Tamoxifen Subject

The effects of raloxifene in premenopausal women have been analyzed in subjects with normal ovarian function treated with high doses (100 to 400 mg daily) at either different time points of their menstrual cycle or continuously for 4 weeks (Baker et al. 1998). Raloxifene did not prevent ovulation, nor did it alter the length of the menstrual cycle or the day of the LH surge. However, it did stimulate FSH secretion, increase serum estradiol levels, and decrease serum PRL. These results are also similar to those reported for premenopausal women taking tamoxifen (Jordan et al. 1991) and are indicative of some antiestrogenic action at either the hypothalamic and/or pituitary level. 

As for tamoxifen, in the aforementioned studies by Mourits et al. (2002) on breast cancer patients analyzing the effects on subjective and psychosexual well-being, disturbed sleep (55% of patients) correlated with hot flashes and concentration problems. 

Mourits MJ, Bockermann I, de Vries EG, van derZee AG, ten Hoor KA,van derGraaf WT, Sluiter WJ, Willemse PH (2002) Tamoxifen effects on subjective and psychosexual wellbeing, in a randomised breast cancer study comparing high-dose and standard-dose chemotherapy. Br J Cancer 86 1546-1550... 

Six cases of endometrial carcinoma were subsequently reported from France (96), and 36 cases in all had been reported up to that time (97). Although the effect can be caused by tamoxifen alone in women aged over 55, in younger women it is more likely to be an additive one, attributable to use of both tamoxifen and pelvic irradiation in the same subject. 

The risk that tamoxifen may cause endometrial cancer has been the subject of lively correspondence in the Lancet... 

LC/tandem MS assays for tamoxifen metabolites have been described by numerous investigators and used for research purposes [10-12], Figure 1 shows a typical chromatogram for the analyses of these metabolites from a serum sample. Following chronic administration of a standard 20 mg tamoxifen per day dosage on presumably wild-type subjects, typical serum concentrations at steady state were 150 ( 50)ng/mL for tamoxifen, 180 ( 70)ng/mL for /V-desmethytam, 2.5 ( 1.2)ng/mL for 4-hydroxytam, and 5.0 ( 2.5)ng/mL for endoxifen [10],... 

As mentioned in the introduction, metallocene-type complexes based on the early transition metals were evaluated as anticancer compounds shortly after the discovery of cisplatin. While the biological activity of each of the metallocene dihalides is unique, titanocene dichloride 7 has been the subject of a number of studies and even entered clinical evaluation, although evaluation was discontinued (not due to its anti-proliferative properties), principally due to formulation problems, despite showing superior activity to certain cancers than other established drugs. This class of compound continues to be modified and studied for anticancer activity, for example, the titanocene-type derivative of tamoxifen 1, described above, and other developments described below. 

This methodology was used by researchers at Eli Lilly to generate benzothiophene derivatives of tamoxifen. The cyclization and rearrangement reaction to produce the desired 2-aryl benzothiophene derivatives were promoted by polyphosphoric acid (PPA). These 2-aryl benzothiophene were then subjected to several additional transformations to produce LYl 56758 (raloxifene). 

One must note that the clinical utility of measuring tamoxifen and its metabolite in serum has yet to be shown. If and how this data will be used clinically is currendy a subject of research. At this time, only one study has been performed looking directly at the relationship between endoxifen concentration and outcomes (WHEL, in press). The results of this study suggest that breast cancer patients undergoing tamoxifen adjuvant therapy, who have serum endoxifen concentrations in the lowest quintile, are at increased risk for breast cancer recurrence. Replication of these findings, as well as prospective trials, would increase support of the use of therapeutic drug monitoring for tamoxifen, NDTam, and endoxifen. 

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... 

---