Evista
Raloxifene is associated with less side effects than tamoxifen in women with early breast cancer: a questionnaire study from one physician's practice.

Rohatgi N, Blau R, Lower EE.

Department of Internal Medicine, Division of Hematology/Oncology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0562, USA.

OBJECTIVE: Selective estrogen receptor modulators (SERMs) are being used increasingly for the prevention and treatment of breast cancer. The currently available SERMs, tamoxifen and raloxifene, are both associated with antiestrogenic side effects that can be bothersome. However, no data exist on how they compare in this regard. We conducted a retrospective, questionnaire-based study to answer this question. METHODS: Women with early breast cancer in one physician's practice who had received either or both of these drugs were surveyed using a self-administered questionnaire. Respondents graded the frequency and severity of side effects related to estrogen deprivation, such as vaginal dryness, mood changes, hot flashes, weight gain, and changes in libido, as well as other side effects, such as vaginal discharge. They were separated into three groups for analysis (group 1, tamoxifen only; group 2, raloxifene only; group 3, both drugs). Side effects graded 4 or 5 (or weight gain >10 pounds) were considered severe. RESULTS: Two hundred sixty-four questionnaires were available for analysis. Women on raloxifene had a shorter average duration of therapy. In comparing the tamoxifen and raloxifene groups, vaginal discharge, severe hot flashes, and weight gain of >10 pounds were significantly more frequent with tamoxifen. However, weight gain was also related to the duration of therapy with either drug. CONCLUSIONS: In this observational study, antiestrogenic side effects were common with either tamoxifen or raloxifene. Raloxifene is associated with significantly less vaginal discharge and severe hot flashes than tamoxifen in women with early breast cancer. Although weight gain of >10 pounds may also occur less frequently on this drug, this may be confounded by the shorter average duration of raloxifene therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11988138&dopt=Abstract raloxifene Evista



Evista
Estradiol, but not raloxifene, improves aspects of spatial working memory in aged ovariectomized rhesus monkeys.

Lacreuse A, Wilson ME, Herndon JG.

Yerkes Regional Primate Research Center, Emory University, Atlanta, GA 30322, USA. alacreu rmy.emory.edu

Estrogen replacement therapy (ERT) alleviates many postmenopausal symptoms but whether it also benefits cognitive function remains controversial. Further, since estrogen increases the risk of breast and uterine cancers, a new class of compounds, called selective estrogen receptor modulators (SERMs) is being considered as possible alternative to ERT. The SERM raloxifene is particularly interesting because, like estrogen, it improves lipid metabolism and reduces bone loss, without adverse effects on the breast or uterus. Little is known, however, about its effect upon cognitive function.We used a rhesus monkey model of human menopause to examine the effects of ERT and raloxifene on cognitive function. We tested 5 aged females (21-24 years old) ovariectomized long-term (10-16 years) on a battery of age-sensitive tasks, including the Delayed Response (DR), the Delayed Non-Matching-to-Sample-10 min (DNMS-10 min) and the spatial-Delayed Recognition Span Test (DRST). Monkeys were tested 5 days a week on each task for 9 consecutive months, while undergoing treatments with placebo, ethinyl estradiol (EE(2)), and raloxifene in alternating 28-days blocks. EE(2) transiently enhanced the working memory component of the spatial-DRST, but did not affect performance on the other tasks of the battery. Raloxifene had no effect on cognitive performance. These findings indicate that estradiol is able to enhance some aspects of spatial working memory in aged monkeys despite many years of estrogenic deprivation. Further, they suggest that raloxifene does not affect cognitive function after long-term ovarian hormone deprivation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12009508&dopt=Abstract raloxifene Evista



Evista
Characterization of raloxifene glucuronidation in vitro: contribution of intestinal metabolism to presystemic clearance.

Kemp DC, Fan PW, Stevens JC.

University of North Carolina, Curriculum of Toxicology, Chapel Hill, North Carolina, USA.

Raloxifene, a selective estrogen receptor modulator used for the treatment of osteoporosis, undergoes extensive conjugation to the 6-beta- and 4'-beta-glucuronides in vivo. This paper investigated raloxifene glucuronidation by human liver and intestinal microsomes and identified the responsible UDP-glucuronosyltransferases (UGTs). UGT1A1 and 1A8 were found to catalyze the formation of both the 6-beta- and 4'-beta-glucuronides, whereas UGT1A10 formed only the 4'-beta-glucuronide. Expressed UGT1A8 catalyzed 6-beta-glucuronidation with an apparent K(m) of 7.9 microM and a V(max) of 0.61 nmol/min/mg of protein and 4'-beta-glucuronidation with an apparent K(m) of 59 microM and a V(max) of 2.0 nmol/min/mg. Kinetic parameters for raloxifene glucuronidation by expressed UGT1A1 could not be determined due to limited substrate solubility. Based on rates of raloxifene glucuronidation and known extrahepatic expression, UGT1A8 and 1A10 appear to be primary contributors to raloxifene glucuronidation in human jejunum microsomes. For human liver microsomes, the variability of 6-beta- and 4'-beta-glucuronide formation was 3- and 4-fold, respectively. Correlation analyses revealed that UGT1A1 was responsible for 6-beta- but not 4'-beta-glucuronidation in liver. Treatment of expressed UGTs with alamethicin resulted in minor increases in enzyme activity, whereas in human intestinal microsomes, maximal increases of 8-fold for the 6-glucuronide and 9-fold for the 4'-glucuronide were observed. Intrinsic clearance values in intestinal microsomes were 17 microl/min/mg for the 6-glucuronide and 95 microl/min/mg for the 4'-isomer. The corresponding values for liver microsomes were significantly lower, indicating that intestinal glucuronidation may be a significant contributor to the presystemic clearance of raloxifene in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12019197&dopt=Abstract raloxifene Evista



Evista
Transvaginal color Doppler sonographic evaluation of the uterus in postmenopausal women on daily raloxifene therapy.

Chittacharoen A, Theppisai U, Manonai J.

Department of Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand 10400.

OBJECTIVE: To evaluate the effect of raloxifene on the endometrium and the uterus by transvaginal color Doppler sonography. METHODS: The study group was composed of 34 asymptomatic postmenopausal women. All had been treated with raloxifene 60 mg/day for 6 months. The patients underwent transvaginal color Doppler sonography before starting raloxifene and after treatment. The uterus was scanned by transvaginal ultrasound to evaluate the pulsatility (PI) and resistance (RI) indices of both uterine arteries. The mean values for the uterine arteries were analyzed. RESULTS: The mean age of the women was 57.56 +/- 4.44 years (range 48-64 years), and mean number of years since the menopause was 8.67 +/- 5.44 (range 1-25 years). The mean endometrial thickness (3.62 +/- 1.13 vs. 3.59 +/- 0.95 mm) and uterine volume (40.67 +/- 18.36 vs. 38.05 +/- 19.47 ml) were not significantly different before starting treatment and after treatment (p > 0.05). The mean values of the PI (3.49 +/- 1.56 vs. 3.90 +/- 1.38) and RI (0.94 +/- 0.11 vs. 0.98 +/- 0.10) of the uterine arteries were not significantly different before starting treatment and after treatment (p > 0.05). CONCLUSION: Daily therapy with raloxifene did not stimulate the endometrium, the uterus or uterine blood flow.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12051111&dopt=Abstract raloxifene Evista



Evista
Regulation of estrogen target genes and growth by selective estrogen-receptor modulators in endometrial cancer cells.

Dardes RC, Schafer JM, Pearce ST, Osipo C, Chen B, Jordan VC.

Department of Gynecology, Federal University of Sao Paulo, Sao Paulo, Brazil.

OBJECTIVE:Tamoxifen has mixed agonist/antagonist activities, leading to tissue-specific estrogen-like actions and endometrial cancer. The purpose of this study was to evaluate the effects of antiestrogens on the growth of estrogen receptor (ER)-positive ECC-1 endometrial cancer cells in vitro and in vivo. METHODS: We performed growth studies and luciferase assays using ERE-tK and AP-1 reporters. ERalpha protein expression was measured by Western blot after antiestrogen treatments. We investigated the actions of antiestrogens on the transcription of the pS2 gene in situ measured by Northern blot and the actions of antiestrogens on the VEGF protein secreted by ELISA. ERalpha, ERbeta, EGFR, and HER2/neu mRNAs were determined by RT-PCR. Last, ECC-1 tumors were developed by inoculation of cells into ovariectomized athymic mice and treated with estradiol (E2), tamoxifen, raloxifene, and a combination. RESULTS: E2 induced cell proliferation while antiestrogens did not. E2 and raloxifene down regulated ERalpha protein; in contrast, 4OHT did not. ICI182,780 completely degraded the receptor. ECC-1 cells express ERbeta at insignificant levels. Luciferase assays did not show any induction in ERE- nor AP-1-mediated transcription by antiestrogens. E2 caused a concentration-dependent increase in pS2 mRNA but antiestrogens did not. E2 increased VEGF expression in a dose-dependent manner and antiestrogens blocked E2 action. E2 down regulated HER2/neu while 4OHT and raloxifene did not change HER2/neu levels compared to control. In addition, EGFR mRNA was down regulated by E2 but raloxifene did not change it. Tamoxifen and raloxifene did not promote tumor growth in vivo. However, raloxifene (1.5 mg daily) only partially blocked E2-stimulated growth. CONCLUSION: Tamoxifen and raloxifene are antiproliferative agents and antiestrogens in ECC-1 endometrial cells in vitro and in vivo. The observation that selective estrogen-receptor modulators do not down regulate EGFR and HER2/neu mRNA may provide a potential role for these oncogenes in the development of raloxifene- or tamoxifen-stimulated endometrial cancer. The ECC-1 cell line could provide important new clues about the evolution of drug resistance to tamoxifen and raloxifene.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12051881&dopt=Abstract raloxifene Evista



Evista
Effects of a new clinically relevant antiestrogen (GW5638) related to tamoxifen on breast and endometrial cancer growth in vivo.

Dardes RC, O'Regan RM, Gajdos C, Robinson SP, Bentrem D, De Los Reyes A, Jordan VC.

Department of Gynecology, Federal University of Sao Paulo, SP, Brazil 04023-900.

PURPOSE: Cross-resistance is an important issue for the evaluation of new antiestrogens to treat advanced breast cancer patients who have failed tamoxifen therapy. In addition, postmenopausal patients treated with long-term adjuvant tamoxifen show a 3-4-fold increase in the risk of developing endometrial cancer. Consequently, a new second line agent should be more antiestrogenic and less estrogen-like on the uterus, and be effective at controlling the growth of breast cancer after exposure to tamoxifen. The purpose was to evaluate the effects of the new tamoxifen analogue GW5638 on breast and endometrial cancer growth. EXPERIMENTAL DESIGN: Athymic mice were transplanted with an endometrial tumor model (ECC-1 E2) that is responsive to estrogen and has never been exposed to antiestrogen. In addition, we used three breast tumor models: a tamoxifen-naive tumor (T47D-E2) and two tamoxifen-stimulated tumors (MT2 TAM and MCF-7 TAM LT). The antiestrogen GW5638 (1.5 mg daily), tamoxifen (0.5 mg or 1.5 mg daily), and raloxifene (1.5 mg daily) were given p.o. The pure antiestrogen ICI182,780 (5 mg once a week) was given s.c. Western blots from MCF-7 TAM breast tumors were performed to demonstrate the regulation of estrogen receptor alpha expression by different ligands. RESULTS: Estradiol and GW5638 down-regulated the receptor compared with control. ICI182,780 completely degraded the receptor but tamoxifen had no effect. GW5638 did not promote tumor growth, and was effective in blocking the effects of postmenopausal estradiol on the growth of tamoxifen-naive breast and endometrial tumors. However, raloxifene did not completely block the effects of postmenopausal estradiol on the growth of tamoxifen-naive endometrial tumor after 14 weeks. GW5638 and ICI182,780 but not raloxifene were also effective in blocking the tamoxifen-stimulated breast tumor growth in athymic mice. CONCLUSIONS: GW5638 is more effective than raloxifene in blocking the effect of estrogen on tamoxifen-naive endometrial cancer. More importantly, GW5638, like the pure antiestrogen ICI182,780, is able to block the growth of breast cancer stimulated by tamoxifen differently from raloxifene. GW5638 down-regulates estrogen receptor but does not completely destroy the receptor. Therefore, based on our findings, GW5638 could be developed as a second line agent for advanced breast cancer patients and an important first line agent to evaluate as an adjuvant treatment or chemopreventive.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12060645&dopt=Abstract raloxifene Evista