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.
Magy Onkol. 2003;47(2):133-40. Epub 2003 Sep
16.
Perspectives for the hormonal therapy of breast cancer.
Eckhardt S.
Orszagos Onkologiai Intezet, Budapest 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.
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.
Anticancer Drugs. 2003 Apr;14(4):265-73.
Update on the current use of hormonals as therapy in advanced
breast cancer.
Vogel CL.
Cancer Research Network, Plantation, FL, USA.
Hormonal agents have a confirmed role in the management of postmenopausal
women with receptor-positive advanced breast cancer. Until recently,
tamoxifen has been the accepted agent for treating these patients.
However, accumulating evidence suggests that the new antiaromatase
agents will replace the antiestrogens as the preferable option
in hormone-naive patients. Comparative trials indicate that the
aromatase inhibitors, anastrozole and letrozole, and the aromatase
inactivator, exemestane, have at least equivalent efficacy to
tamoxifen with similar or superior tolerability. These agents
are also more effective than the progestin, megestrol acetate,
when studied in patients progressing on tamoxifen. The improved
aromatase selectivity and high potency of these antiaromatase
agents when compared with earlier agents have resulted in improved
efficacy and tolerability. Additionally, no cross-resistance has
been reported between the antiaromatase agents and tamoxifen or,
in some instances, among the antiaromatase agents themselves.
The role of antiaromatase agents will certainly expand in the
near future to include not only treatment of metastatic breast
cancer, but use in the adjuvant and neoadjuvant settings as well,
and, ultimately, breast cancer prevention. The results of ongoing
investigations are awaited with interest.
Zhonghua Zhong Liu Za Zhi. 2002 Nov;24(6):537-9.
Synergistic effect of toremifene and cisplatin on human lung cancer
cell line A549.
Zhang X, Li Q, Han Y, Liu Z.
Department of Respiratory Medicine, Chang Hai Hospital, Second
Military Medical University, Shanghai 200433, China.
OBJECTIVE: To study the toxic effect of toremifene (TOR) and its
synergistic effect with cisplatin (DDP) on human lung adenocarcinoma
cell line A549. METHODS: The cytotoxic effects of these agents
on human lung cancer cell line A549 were monitored by a tetrazolium-based
colorimetric assay (MTT assay). The cell cycle and DNA content
were detected by flow cytometer technic. p21 expression level
was monitored by Western blot. RESULTS: Toremifene inhibited the
growth of A549 cell, with > or = 5 micromol/L significantly
enhancing the chemosensitivity of cisplatin. TOR enhanced the
antitumor activity of DDP at S, G(2) and M phases of cells. And
p21 expression was increased after TOR and DDP had been given.
CONCLUSION: Toremifene (> or = 5 micromol/L) combined with
cisplatin shows significant synergistic anti-tumor effect on A549
cells.
J Bone Miner Res. 2003 Mar;18(3):473-81.
The effects of tamoxifen and toremifene on bone cells involve
changes in plasma membrane ion conductance.
Lehenkari P, Parikka V, Rautiala TJ, Weckstrom M, Dahllund J,
Harkonen PL, Vaananen HK.
Department of Surgery and Anatomy, University of Oulu, Oulu, Finland.
Selective estrogen receptor modulators (SERMs), tamoxifen (Tam)
and toremifene (Tor), are widely used in the treatment of breast
cancer. In addition, they have been demonstrated to prevent estrogen
deficiency-induced bone loss in postmenopausal women. These effects
are thought to be caused by the interaction of the SERMs with
the estrogen receptor, although SERMs have also been shown to
conduct non-receptor-mediated effects such as rapid changes in
membrane functions. We compared the effects of Tam, Tor, and 17beta-estradiol
(E2) on the viability of rat osteoclasts and osteoblasts. Both
Tam and Tor were found to cause osteoclast apoptosis in in vitro
cultures, which was reversed by E2. In addition, at higher concentration
(10 microM), both SERMs had an estrogen receptor-independent effect,
which involved interaction with the plasma membrane as demonstrated
with UMR-108 osteosarcoma cells by Tam and Tor, but not E2. A
leak of protons leading to changes in intracellular pH was shown
both in medullary bone derived membrane vesicles and in intact
cells. These effects were followed by a rapid loss of cell viability
and subsequent cell lysis. Our results show that both Tam and
Tor have an ionophoric effect on the plasma membranes of bone
cells and that these SERMs differed in this ability: Tor induced
rapid membrane depolarization only in the presence of high concentration
of potassium. These non-receptor-mediated effects may be involved
in therapeutic responses and explain some clinical side effects
associated with the treatment of patients with these SERMs.
Clin Ther. 2002;24 Suppl C:C3-25.
Evolving uses of hormonal agents for breast cancer therapy.
Cummings FJ.
University Medical Group-Roger Williams Medical Center, Providence,
Rhode Island 02908, USA.
BACKGROUND: During the past decade, a number of new hormonal therapies
(HTs) have been developed, including the selective estrogen receptor
modulators (SERMs), aromatase inhibitors (AIs), and estrogen receptor
(ER) antagonists. Their uses in breast cancer are continually
evolving as new clinical trial results become available. Although
tamoxifen, the most widely used HT for breast cancer, was originally
approved for and used in the treatment of metastatic breast cancer
(MBC), its effectiveness as MBC therapy led to its subsequent
assessment and use as adjuvant and risk-reduction therapy for
breast cancer. However, tamoxifen is not universally effective
in these settings and is associated with infrequent known toxicities
such as increased risk of thromboembolism and endometrial cancer;
therefore, a search for more effective and more tolerable HTs
has evolved. OBJECTIVE: This article reviews the data supporting
the use of newer HTs as initial treatment of MBC and their potential
use as adjuvant, neoadjuvant, and chemopreventive therapies. METHODS:
Articles for inclusion in this manuscript were identified through
the following searches, limited to English-language publications:
MEDLINE (mid 1960s to January 2002), American Society of Oncology
abstracts (1997-2001), and San Antonio Breast Cancer Symposium
abstracts (2001 and 2002). The following search terms were used:
breast cancer, breast cancer guidelines, hormonal therapies, tamoxifen,
toremifine, letrozole, anastrozole, exemestane, megestrol acetate,
fulvestrant, and ICI 182,780. RESULTS: Recent studies have focused
on newer agents as initial and subsequent treatment of MBC, adjuvant
or neoadjuvant treatments of breast cancer, and chemopreventive
agents in both healthy women and women with a history of ductal
carcinoma in situ (DCIS). Results of clinical trials comparing
AIs with tamoxifen as first-line MBC treatment show that AIs are
as effective as, or more effective than, tamoxifen and are associated
with fewer serious adverse events. Tamoxifen remains the gold
standard for adjuvant therapy. However, preliminary results of
ongoing clinical trials comparing tamoxifen with anastrozole suggest
that anastrozole may be the superior agent. Both tamoxifen and
the AIs have been shown to be active in the neoadjuvant treatment
of breast cancer. Trial results have shown that tamoxifen is effective
for breast cancer prevention in patients at high risk of developing
breast cancer but who are otherwise healthy, patients with a history
of DCIS, and patients with lobular carcinoma in situ. CONCLUSIONS:
Although tamoxifen has been the gold standard of HT for breast
cancer, results of ongoing trials assessing the newer HTs as initial,
neoadjuvant, adjuvant, and chemopreventive therapies may substantially
change our current clinical practice patterns.
Minerva Ginecol. 2002 Jun;54(3):245-51.
Antiestrogen therapy in the treatment of breast neoplasms.
Alba E, Ragonesi G, Colla F, Mazzoleni A, Farina C.
Dipartimenti di Discipline Ginecologiche ed Ostetriche Cattedra
B, Universita degli Studi, Turin, Italy.
During recent years the development of hormone therapy for the
treatment breast neoplasms has seen, in addition to classic aspecific
antiestrogens (AE) like tamoxifen (TAM) and to a lesser extent
toremifen, a major development of new molecules divided into two
groups: the first is the so-called selective estrogen receptor
modulators (SERMs), the most important of which is Raloxifen,
which mediate estrogen-agonist effects in some tissues and estrogen-antagonist
effects in others; the second group includes the aromatase inhibitors
(AI), important enzymes for peripheral estrogen conversion. Some
studies compare or associate classic AE with the new SERMs and
AI, both in adjuvant therapy and in treatment for advanced forms.
Other trials assess the anti-osteoporotic activity of some SERMs
which present concomitant inhibitory activity on the breast and
endometrium.
Oncol Rep. 2002 May-Jun;9(3):469-74.
Breast-conservation treatment for bilateral breast cancer in five
Japanese women.
Hamada N, Ogawa Y, Nishioka A, Kariya S, Terashima M, Yoshida
S, Tochika N, Tanaka Y, Kumon M, Inomata T.
Department of Radiology, Hosogi Hospital, Kochi 780-8535, Japan.
Between August 1989 and September 1999, breast-conservation treatment
(BCT) was performed in 250 of 256 breast cancer patients. Five
of the 250 patients had bilateral breast cancer, and 4 with synchronous
bilateral breast cancer of the 5 were concomitantly treated by
chemo-endocrine therapy before simultaneous breast-conservation
surgery for bilateral breast cancer. Chemotherapy was performed
using cyclophosphamide, pirarubicin, and 5-fluorouracil, while
endocrine therapy was performed using an antiestrogen agent (tamoxifen
or toremifene). All patients were also treated by radiotherapy.
Since no severe side effects or complications were induced by
these therapeutic approaches, bilateral breast cancer may be successfully
treated by BCT as in unilateral breast cancer. However, of the
5 patients with bilateral breast cancer, cancer recurrence in
the axillary lymph nodes was detected only in 1 patient with T2N1
cancer 78 months after simultaneous breast-conservation surgery
for bilateral breast cancer.
Cancer Res. 2002 Mar 1;62(5):1370-6.
Toremifene prevents prostate cancer in the transgenic adenocarcinoma
of mouse prostate model.
Raghow S, Hooshdaran MZ, Katiyar S, Steiner MS.
niversity of Tennessee Urologic Research Laboratories, Memphis,
Tennessee 38163, USA.
The chemopreventive efficacy of toremifene, an antiestrogen, was
evaluated in the transgenic adenocarcinoma of mouse prostate (TRAMP)
model. TRAMP mice were segregated into three groups: (a) the low-dose
toremifene group (6.6 mg/kg/day); (b) the high-dose toremifene
group (33 mg/kg/day); and (c) the control placebo group. Efficacy
of treatment was measured by the absence of palpable tumor. To
extend these studies using more sensitive techniques, TRAMP mice
were then treated with placebo, flutamide (an antiandrogen; 33
mg/kg/day), or toremifene (10 mg/kg/day). Animals from each treatment
group were sacrificed at 7, 10, 15, 20, 25, and 30 weeks of age,
and prostate tissues and seminal vesicles were harvested. Tissues
from animals (n = 5) in each group were evaluated by wholemount
dissections of genitourinary tracts, histology, immunohistochemistry,
and Western blot analyses. Blood was pooled per group to measure
estradiol and testosterone hormonal levels. Tumors formed at week
17 in the placebo group (n = 10), at week 21 in the high-dose
toremifene group (n = 12), and at week 29 in the low-dose toremifene
group (n = 12). This represents an increased tumor latency of
up to 12 weeks. By 33 weeks, all animals in the placebo group
had tumors compared with only 35% of the animals treated with
toremifene. Although both flutamide and toremifene decreased tumor
incidence compared with the placebo, toremifene was more effective
than flutamide. High-grade prostatic intraepithelial neoplasia
was observed in animals in the placebo group, but not in animals
treated with toremifene. Moreover, toremifene-treated animals
had prolonged survival compared with placebo-treated animals.
By 33 weeks of age, 100% of the placebo-treated animals had developed
palpable tumors and died, whereas 60% of the toremifene-treated
animals were tumor free. T antigen levels in the prostate of toremifene-treated
animals were similar to those of placebo-treated, age-matched
animals. Whereas serum estradiol levels remained unchanged, the
total and free testosterone levels were elevated in the toremifene-treated
group. Toremifene treatment did not affect androgen receptor levels.
Because toremifene prevented prostate cancer in a milieu of elevated
blood free testosterone levels with no change in prostate androgen
receptor expression, the mechanism of toremifene's chemopreventive
activity may be through nonandrogenic pathways, such as estrogen
receptor signaling.
Chemotherapy. 2002 Dec;48(5):238-43.
Antiproliferative properties of toremifene on AIDS-related Kaposi's
sarcoma cells.
Hong A, Leigh BR.
Department of Radiation Oncology, Sydney Cancer Center, Royal
Prince Alfred Hospital, Sydney, Australia.
BACKGROUND: Kaposi's sarcoma (KS) is the most common neoplastic
apoptosis manifestation of acquired immunodeficiency syndrome.
Toremifene is known to upregulate transforming growth factor beta-1
(TGF-beta1), which is a growth-inhibitory factor for KS. We investigated
the in vitro effect of toremifene on KS cells. METHODS: MTT assay
was used to measure the growth of four KS cell lines and a human
umbilical vein endothelial (HUVE) cell line after incubation with
toremifene. Reverse transcription polymerase chain reaction and
ELISA were used to measure the level of TGF-beta1. RESULTS: The
IC(50) for the KS cells ranged from 2.2 to 3.2 microM, and 80%
of the growth inhibition occurred within 24 h. Toremifene enhanced
TGF-beta1 mRNA expression, and the level of TGF-beta1 increased
from 103 to 473 pg/ml after 48 h of incubation. Toremifene had
no effect on the growth of HUVE cells. CONCLUSION: Toremifene
has a specific antiproliferative effect on KS cells. The stimulation
of TGF-beta1 production may play a role in the antiproliferative
process.
Int J Cancer. 2002 Jul 20;100(3):337-41.
Tamoxifen and toremifene treatment of breast cancer and risk of
subsequent endometrial cancer: a population-based case-control
study.
Pukkala E, Kyyronen P, Sankila R, Holli K.
Finnish Cancer Registry, Institute for Statistical and Epidemiological
Cancer Research, Helsinki, Finland.
A population-based case-control study was performed to evaluate
the risk of endometrial cancer related to tamoxifen or toremifene
treatment. All patients with breast cancer diagnosis since 1980
in Finland who subsequently developed an endometrial cancer by
the end of 1995 and 3 matched controls were identified among the
38,000 breast cancer patients of the Finnish Cancer Registry database.
Detailed information on treatment of breast cancer and potential
confounders was collected from hospital records. The OR for tamoxifen
treatment (59 cases), adjusted for significant cofactors (increased
risk associated with obesity, low parity and PR positivity) was
2.9 (95% CI 1.8-4.7). The OR for toremifene (3 cases) was 0.9
(95% CI 0.3-3.9). The OR related to adjuvant tamoxifen treatment
reached its maximum 2-5 years after the beginning of treatment
(OR 5.1, 95% CI 2.1-13), while the OR for tamoxifen used for palliative
treatment of advanced breast cancer was especially high after
a lag of over 5 years (OR 9.5, 95% CI 2.5-36). The risk increase
due to tamoxifen was slightly higher if the age at initiation
was below 55, and risk was more pronounced among patients with
well-differentiated endometrial cancer than patients with cancers
of clinical grades 2 or 3. According to our results, treatment
with tamoxifen increases the risk of endometrial cancer. Due to
the rare use of toremifene up to the mid-1990s, the risk assessment
concerning it was inconclusive.
Oncol Rep. 2002 May-Jun;9(3):475-8.
An elderly patient with DCIS of the breast effectively treated
with toremifene alone.
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 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.
Gan To Kagaku Ryoho. 2001 Aug;28(8):1099-104.
Antiangiogenic and antimetastatic effects of toremifene citrate.
Okada M, Ogasawara A, Sekine K, Seno C, Nishikawa K.
Research and Development Division, Nippon Kayaku Co., Ltd.
In this study, we demonstrated that toremifene citrate (TOR) inhibited
the tube formation and migration of human umbilical vein endothelial
cells (HUVEC) in vitro. Moreover, TOR suppressed angiogenesis
in rabbit cornea and lung metastasis of human fibrosarcoma HT-1080
cells in nude mice. The antiangiogenic activity in vitro was apparent
at the concentration of 5 microM which is clinically achievable
by oral administration of 120 mg/kg of TOR. These results suggest
that clinical treatment with 120 mg/day of TOR might be expected
to exhibit antiangiogenesis and antimetastasis effects, in addition
to inhibition of estrogen-dependent tumor cell growth.
Eur J Cancer. 2000 Sep;36 Suppl 4:S61-2.
Toremifene. where do we stand?
Maenpaa J, Holli K, Pasanen T.
Departments of Obstetrics and Gynecology, and Oncology and Radiotherapy,
University Hospital, PO Box 2000, FIN-33521, Tampere, Finland.
Toremifene is a chlorinated triphenylethylene that is indicated
for postmenopausal breast cancer. For advanced disease, toremifene
has been found to be as effective and at least as well tolerated
as tamoxifen. The same appears to apply for adjuvant setting.
After a total cumulative clinical exposure to toremifene of approximately
140000 patient-years, only 9 cases of endometrial carcinoma have
been reported. The annual hazard rate (per 1000 patient-years)
of developing endometrial carcinoma in breast cancer patients
on adjuvant toremifene is 1.14 (versus tamoxifen 2.0 and placebo
0.4). Although toremifene (being a partial agonist) may unmask
pre-existing endometrial tumours, there is no clinical data implying
that it would per se cause endometrial carcinoma.
Drugs Aging. 1997 Oct;11(4):261-70.
Toremifene in postmenopausal breast cancer. Efficacy, safety and
cost.
Maenpaa JU, Ala-Fossi SL.
Department of Obstetrics and Gynecology, University Hospital,
Tampere, Finland.
Toremifene is a chlorinated tamoxifen analogue that is indicated
for the treatment of postmenopausal hormone-dependent breast cancer.
It competes with estradiol for estrogen receptors and has growth-inhibitory
effects on MCF-7 breast cancer cells. At concentrations < 10(-6)
mol/L, this growth inhibition can be reversed by estradiol, but
at higher concentrations toremifene is cytotoxic. In dimethylbenzanthracene
(DMBA)-induced mammary cancer in rats, toremifene has been shown
to decrease the number of new tumours and to inhibit the growth
of existing tumours. Toremifene causes growth inhibition by suppressing
mitosis and inducing apoptosis. The mechanism by which these events
occur may involve the induction of transforming growth factor-beta
1 and inhibition of insulin-like growth factor-1 (mecasermin).
Toremifene is primarily an antiestrogen, but it has some estrogen
agonist properties in postmenopausal women. The latter are reflected
by the fall in luteinising hormone and follicle-stimulating hormone
levels and the rise in sex hormone-binding globulin levels that
are associated with its use in most women. After estrogen priming,
toremifene 68mg administered orally has been found to exert a
similar antiestrogenic effect on the vaginal epithelium in postmenopausal
women as tamoxifen 60mg. The half-life of toremifene in plasma
is 5 days, and the drug is > 99% bound to plasma proteins.
The main metabolites of toremifene are N-demethyl-toremifene and
deaminohydroxy-toremifene. Altered liver, but not kidney, function
affects the pharmacokinetics of toremifene. Toremifene 60mg daily
is as effective as tamoxifen 20mg daily in the treatment of postmenopausal
hormone-dependent breast cancer, producing a response in about
50% of patients. Soft tissue and visceral metastases respond better
to toremifene than bone metastases. Most of the adverse effects
of toremifene are related to its activity at estrogen receptors
and include hot flashes, vaginal discharge and nausea. Although
toremifene decreases antithrombin III levels slightly, the incidence
of thromboembolic complications is low. Thus far, no carcinogenic
effects have been noted in humans, and preclinical data are mostly
reassuring. Toremifene has favourable effects on serum lipids,
and thus has potential in preventing coronary heart disease. Although
toremifene is somewhat more expensive to use than tamoxifen, toremifene
is an effective and well tolerated alternative to tamoxifen in
the treatment of postmenopausal women with hormone-dependent breast
cancer. No formal pharmacoeconomic comparisons of toremifene and
tamoxifen have yet been published. Toremifene is potentially safer
than tamoxifen in relation to carcinogenic effects and effects
on serum lipids.
Drugs. 1997 Jul;54(1):141-60.
Toremifene. A review of its pharmacological properties and clinical
efficacy in the management of advanced breast cancer.
Wiseman LR, Goa KL.
Adis International Limited, Auckland, New Zealand.
The triphenylethylene antiestrogen toremifene is a chlorinated
derivative of the antiestrogen tamoxifen, an agent which has been
widely and successfully used in the treatment of breast cancer.
Clinical trials investigating the efficacy of toremifene as first-line
endocrine therapy in postmenopausal women with advanced breast
cancer (estrogen receptor status positive or unknown) have shown
this drug to have similar antitumour activity to that of tamoxifen.
In multicentre comparative trials, objective responses (complete
and partial) occurred in 20 to 29% of patients treated with toremifene
(60 to 240 mg/day) and in 19 to 37.5% of tamoxifen (20 or 40 mg/day)
recipients. The duration of response, time to disease progression
and median overall survival time were generally similar in both
treatment groups. Toremifene is well tolerated. Most drug-related
adverse effects are mild or moderate in severity and rarely necessitate
discontinuation of therapy. The tolerability profile of toremifene
is similar to that reported for tamoxifen, the most common adverse
effects being hot flushes, sweating, nausea and/or vomiting, dizziness,
oedema, and vaginal discharge and/or bleeding. Thus, toremifene
provides an equally effective and well tolerated alternative to
tamoxifen for the first-line endocrine therapy of postmenopausal
advanced breast cancer. Preclinical studies showing toremifene
to have a lower carcinogenic potential than tamoxifen indicate
that toremifene may be a preferable agent for long term treatment
regimens; however, these findings require confirmation in the
clinical setting.
Oncology (Huntingt). 1997 May;11(5 Suppl 4):19-22.
Phase I and II studies of toremifene.
Hamm JT.
University of Louisville Alliant Health Systems, Kentucky, USA.
Toremifene (Fareston) is a triphenylethylene derivative structurally
similar to tamoxifen (Nolvadex) that was selected for development
based on its in vitro activity against breast cancer and its lesser
uterotrophic effect than tamoxifen in rat models. In phase I and
II studies conducted in several countries, toremifene was well
tolerated over a wide range of doses (10 to 680 mg/d). The major
side effects were hot flashes, nausea, and vomiting. Toremifene's
excretion half-life is 5 days. It produces a modest decline in
serum levels of luteinizing hormone, follicle-stimulating hormone,
and antithrombin III, as well as an increase in sex hormone-binding
globulin levels. In studies in which toremifene was used as first-line
therapy in patients with estrogen receptor (ER)-positive or ER-unknown
tumors, response rates to doses of 40 to 60 mg/day ranged from
30% to 54%. In two larger studies of patients who had proved refractory
to tamoxifen therapy, toremifene produced an objective response
rate of 4% to 5%. When patients with stable disease were added
to those with objective responses, 27% to 28% of patients were
considered to derive clinical benefit from toremifene. The dose
range chosen for further study was 40 to 60 mg/d.
Vopr Onkol. 1996;42(5):105-9.
Hormone therapy of advanced renal cancer with high-dose toremifene
(Fareston).
Gershanovich ML, Moiseenko VM, Vorob'ev AV, Kiapiulia K.
oremifene (Fareston)-a novel antiestrogenic drug with a triphenylethylene
structure-has been effective in the treatment of postmenopausal
breast cancer patients. It is safely administered even in high
doses up to 300 mg/day. The purpose of the study was to investigate
the effect and tolerability of high dose toremifene in the treatment
of patients with advanced renal cell carcinoma (RCC). Thirty six
patients started the treatment with toremifene 300 mg/day. There
were 26 males and 10 females. Mean age was 56.0 years, range 35-75
years. Nineteen patients were nephrectomized. One patient was
not evaluable for response because of too short treatment time.
The response rate was 17.1%, including 1 CR (2.9%) lasting for
121 + weeks and 5 PR (14.3%) with the mean duration of 39.8 +
weeks. Ten cases of NC (28.6%) had the mean duration of 23.7 weeks.
There were no significant differences in response rate when patients
with lung metastases only were compared to patients with metastases
of other sites with or without lung metastases. Total pain control
was achieved in 45% and partial control in 20% of those patients
who had pains in the beginning of the treatment. Ten patients
(27.8%) had adverse reactions which led to discontinuation of
the treatment in one case. It can be concluded that high-dose
toremifene is an effective and safe means of palliative treatment
in advanced RCC.
