Fareston is the brand name of toremifene, a drug belonging to class of medicines known as anti-hormones. Its main use lies in the treatment of breast cancer, although it can be used as an aid to other forms of therapy in many different cancers. It is mainly prescribed to women whose cancer has spread around their body or who have been operated but the cancer has come back. The way it works is that it blocks the action of the hormone estrogen which is a key in several types of cancers, because the hormone attaches to the cancer cells and allows them to grow and replicate. Cells like this are known as estrogen receptor positive and toremifene is highly effective against them. New research has suggested that Fareston exerts protective effects on the heart because it lowers the levels of fat in the blood. It has also been observed that the drug helps to prevent bone loss, which indicates that any program for the prevention of osteoporosis and/or heart disease has to include toremifene.
Int J Fertil Womens Med. 2004 Nov-Dec;49(6):278-80.
Toremifene, a new agent for treatment of mastalgia: an open study.
Hamed H, Kotheri A, Beechey-Newman N, Fentiman IS.
Department of Academic Oncology, Breast Unit, Guy's and St Thomas'
Hospital Trust, London, UK.
OBJECTIVE: Endocrine agents have been widely used in the treatment of
mastalgia. Toremifene is an agent that predominantly has antiestrogenic
properties with minimal estrogenic activities. This study was aimed at
investigating this drug in the treatment of mastalgia and to evaluate
its tolerability and efficacy. METHODS: Seventeen premenopuasal women
with a mean age of 37.7 years complaining of moderate to severe mastalgia
received toremifene 60 mg daily. The treatment period was 12 weeks. 70%
of patients had cyclical and 30% had noncyclical mastalgia. RESULTS: All
women with cyclical mastalgia responded to toremifene compared with only
75% of those with non-cyclical mastalgia. Four patients withdrew from
the study after 4 weeks because of side effects, accounting for 23.5%
of patients in the study. CONCLUSION: This small study has shown that
toremifene is an effective agent in the treatment of mastalgia, but a
high incidence of side effects makes it ineligible as an agent of choice
for treatment of mastalgia.
Br J Cancer. 2005 Mar 28;92(6):1098-103.
K-ras mutation in the endometrium of tamoxifen-treated breast
cancer patients, with a comparison of tamoxifen and toremifene.
Hachisuga T, Tsujioka H, Horiuchi S, Udou T, Emoto M, Kawarabayashi
T.
Department of Obstetrics and Gynecology, the School of Medicine, Fukuoka
University, 45-1, 7-chome, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
hachisug@fukuoka-u.ac.jp
The putative presence of a mutation in codon 12 of the K-ras gene was
investigated in the endometrium of tamoxifen (TAM) and toremifene (TOR)-treated
breast cancer patients. DNA was extracted from fresh cytologic samples
of the endometrium in 86 TAM and 21 TOR-treated breast cancer patients.
Mutations were detected by enriched PCR and an enzyme-linked mini-sequence
assay (ELMA). K-ras mutation was found in 35 TAM-treated endometrial samples,
and in only one TOR-treated endometrium (P<0.003). In 24 premenopausal
patients, K-ras mutation was found in seven (43.8%) of 16 patients with
less than 47 months of TAM treatment, while none was found in eight patients
with more than 48 months of TAM treatment (P<0.03). In 62 postmenopausal-amenorrheic
patients, K-ras mutation was found in three (15.8%) of 19 patients with
less than 23 months of TAM treatment, while it was found in 16 (61.5%)
of 26 patients with 24-47 months of TAM treatment and nine (52.9%) of
17 patients with more than 48 months of TAM treatment (P=0.002). The presence
of K-ras mutation is significantly influenced by the duration of TAM treatment
and menstrual status of the patients. TOR may have a lower potential genotoxicity
than TAM.
Biol Reprod. 2005 Feb;72(2):423-35. Epub 2004 Oct 06.
Effects of neonatal exposure to diethylstilbestrol, tamoxifen,
and toremifene on the BALB/c mouse mammary gland.
Hovey RC, Asai-Sato M, Warri A, Terry-Koroma B, Colyn N, Ginsburg E, Vonderhaar
BK.
Molecular and Cellular Endocrinology Section, Mammary Biology and
Tumorigenesis Laboratory, National Cancer Institute, National Institutes
of Health, Bethesda, Maryland 20892-1402, USA.
In this study, we compared the long-term effects of neonatal exposure
to diethylstilbestrol (DES, 0.0125-50 microg), tamoxifen (TAM, 0.0125-50
microg), and toremifene (TOR, 53 microg) on mammary gland development
and differentiation. Allometric growth of the mammary ducts was stimulated
by neonatal DES exposure (12.5 microg) and impaired by exposure to TAM
(25 microg). Neonatal treatment with high doses of DES resulted in mammary
ducts that displayed extensive dilatation and precocious lactogenesis
in postpubertal, nulliparous females. Initiation of this precocious differentiation
coincided with the absence of corpora lutea, increased levels of serum
prolactin (PRL), and the induction of Prl mRNA expression within the mammary
glands. Neonatal exposure to 1.25 microg TAM increased alveolar development
in postpubertal, nulliparous females similar to that recorded in females
treated with low doses of DES. Lower doses of TAM did not affect alveolar
development, whereas branching morphogenesis and alveolar development
were impaired by higher doses. Increased alveolar development in females
exposed to 1.25 microg TAM was associated with elevated serum progesterone
(P) and increased alveolar development in response to exogenous P. Taken
together, our findings demonstrate that neonatal exposure to both DES
and TAM exerts long-lasting effects on the proliferation and differentiation
of the mammary glands in female BALB/c, primarily as the result of endocrine
disruption.
Gynecol Oncol. 2005 Mar;96(3):846-9.
Ovarian luteinized thecoma with sclerosing peritonitis in an adult
woman treated with leuprolide and toremifene in complete remission at
5 years.
Bianco R, de Rosa G, Staibano S, Somma P, Bianco AR.
Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica,
Universita Federico II, Nuovo Policlinico, Via S. Pansini 5, 80131 Naples,
Italy.
BACKGROUND.: Luteinized thecoma of the ovary associated with sclerosing peritonitis is a rare pathologic condition without a standard strategy of treatment. CASE.: We present the case of an ovarian luteinizing sclerosing thecoma in a 39-year-old woman. The patient underwent three laparotomic operations for subocclusive symptoms, revealing in both occasions the presence of sclerosing peritonitis, with large abdominal masses, including cysts containing clear fluid. Treatment with toremifene 20 mg/day and leuprolide resulted in a dramatic improvement of the performance status and complete remission of all the abdominal lesions. After 60 months follow-up, the patient is still disease-free. DISCUSSION.: Antiestrogens plus LHRH agonists might be a noninvasive, effective and well-tolerated therapy for sclerosing peritonitis in patient operated for luteinized thecomas.
Int J Fertil Womens Med. 2004 Nov-Dec;49(6):278-80.
Toremifene, a new agent for treatment of mastalgia: an open study.
Hamed H, Kotheri A, Beechey-Newman N, Fentiman IS.
Department of Academic Oncology, Breast Unit, Guy's and St Thomas'
Hospital Trust, London, UK.
OBJECTIVE: Endocrine agents have been widely used in the treatment of
mastalgia. Toremifene is an agent that predominantly has antiestrogenic
properties with minimal estrogenic activities. This study was aimed at
investigating this drug in the treatment of mastalgia and to evaluate
its tolerability and efficacy. METHODS: Seventeen premenopuasal women
with a mean age of 37.7 years complaining of moderate to severe mastalgia
received toremifene 60 mg daily. The treatment period was 12 weeks. 70%
of patients had cyclical and 30% had noncyclical mastalgia. RESULTS: All
women with cyclical mastalgia responded to toremifene compared with only
75% of those with non-cyclical mastalgia. Four patients withdrew from
the study after 4 weeks because of side effects, accounting for 23.5%
of patients in the study. CONCLUSION: This small study has shown that
toremifene is an effective agent in the treatment of mastalgia, but a
high incidence of side effects makes it ineligible as an agent of choice
for treatment of mastalgia.
Ann Oncol. 2004 Dec;15(12):1749-59.
Toremifene and tamoxifen are equally effective for early-stage
breast cancer: first results of International Breast Cancer Study Group
Trials 12-93 and 14-93.
Pagani O, Gelber S, Price K, Zahrieh D, Gelber R, Simoncini E,
Castiglione-Gertsch M, Coates AS, Goldhirsch A; International Breast Cancer
Study Group.
Instituto Oncologico Svizzera Italiana IOSI, Ospedale Beata Vergine,
Mendrisio, Switzerland. opagani@siak.ch
BACKGROUND: Toremifene is a chlorinated derivative of tamoxifen, developed
to improve its risk-benefit profile. The International Breast Cancer Study
Group (IBCSG) conducted two complementary randomized trials for peri-
and postmenopausal patients with node-positive breast cancer to compare
toremifene versus tamoxifen as the endocrine agent and simultaneously
investigate a chemotherapy-oriented question. This is the first report
of the endocrine comparison after a median follow-up of 5.5 years. PATIENTS
AND METHODS: 1035 patients were available for analysis: 75% had estrogen
receptor (ER)-positive primary tumors, the median number of involved axillary
lymph nodes was three and 81% received prior adjuvant chemotherapy. RESULTS:
Toremifene and tamoxifen yielded similar disease-free (DFS) and overall
survival (OS): 5-year DFS rates of 72% and 69%, respectively [risk ratio
(RR)=0.95; 95% confidence interval (CI)=0.76-1.18]; 5-year OS rates of
85% and 81%, respectively (RR = 1.03; 95% CI = 0.78-1.36). Similar outcomes
were observed in the ER-positive cohort. Toxicities were similar in the
two treatment groups with very few women (<1%) experiencing severe
thromboembolic or cerebrovascular complications. Quality of life results
were also similar. Nine patients developed early stage endometrial cancer
(toremifene, six; tamoxifen, three). CONCLUSIONS: Toremifene is a valid
and safe alternative to tamoxifen in postmenopausal women with endocrine-responsive
breast cancer.
Gan To Kagaku Ryoho. 2004 Jun;31(6):911-4.
A case of breast cancer with multiple bone metastases demonstrating
complete remission with high-dose toremifene therapy
Saito Y, Amano S, Kashio M, Abe H, Kuboi Y, Sakurai K, Aoki N, Hata S,
Negishi N.
Dept. of Breast and Endocrine Surgery, Nihon University School of Medicine.
We report a 64-year-old woman who underwent mastectomy for stage II (T2N1M0)
advanced breast cancer, in whom multiple spine metastases developed 18
months postoperatively. She received 6 cycles of CA (cyclophosphamide
500 mg/m2, ADM 50 mg/m2 3 wq) therapy and oral tamoxifen (20 mg/body)
administration for adjuvant therapy. The multiple bone metastases of the
spine were revealed by technetium bone scan. The level of serum tumor
marker CA15-3 increased two times over the normal range 18 months after
surgery. She also developed osteoporosis a few years later, so we selected
high-dose toremifene administration (120 mg/body) as a second-line therapy.
No adverse effects have occurred and bone metastases disappeared. Moreover,
the tumor marker was also normalized 6 months after toremifene therapy
started. It was shown that high-dose treatment of toremifene was useful
for recurrent breast cancer with bone metastasis.
Clin Cancer Res. 2004 Feb 1;10(3):1057-63.
A high serum matrix metalloproteinase-2 level is associated with an adverse prognosis in node-positive breast carcinoma.
Leppa S, Saarto T, Vehmanen L, Blomqvist C, Elomaa I.
Department of Oncology, Helsinki University Central Hospital, PO Box 180, FIN-00029 Helsinki, Finland. sirpa.leppa@hus.fi
PURPOSE: The aim of this study was to determine whether serum matrix metalloproteinase (MMP) -2 and MMP-9
levels could predict overall and disease-free survival in primary node-positive breast cancer. EXPERIMENTAL
DESIGN: MMP-2 and MMP-9 levels were quantitatively measured in serum after surgery from 133 patients with
primary node-positive breast cancer using enzyme-linked immunoassays. All of the patients received adjuvant
therapy, postmenopausal endocrine treatment (tamoxifen or toremifen for 3 years) and premenopausal six cycles
of CMF chemotherapy. The follow-up time for all of the patients was 5 years. RESULTS: Overall survival (OS)
and disease-free survival (DFS) rates were better among patients with low MMP-2 levels than in patients with
high levels (OS, 91% versus 75%, P = 0.020; DFS, 82% versus 58%, P = 0.005). The appearance of bone and visceral
metastases was also significantly lower in patients with low serum MMP-2 levels (bone metastases, 10% versus 23%,
P = 0.050; visceral metastases, 12% versus 34%, P = 0.018). The prognostic value of MMP-2 levels was most pronounced
among a subgroup of estrogen receptor-positive patients (OS, 96% versus 78%, P = 0.052; DFS, 85% versus 58%, P = 0.014),
whereas no significant difference was found among estrogen receptor-negative patients (OS, 73% versus 69%, P = 0.25; DFS,
73% versus 63%, P = 0.32). In multivariate analysis, MMP-2 level together with nodal status (NS), progesterone receptor (PgR),
and tumor size (T) remained independent predictors for DFS (NS, P = 0.002; PgR, P = 0.004; T, P = 0.023; MMP2, P = 0.039) and
OS (NS, P = 0.0002; PgR, P = 0.004; T, P = 0.004; MMP2, P = 0.032). MMP-9 levels did not correlate with survival.
CONCLUSIONS: The results suggest that serum postoperative MMP-2 level is a predictor of DFS and OS, and could help
to stratify breast cancer patients with primary node-positive disease into low- and high-risk groups.
Oncol Rep. 2004 Feb;11(2):365-70.
Primary toremifene treatment for elderly postmenopausal women with breast cancer.
Hamada N, Ogawa Y, Nishioka A, Kariya S, Yoshida S.
Department of Radiology, Hosogi Hospital, Daizen-cho 37, Kochi-shi, Kochi 780-8535, Japan.
Among patients with breast cancer who consulted the Department of Radiology, Kochi Medical School
to undergo breast-conservation treatment, toremifene (TOR) alone was administered to 7 postmenopausal
women as initial treatment for reasons such as the patient's desire, advanced age, and concomitant disease.
In 6 patients, breast-conserving surgery was performed 1-12 months after the start of the administration of
TOR alone. A 90-year-old patient has been treated with TOR alone for 56 months, and is being followed up. Six
of 7 patients showed 50% or greater reduction of tumors, including 1 in whom the administration of TOR alone for
5 months reduced the tumor from a clinical diagnosis of skin invasion (T4b) to T1c, allowing lumpectomy under local
anesthesia. In one patient, there were no changes (reduction ratio: 14%). No progressive disease was detected in any
patient. In this study, the administration of TOR alone markedly reduced tumors in patients with estrogen receptor
(ER)-positive breast cancer, facilitating down-staging. Treatment with TOR alone may be a useful neoadjuvant therapy or
single therapy in elderly patients.
Acta Oncol. 2004;43(5):443-52.
Differential effects of toremifene on doxorubicin, vinblastine and Tc-99m-sestamibi in P-glycoprotein-expressing breast and
head and neck cancer cell lines.
Mubashar M, Harrington KJ, Chaudhary KS, Lalani el-N, Stamp GW, Peters AM.
Department of Imaging, Hammersmith Hospital, London, UK.
The effect of toremifene on P-glycoprotein-mediated multidrug resistance (MDR) in breast and head and neck cancer
cell lines was measured in vitro and in vivo. Pgp expression was low and high, respectively, in drug-sensitive
(MCF7-S, KB) and drug-resistant (MCF7-R, MCF7-R1, KBV1) cell lines. Toremifene (7.5 microM) significantly enhanced
cytoplasmic and nuclear accumulation of doxorubicin in drug-resistant cells. Toremifene (10 microM) increased the
in vitro cytotoxicity of doxorubicin in drug-resistant breast cancer cells (13-fold and 21-fold for MCF7-R and MCF7-R1,
respectively) without affecting the sensitivity of MCF7-S cells. Similarly, toremifene (10 microM) caused a 12-fold
increase in the sensitivity of KBV1 cells to vinblastine. In contrast, toremifene (5 microM) reduced the net uptake
of the radiolabelled Pgp substrate, Tc-99m-sestamibi, in the Pgp-overexpressing cell lines by factors of 0.32 and
0.42 for MCF7-R1 and KBV1 cells, respectively (p < 0.01), and, to a lesser extent, by corresponding factors of 0.89
and 0.86 in the drug-sensitive cell lines (p < 0.05 and p > 0.05, respectively). In nude mice bearing both KB and
KBV1 xenograft tumours, significantly higher tumour levels of Tc-99m-sestamibi were recorded in KB tumours compared
with KBV1 tumours. After 3 days of treatment with intraperitoneal toremifene (25 mg/kg), tumour levels of Tc-99m-sestamibi
were reduced in KB and KBV1 tumours but only statistically significantly for KB tumours. Toremifene is a potent MDR
modulating agent with respect to chemotherapeutic agents but has the opposite effect with respect to Tc-99m-sestamibi.
This finding is of importance in view of the widespread use of Tc-99m-sestamibi as an imaging surrogate for a chemotherapeutic agent.
Dis Colon Rectum. 2004 Jan;47(1):118-22. Epub 2004 Jan 14.
Antiangiogenic treatment of mesenteric desmoid tumors with toremifene and interferon alfa-2b: report of two cases.
Heidemann J, Ogawa H, Otterson MF, Shidham VB, Binion DG.
Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
PURPOSE: Desmoid tumors are uncommon, benign, fibrous lesions occurring sporadically and in association with familial
adenomatous polyposis. Typical clinical features include a locally aggressive behavior, an unpredictable course,
and a high propensity for recurrence after surgical resection. There are no standard medical or surgical approaches, and
no markers for monitoring medical therapy of desmoid tumors. METHODS: We report two cases of mesenteric desmoid tumors
treated with interferon alfa-2b and toremifene, a novel regimen devised to block angiogenesis. Pre- and posttreatment
desmoid tumor tissues were obtained in one patient during a repeat resection for recurrent stenosing Crohn's disease and examined
for mean vessel count and cellular proliferation levels by immunostaining for the endothelial surface antigen CD31
and the proliferation associated nuclear antigen, Ki-67, respectively. We assessed plasma D-dimers, a potential
marker of angiogenic activity, and followed this throughout the course of antiangiogenic therapy in our two patients.
RESULTS: Examination of posttreatment tissue revealed a significant decrease in microvessel density (P<0.02)
and Ki-67-positive nuclei (P<0.0001) compared with pretreatment tissue. Both patients demonstrated a prompt and
sustained drop in previously elevated plasma D-dimer levels, which correlated clinically with lesion regression and
sustained remission. CONCLUSIONS: Treatment with toremifene and interferon alfa-2b was successful and well tolerated
in our two patients. Our data suggest a combined antiangiogenic and antiproliferative mechanism of action. Furthermore, normalization
of previously elevated plasma D-dimers may emerge as a strategy to monitor treatment efficacy
in mesenteric desmoid tumors.
Neurochem Res. 2004 Jan;29(1):305-11.
Toxicity of selected cationic drugs in retinoblastomal cultures and in cocultures of
retinoblastomal and retinal pigment epithelial cell lines.
Maenpaa H, Toimela T, Mannerstrom M, Saransaari P, Tahti H.
Cell Research Center, Medical School, University of Tampere, Tampere, Finland. hanna.maenpaa@uta.fi
Tamoxifen and toremifene are antiestrogenic drugs successfully used in the therapy of breast cancer. Rheumatoid
arthritis and malaria have been treated with chloroquine for decades. Unfortunately, tamoxifen and chloroquine
are reported to induce retinal changes as a side effect. We now studied the effects of tamoxifen, toremifene,
and chloroquine on the viability of the human retinoblastomal cell line Y79, using the WST-1 test or measurement
of the cellular ATP content. The studies were made on Y79 cell cultures and on cocultures of Y79 cells and retinal
pigment epithelial cell line ARPE-19. The cocultures were used to clarify the effect of retinal pigment epithelium on
toxicity to Y79 cells. In the coculture, the drugs were applied to ARPE-19 cells growing in the culture inserts on top
of Y79 cells and the viability of ARPE-19 and Y79 cells was assessed separately. Tamoxifen, toremifene, and chloroquine
reduced dose-dependently the viability of Y79 cells after 24-h exposure. The ARPE-19 cells proved to be protective
after chloroquine exposure in the coculture. The results shed light on the toxicity of tamoxifen and chloroquine
in Y79 cells in vitro. With the coculture we were able to simulate the in vivo route of chloroquine to the retina
via the retinal pigment epithelium.
Vascul Pharmacol. 2003 Dec;40(5):261-8.
Chronic effects of toremifene on the vasculature of menopause-induced rats.
Gonzalez-Perez J, Crespo MJ.
Department of Physiology, University of Puerto Rico-School of Medicine, San Juan.
During menopause, women have a higher propensity for developing cardiovascular diseases. Recent studies have shown that treatment with selective estrogen receptor modulators (SERMs) improves cardiovascular status in menopausal women. The mechanisms involved, however, have not been elucidated. The present study evaluates the effect of toremifene (10 mg/kg/day), a new member of SERM family, on the vasculature of ovariectomized (Ovx) Sprague-Dawley rats that have been treated with the drug for a 4-week period. Age-matched sham, Ovx-untreated, and Ovx 17beta-estradiol-treated rats were used as controls. Aortic rings from treated and untreated animals were used to determine vascular responses to norepinephrine, acetylcholine, and sodium nitroprusside. Systolic blood pressure (SBP), plasmatic nitric oxide (NO) concentration, estrogen levels, aortic wall thickness, and cholesterol profiles were also determined. Toremifene displaces the concentration-response curve (CRC) for the acetylcholine-induced relaxation to the left and increases the Emax by 34% (from 59.2 +/- 4.2% in Ovx-untreated to 90.2 +/- 3.1% in Ovx-treated rats, n = 9, P < .05). Toremifene increases the Emax (by 22%) without modifying the EC5o for the NE-induced contraction. In addition, toremifene amplifies the relaxing responses to sodium nitroprusside compared to Ovx-untreated group (P < .05). SBP was significantly reduced in the Ovx toremifene-treated group when compared to the Ovx-untreated group (124 +/- 3.5 mm Hg for Ovx toremifene-treated vs. 161 +/- 4.3 mm Hg for Ovx-untreated, n = 10, P < .05). Rats treated chronically with toremifene also exhibited a significantly higher plasmatic NO levels, and a decrease in basal resting tension and aortic wall thickness. The drug, however, did not affect the plasmatic high-density lipoprotein (HDL)/total cholesterol ratio. These results suggest that chronic administration of toremifene improves cardiovascular performance in menopause-induced rats by reversing endothelial dysfunction and decreasing vascular resting tone. Thus, use of toremifene may help to diminish total peripheral resistance and improve cardiovascular status in Ovx rats.
Vascul Pharmacol. 2003 Nov;40(4):205-11.
Acute effects of toremifene on the vasculature of intact and menopause-induced rats.
Gonzalez-Perez J, Crespo MJ.
Department of Biology, University of Puerto Rico-Rio Piedras, San Juan, Puerto Rico.
Clinical studies have shown that cardiovascular performance in postmenopausal women could be modified by treatment
with selective estrogen receptor modulators (SERM). However, the mechanisms by which these drugs act on the
cardiovascular system have not been elucidated. This work evaluates the effect of toremifene, a new member of
the SERM family, on the vasculature of intact and ovariectomized adult Sprague-Dawley rats. The responsiveness
of rings from the thoracic aorta to norepinephrine, potassium chloride, acetylcholine and sodium nitroprusside was
assessed before and after 15 min of incubation with 1.0-microM toremifene. Toremifene displaced the concentration-response
curve for norepinephrine-induced contractions to the right in both groups of animals. Moreover, the EC(50) values for the
curves increased from 154+/-31 to 754+/-162 nM (P<.05) in intact rats and from 88+/-11 to 230+/-71 nM (P<.05) in ovariectomized
rats. Toremifene also reduced contractile responses to potassium chloride (10-120 mM), displacing the entire curve to the right
in both groups of animals without modifying the EC(50) values. The drug shifted the concentration-response curve for the
acetylcholine-induced relaxation to the left and significantly increased E(max) values (18% for ovariectomized rats vs. 16%
for controls) without affecting EC(50) values in either group tested. In addition, toremifene potentiated the relaxing responses
to physiological doses (0.1-1.0 nM) of sodium nitroprusside in both groups, suggesting a direct effect at the level of the
vascular smooth muscle. Acute toremifene incubation increased basal relaxation in aortic rings from both intact and ovariectomized
rats. These results suggest that toremifene, by improving the functional status of the endothelium-smooth muscle unit, may have a
beneficial effect on the cardiovascular status of menopause-induced rats.
Acta Ophthalmol Scand. 2003 Oct;81(5):495-9.
Ocular side-effects in breast cancer patients treated with tamoxifen and toremifene: a randomized follow-up study.
Parkkari M, Paakkala AM, Salminen L, Holli K; Finnish Breast Cancer Group.
Department of Ophthalmology, Tampere University Hospital, PO Box 2000, 33501 Tampere, Finland. minna.parkkari@uta.fi
PURPOSE: 3Tamoxifen and toremifene are non-steroidal anti-oestrogens widely used in the treatment of
advanced breast cancer and as adjuvant therapy following surgery in early stage disease. Tamoxifene has
also been approved for use in reducing the incidence of breast cancer amongst high risk women. However, certain
well documented adverse effects, mainly involving the reproductive organs, have been reported amongst users of
both drugs. The aim of this study was to monitor the ocular side-effects of both of these commonly used anti-oestrogens.
METHODS: Sixty postmenopausal (age range 50-79 years) breast cancer patients were randomized into adjuvant tamoxifen or
toremifene therapy groups for 3 years. Prior to commencement of medication, a thorough ocular examination was undertaken.
The first follow-up visit took place after 6 months and the remaining three at 12-month intervals thereafter. RESULTS: Sixteen
patients had cataract at the first visit (seven in the tamoxifen group and nine in the toremifene group). Ten patients developed
cataract during the study period (five in each group), giving annual cataract rates of 6.8% and 6.2% in the tamoxifen and
toremifene groups, respectively. Three patients had macular crystals at the first visit (one in the tamoxifen group and
two in the toremifene group). The crystals remained stable throughout the follow-up. Macular drusen were diagnosed in
five patients at the first ophthalmological check-up (two in the tamoxifen and three in the toremifene group). Two patients
in the toremifene group developed drusen maculopathy during follow-up visits. Yellowish spots in the macular area were
found in one tamoxifen-treated patient at the second visit. At the final visit after 3.5 years' follow-up the spots had
disappeared. No abnormal corneal findings or keratopathy were documented during the follow-up. CONCLUSION: We observed no
serious ocular side-effects among the 60 breast cancer patients treated with tamoxifen or toremifene over a 3.5-year period.
Pharmacol Toxicol. 2003 Oct;93(4):174-9.
Kinetics of inhibition of glutamate uptake by antioestrogens.
Maenpaa H, Saransaari P, Tahti H.
Medical School, University of Tampere, Tampere, Finland.
The antioestrogens, tamoxifen and its more recent homologue toremifene, are used in the therapy of breast cancer.
Tamoxifen has been reported to cause retinal changes as side effects. Both compounds inhibited glutamate uptake in
retinal pigment epithelial cells, and the present study was conducted to clarify the mechanism of this inhibition.
Retinal pigment epithelial cells are part of the blood-retina barrier, and their glutamate transporters are essential
for retinal glutamate homeostasis. Glutamate uptake was investigated in human retinal pigment epithelial cell line D407
and in cultured pig retinal pigment epithelial cells using L-[3H]glutamate as a tracer. The cells were exposed to 7.5
microM tamoxifen and toremifene. beta-Hydroxyaspartate, a transportable inhibitor of glutamate transport, was used as a
reference compound. In kinetic analyses, beta-hydroxyaspartate increased the Km constant for glutamate transport. Tamoxifen
and toremifene exhibited the same effect, which indicates that inhibition evoked by them is also competitive in nature.
Both drugs were more effective in the human retinal pigment epithelial cell line than in the pig retinal pigment
epithelial cells. The results show for the first time that the antioestrogens tamoxifen and toremifene could
possibly hamper glutamate transport by replacing glutamate as the substrate.
Magy Onkol. 2003;47(2):133-40. Epub 2003 Sep 16.
Perspectives for the hormonal therapy of breast cancer
Eckhardt S.
Orszagos Onkologiai Intezet, Bp. 1122, Hungary.
The role of estrogens, including its sources, tissue distribution, metabolism,
and mechanism of action, is discussed in this review. The ER alpha and
beta are functioning separately, and there is a physiological balance
between their activity. Whenever this balance is over thrown due to endogenous
or exogenous carcinogenic factors, malignancy develops. Risk factors of
breast cancer are listed and evaluated individually. It should be stressed
however, that their carcinogenic effect sums up. The knowledge of established
risk factors rises the possibility of chemoprevention, which might be
highly desirable in case of gene carriers. Special emphasis is attached
to the SERM molecules which act as antiestrogens. Their antitumour effect
is largely used in the treatment of hormone sensitive advanced breast
cancer patients, and their efficacy has been proved in adjuvant therapy
as well. Their preventive use might also be justified, especially in gene
carriers. Aromatase inhibitors form a special class among the SERM molecules.
In Hungary, anastrozole, letrozole and exemestane are widely applied for
the therapy of breast cancer patients, while raloxifene has only been
introduced recently, mainly in order to prevent osteoporosis. The therapeutic
value of fulvestrant is unknown yet and its antitumour effect has to be
explored. The therapeutic significance of these molecules lies in the
fact that they might be effective after the development of tamoxifen resistance.
There are several explanations for this phenomenon offering new targets
for the further development of a succesful antitumour chemotherapy.
Gan To Kagaku Ryoho. 2003 May;30(5):669-75.
Combined effects of toremifene and paclitaxel on human breast cancer
cell lines
Maruyama S, Kuroiwa S, Saimoto A, Nishikawa K.
Research and Development Division, Nippon Kayaku Co., Ltd.
Effects of toremifene (TOR) in combination with paclitaxel (TXL) on various
human breast cancer cell lines were evaluated. TOR and TXL exhibited additive
effects on estrogen receptor (ER)-positive cancer cell lines, MCF-7 and
T-47D, and a sub-additive effect on a tamoxifen (TAM)-resistant line,
T-47D/TAM. To all three ER-negative cancer cell lines, the combined treatment
also showed additive effects on MDA-MB-134VI, MDA-MB-231 and MDA-MB-453.
Furthermore, a synergistic effect was observed on a multi-drug resistant
(MDR) line, Adr. This synergistic effect was more potent in the combination
with TOR than that with TAM. The combined treatment increased intracellular
TXL, and the accumulation by TOR was 1.5-fold that by TAM. Consequently,
the ratio of G2M arrested cells was higher, with statistical significance,
in the TOR combination than in the TAM combination. In addition, these
synergistic effects in MDR cells were also observed in the combination
of TXL with major clinical active metabolites, N-desmethyl-TOR (TOR-1)
and 4-hydroxy-TOR (TOR-2). These results suggest that the combination
therapy of TOR and TXL might be an effective clinical treatment for breast
cancer patients.
Folia Med (Plovdiv). 1997;39(4):5-10
Simeonov S, Pavlova M, Mitkov M, Mincheva L, Troev D.
Endocrinology and Metabolic Disorders Clinic, Higher Medical Institute,
Plovdiv, Bulgaria.
Therapeutic efficacy of "Milgamma" in patients with painful
diabetic neuropathy.
Acta Ophthalmol Scand. 2003 Oct;81(5):495-9.
Parkkari M, Paakkala AM, Salminen L, Holli K; Finnish Breast Cancer Group.
Department of Ophthalmology, Tampere University Hospital, PO Box 2000,
33501 Tampere, Finland. minna.parkkari@uta.fi
Ocular side-effects in breast cancer patients treated with tamoxifen
and toremifene: a randomized follow-up study.
3Tamoxifen and toremifene are non-steroidal anti-oestrogens widely used
in the treatment of advanced breast cancer and as adjuvant therapy following
surgery in early stage disease. Tamoxifene has also been approved for
use in reducing the incidence of breast cancer amongst high risk women.
However, certain well documented adverse effects, mainly involving the
reproductive organs, have been reported amongst users of both drugs. The
aim of this study was to monitor the ocular side-effects of both of these
commonly used anti-oestrogens. Sixty postmenopausal (age range 50-79 years)
breast cancer patients were randomized into adjuvant tamoxifen or toremifene
therapy groups for 3 years. Prior to commencement of medication, a thorough
ocular examination was undertaken. The first follow-up visit took place
after 6 months and the remaining three at 12-month intervals thereafter.
Sixteen patients had cataract at the first visit (seven in the tamoxifen
group and nine in the toremifene group). Ten patients developed cataract
during the study period (five in each group), giving annual cataract rates
of 6.8% and 6.2% in the tamoxifen and toremifene groups, respectively.
Three patients had macular crystals at the first visit (one in the tamoxifen
group and two in the toremifene group). The crystals remained stable throughout
the follow-up. Macular drusen were diagnosed in five patients at the first
ophthalmological check-up (two in the tamoxifen and three in the toremifene
group). Two patients in the toremifene group developed drusen maculopathy
during follow-up visits. Yellowish spots in the macular area were found
in one tamoxifen-treated patient at the second visit. At the final visit
after 3.5 years' follow-up the spots had disappeared. No abnormal corneal
findings or keratopathy were documented during the follow-up. We observed
no serious ocular side-effects among the 60 breast cancer patients treated
with tamoxifen or toremifene over a 3.5-year period.
Oncol Rep. 2002 May-Jun;9(3):475-8.
Hamada N, Ogawa Y, Nishioka A, Kariya S, Terashima M, Yoshida S, Tanaka
Y, Inomata T.
Department of Radiology, Hosogi Hospital, Kochi 780-8535, Japan.
An elderly patient with DCIS of the breast effectively treated with
toremifene alone.
An elderly patient with breast cancer received toremifene monotherapy
for one year, and about 60% tumor remission rate was obtained. Since viability
of the residual tumor was suspected on ultrasonography (US), computed
tomography (CT), and magnetic resonance imaging (MRI), lumpectomy was
performed under local anesthesia. The histopathological diagnosis was
ductal carcinoma in situ (DCIS). The patient did not undergo axillary
lymph node dissection or systemic chemotherapy. The patient is alive without
disease under postoperative radiotherapy and toremifene treatment. Toremifene
monotherapy and/or preoperative adjuvant therapy with toremifene alone
may be useful methods for elderly patients with breast cancer considering
the patients' quality of life.
