes and nausea and vomiting occur in 25% of patients, and many other minor adverse effects are observed. Studies of patients treated with tamoxifen as adjuvant therapy for early breast cancer have shown a 35% decrease in contralateral breast cancer. However, adjuvant therapy extended beyond 5 years in patients with breast cancer has shown no further improvement in outcome. Toremifene is a structurally similar compound with very similar properties, indications, and toxicities. 

Pagano G, de Baise A, Deeva IB, Degan P, Doronin YK, Iaccarino M, Ora, R, Trieff NM, Warnau M, Korkina LG. 2001. The role of oxidative stress in developmental and reproductive toxicity of tamoxifen. Life Sci 68 1735-1749. 

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