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PubMed2003

Chronic effects of toremifene on the vasculature of menopause-induced rats.

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.

Animals↗
PubMed1999

In vitro evaluation of biodegradable epsilon-caprolactone-co-D, L-lactide/silica xerogel composites containing toremifene citrate.

Poly(epsilon-caprolactone-co-D,L-lactide) polymers were blended with toremifene citrate or with toremifene citrate impregnated silica xerogel in order to develop a controlled release formulation. The copolymers were synthesized by bulk polymerization and characterized by nuclear magnetic resonance, size exclusion chromatography and differential scanning calorimetry analyses. The in vitro release of toremifene citrate, an antiestrogenic compound, and silica was carried out in simulated body fluid (pH 7.4) containing 0.5 wt% sodium dodecylsulphate at 34 degrees C. The in vitro release studies indicate that the release flux of toremifene citrate increases with increasing weight fraction of caprolactone in the copolymer. Silica xerogel had a minor enhancing effect on the release rate of toremifene citrate. Copolymers containing larger amounts of D,L-lactide (PLA-CL20 and PLA-CL40 copolymers) were not suitable matrices for the delivery of toremifene citrate in a controlled manner because of the burst effect. The fraction of toremifene citrate released from PLA-CL80 matrix increased with the increasing loading of toremifene citrate. The results of the study indicate that the in vitro release of toremifene citrate can be adjusted by varying the polymer composition and also the initial drug loading.

Antineoplastic Agents, Hormonal↗
PubMed1998

Comparison of effects of tamoxifen and toremifene on bone biochemistry and bone mineral density in postmenopausal breast cancer patients.

Antiestrogens are used in the treatment, and sometimes even in the prophylaxis, of breast cancer. Tamoxifen is the most commonly used antiestrogen, but toremifene is gaining in popularity. We compared here the effects of tamoxifen and toremifene on bone metabolism and density in 30 postmenopausal patients with breast cancer, who were randomized to receive tamoxifen (20 mg/day, n = 16) or toremifene (40 mg/day, n = 14) for 1 yr. Biochemical markers of bone resorption [urinary hydroxyproline, serum cross-linked carboxyterminal telopeptide of type I collagen, urinary cross-linked aminoterminal telopeptide of type I collagen (NTx)] and bone formation [serum bone-specific alkaline phosphatase, osteocalcin, and aminoterminal and carboxyterminal propeptide of type I procollagen] were assessed before treatment and at 6 and 12 months of the antiestrogen regimen. Bone mineral density (BMD) in the lumbar spine and proximal femur (neck, trochanter, and Ward's triangle) was measured using dual-energy x-ray absorptiometry before treatment and at 12 months of treatment. Urinary NTx decreased after 6 months' use of tamoxifen (mean fall: 33%) and of toremifene (mean fall: 16%). Use of tamoxifen was associated with a significant decrease in osteocalcin (mean fall: 25%) and aminoterminal propeptide of type I procollagen (mean fall: 22%), whereas toremifene failed to influence these markers. Tamoxifen increased BMD, on average, by 2% in the lumbar spine, 1% in the femoral neck, and 5% in Ward's triangle. Toremifene failed to increase BMD at any site measured, and in contrast, a slight trend toward a fall (-0.3 to -0.9%) in BMD was seen in patients treated with toremifene. Falls in urinary NTx, from baseline to 6 months, correlated significantly with changes in the lumbar spine BMD (r = -0.57, P = 0.0002) in the whole patient series. We conclude that tamoxifen (20 mg/day) increases BMD in postmenopausal breast cancer patients, whereas toremifene (40 mg/day) merely prevents the increasing age-associated fall in BMD. More prolonged studies on bone metabolism, comparing these two antiestrogens, are needed; but even now, clinicians should be aware of these differences between tamoxifen and toremifene.

Aged↗
PubMed2002

99mTc-sestamibi imaging in the assessment of toremifene as a modulator of multidrug resistance in patients with breast cancer.

UNLABELLED: Multidrug resistance (MDR) due to expression of a membrane-associated permeability glycoprotein (P-glycoprotein [Pgp]) prevents successful cytotoxic chemotherapy for breast cancer. Identification of MDR would facilitate selection of chemotherapy regimens and MDR modulators. This study aimed to evaluate (99m)Tc-sestamibi imaging for predicting overexpression of Pgp in primary breast cancer and to measure the efficacy of toremifene, the MDR modulator, in vivo. METHODS: Twenty patients with untreated breast cancer had (99m)Tc-sestamibi imaging 20 and 120 min after tracer injection before and after a 3-d course of toremifene (780 mg/d). Tumor samples were obtained during surgery for correlation of imaging and Pgp immunohistochemistry. RESULTS: Sixteen of 20 tumors were visualized with sestamibi. Before toremifene, there was a significant inverse correlation (Spearman rank correlation coefficient [R(S)]) between staining intensity, based on the anti-Pgp monoclonal antibodies C494 and C219, and the tumor-to-background ratio (T/B) at 120 min (R(S) = -0.85; P < 0.001 and R(S) = -0.71; P < 0.001, respectively). However, the correlation between the T/B and immunohistochemistry at 20 min was significant only for C494 (R(S) = -0.57; P < 0.01). Similarly, before toremifene, there was an inverse correlation between staining intensity and the change in the T/B between 20 and 120 min (R(S) = -0.77; P < 0.001 and -0.75; P < 0.001 for C494 and C219). After toremifene, an inverse correlation between staining intensity and the T/B was seen only at 120 min and only with C494 (R(S) = -0.68; P < 0.01). However, the change in the T/B between 20 and 120 min correlated significantly with staining intensity for C494 and C219 (R(S) = -0.68; P < 0.01 and -0.7; P < 0.01 for C494 and C219, respectively). Toremifene did not significantly alter the overall T/B at either 20 or 120 min when data were compared before and after toremifene. Nevertheless, at 120 min, 8 of 8 tumors with low Pgp expression showed reduced uptake after toremifene, whereas 5 of 6 tumors with strong expression showed increased uptake (P < 0.003). Moreover, there was a significant correlation between the change in the T/B and staining intensity with C494 (R(S) = 0.59; P < 0.05) and C219 (R(S) = 0.56; P < 0.05) at 120 min but not at 20 min. CONCLUSION: (99m)Tc-Sestamibi accumulation in breast cancer correlates with Pgp expression. Toremifene has a dual effect on this accumulation, increasing it through an inhibitory effect on Pgp while at the same time reducing it by a direct competition with sestamibi. The latter implies that in response to Pgp modulation the efflux of various agents may be affected differently.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1998

Adjuvant trials of toremifene vs tamoxifen: the European experience.

When results from the phase II trials of toremifene (Fareston) and tamoxifen (Nolvadex) in metastatic breast cancer were published, the Finnish Breast Cancer Group began to plan the first trial of toremifene in an adjuvant setting. This multicenter, randomized trial is comparing toremifene (40 mg/d) to tamoxifen (20 mg/d) in postmenopausal lymph node-positive breast cancer patients. Treatment duration is 3 years. About 1,150 of a planned 1,460 patients have been enrolled to date. The International Breast Cancer Study Group is also conducting two adjuvant trials evaluating 5 years of toremifene (60 mg/d) vs tamoxifen (20 mg/d). More than 1,000 patients have been enrolled in these studies to date. The efficacy of toremifene is being explored in all of these trials. In the Finnish trial, additional protocols are evaluating treatment side effects, including the formation of DNA adducts in the endometrium and leukocytes, certain ocular problems, thromboembolic events, and subjective side effects. The effects of toremifene on lipid levels and bone density are also being studied. An interim safety analysis, performed in the Finnish study after 500 patients were enrolled (mean follow-up, 18 months), showed no significant differences between toremifene and tamoxifen in terms of efficacy or side effects. Toremifene seems to be well tolerated and may have additional positive effects. Ongoing trials will soon reveal how beneficial toremifene is in the adjuvant setting and whether it is devoid of the adverse effects observed with tamoxifen.

Antineoplastic Agents, Hormonal↗
PubMed1993

Targeting chemosensitizing doses of toremifene based on protein binding.

Toremifene is currently being evaluated as a chemosensitizing agent in doxorubicin-resistant patients. Although concentrations of > 2 microM reverse resistance in vitro, target concentrations required to reverse multidrug resistance (MDR) in vivo may be highly influenced by variables such as protein binding in serum. We examined the effects of high serum concentrations on the cellular accumulation of toremifene in an MDR MDA-MB-A-1 human breast-cancer cell line. We then examined the cellular accumulation of doxorubicin at various toremifene concentrations in 5% - 100% serum. We also measured the concentrations of toremifene and its major metabolites in plasma specimens obtained from two patients receiving 360 mg/day for 5 days in a phase I study. Our results show that (1) high serum concentrations decrease toremifene accumulation, (2) toremifene concentrations of < or = 2.5 microM enhance doxorubicin accumulation, and (3) patients achieve plasma toremifene concentrations of 10-15 microM following doses of 360 mg/day x 5 days. Our findings suggest that in vivo toremifene concentrations well above those used to reverse resistance in vitro are required to overcome the effect of high serum-protein binding.

Blood Proteins↗
PubMed1993

Topical toremifene: a new approach for cutaneous melanoma?

The distribution of topically applied toremifene (0.5-1 mg/day for 5 days) in the ultraviolet B (UVB)-induced Monodelphis domestica opossum melanoma model was examined. The mean concentration of toremifene measured in the skin was 1200 nmol/g, or > 500 times that detected in any other tissues (blood, brain, liver, testicles, heart, uterus, eyes). In plasma, toremifene could be detected in only one animal of six (0.04 nmol/ml). Intraperitoneal administration of 0.5 mg toremifene daily for 5 days in three female animals resulted in a mean uterus concentration of 22.9 nmol/g, or 400-fold that achieved by topical administration of 0.5 mg/day in three other female Monodelphis (0.05 nmol/g). The cytostatic effect of toremifene was studied in three human melanoma cell lines and three experimental cell lines derived from UVB-induced melanocytic nevi in M. domestica. Toremifene had a cytostatic effect on all cell lines (50% growth-inhibitory concentrations, 5.8-9.6 microM). Topical toremifene administration yields high local concentration with minimal systemic distribution. In addition, toremifene has a cytostatic effect at achievable concentrations in a variety of melanomatous cell lines.

Administration, Topical↗
PubMed1998

Endocrine mechanism of action of toremifene at the level of the central nervous system in advanced breast cancer patients.

PURPOSE: To differentiate the antagonistic and agonistic effect of toremifene at the level of the hypothalamus-hypophysis axis a leutinizing hormone-releasing hormone (LHRH) test was performed during a phase II clinical trial. METHODS: In 15 postmenopausal patients with advanced breast cancer, follicle-stimulating hormone (FSH) and LH release--induced by an LHRH agonist (Suprefact injection, 0.5 mg s.c.)--was monitored during a 16-week period of toremifene treatment (60 mg/day p.o.). Prolactin, estradiol, and sex hormone-binding globulin (SHBG) levels were also measured. The functional test was carried out prior to toremifene therapy and then 4, 8, 12, and 16 weeks afterward. RESULTS: The drug sensitized the pituitary to the action of the gonadotrophins; the LHRH-induced FSH and LH release showed a considerably increasing tendency during the toremifene therapy. Estradiol levels decreased statistically significantly and SHBG levels showed a statistically significant increase. A decreased level of prolactin is the sign of an antiestrogenic effect of toremifene on the hypophysis and, as a result, provides evidence for a direct influence of toremifene upon the pituitary. An increase in LH and prolactin release in response to the LHRH test was characteristic in the responders. CONCLUSION: According to the LHRH test, the antagonistic effect of toremifene seems to be more dominant than the concomitantly existing agonistic property. Neither clinical nor endocrinological side effects could be observed at the level of the CNS during a prolonged period of toremifene administration.

Antineoplastic Agents, Hormonal↗
PubMed2005

Bone mineral density and lipid changes during 5 years of follow-up in a study of prevention of breast cancer with toremifene in healthy, high-risk pre- and post-menopausal women.

A double-blind, randomised, placebo-controlled pilot study was initiated to evaluate the feasibility of chemoprevention with toremifene 60 mg/day in healthy women at high risk for breast cancer. Enrolment in the study was terminated earlier than planned because of slow patient accrual, although 13% of patients continued for 5 years. The revised efficacy outcomes were change in bone mineral density (BMD) from baseline at four skeletal sites, plus effects on serum lipids. In premenopausal women there was a trend for sustained increase in BMD during toremifene therapy after year 1 in lumbar spine. In postmenopausal women, toremifene had little or no effect on BMD trends. Levels of total and low-density lipoprotein (LDL) cholesterol were largely unchanged from baseline in premenopausal women treated with toremifene but were often slightly lower than in the placebo group during follow-up. Total and LDL cholesterol levels declined slightly from baseline in the postmenopausal women and were, at several points during the first 3 years, significantly lower than in the corresponding placebo group (p < 0.01). We conclude that: (a) assessment of toremifene 60 mg/day in chemoprevention will require further clinical trials; (b) toremifene 60 mg/day has no substantive negative effects on BMD in pre- or postmenopausal women and may exert a minor favourable influence (in particular, the effects of toremifene 60 mg/day on BMD in premenopausal women may make the drug an attractive alternative to tamoxifen 20 mg/day for that patient subset); (c) lipid effects of toremifene 60 mg/day are, at minimum, neutral and may be modestly favourable for reducing cardiovascular risk.

Adult↗
PubMed2003

Ocular side-effects in breast cancer patients treated with tamoxifen and toremifene: a randomized follow-up study.

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.

Aged↗
PubMed1994

Circumvention of daunorubicin resistance by a new tamoxifen derivative, toremifene, in multidrug-resistant cell line.

The reversing effect of toremifene, a new tamoxifen derivative, on multidrug resistance in a K562 subline and its mechanism were studied. K562 cells were cultured in serially increasing concentrations up to 1.0 microM daunorubicin (DNR), and were found to be 28 times more resistant to DNR in comparison to the parent cells. In the resistant cell line (K562/D1-9), intracellular accumulation of DNR was less than that of the parent cell line, and P-glycoprotein was overexpressed. The resistance was reversed by addition of toremifene in a dose-dependent manner in K562/D1-9, while toremifene had no effect in K562. DNR accumulation was also reversed by toremifene in K562/D1-9, but not in K562. However, there was no significant difference of toremifene retention between K562/D1-9 and K562, and neither verapamil nor DNR increased toremifene accumulation in K562/D1-9. Moreover, toremifene and verapamil did not show an additive effect on intracellular DNR accumulation. These results suggested that the reversing mechanism of toremifene is different from that of verapamil, and this compound could be a good candidate for overcoming multidrug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Antiatherogenic effects of adjuvant antiestrogens: a randomized trial comparing the effects of tamoxifen and toremifene on plasma lipid levels in postmenopausal women with node-positive breast cancer.

PURPOSE: To evaluate whether a novel antiestrogen, toremifene, has similar antiatherogenic effects as tamoxifen. PATIENTS AND METHODS: Forty-nine postmenopausal patients with node-positive breast cancer were randomized in a trial that compared the effects of tamoxifen and toremifene on serum lipoproteins. Tamoxifen was given at 20 mg and toremifene at 60 mg orally per day for 3 years. Serum concentrations of apolipoprotein (apo) A-I, A-II, and B, and lipoprotein(a) [Lp(a)], cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol were measured before and after 12 months of antiestrogen therapy. RESULTS: Both antiestrogens significantly reduced serum total and LDL cholesterol and apo B levels. However, the response of HDL cholesterol to treatments was clearly different between the groups. Toremifene increased the HDL level by 14%, whereas tamoxifen decreased it by 5% (P = .001). As a consequence, both cholesterol-to-HDL and LDL-to-HDL ratios decreased more in the toremifene than tamoxifen group (P = .008 and P = .03, respectively). Toremifene also increased the apo A-I level (P = .00007) and apo A-I-to-A-II ratio (P = .018). Both tamoxifen and toremifene decreased the Lp(a) concentration significantly (change, 34% v 41%). CONCLUSION: These results provide positive evidence that toremifene has antiatherogenic properties with potency to improve all lipoproteins that are associated with increased coronary heart disease (CHD) risk.

Antineoplastic Agents, Hormonal↗
PubMed2000

Safety and efficacy results of a randomized trial comparing adjuvant toremifene and tamoxifen in postmenopausal patients with node-positive breast cancer. Finnish Breast Cancer Group.

PURPOSE: In this multicenter trial, toremifene 40 mg/d was compared with tamoxifen 20 mg/d, both given orally for 3 years to postmenopausal, axillary node-positive women after breast surgery. PATIENTS AND METHODS: The first 899 patients (toremifene, n = 459; tamoxifen, n = 440) of the total of 1,480 patients accrued to the trial were included in this scheduled safety analysis. The mean follow-up time was 3.4 years. RESULTS: The two treatment groups were well balanced with respect to patient and disease characteristics. The subjective side-effect profile was similar in both treatment groups. Slightly more vascular complications (deep vein thromboses, cerebrovascular events, and pulmonary embolisms) were seen among tamoxifen-treated patients (5.9%) as compared with toremifene-treated patients (3.5%) (P: =.11), whereas bone fractures (P: =.09) and vaginal leukorrhea (P: =.05) were more common in the toremifene group. The number of subsequent second cancers was similar. The breast cancer recurrence rate was 23.1% (n = 106) in the toremifene group and 26.1% (n = 115) in the tamoxifen group (P: =.31). When only patients with estrogen receptor (ER)-positive cancer were considered (n = 556), the risk for breast cancer recurrence was nonsignificantly lower among the toremifene-treated women, with a hazards ratio of 0.74 (90% confidence interval, 0.52 to 1.04; P: =.14). The mean time to breast cancer recurrence and overall survival were similar in both groups. CONCLUSION: The side-effect profile of toremifene resembles that of tamoxifen. The efficacy of toremifene seems to be no less than that of tamoxifen. The trend for fewer breast cancer recurrences in the ER-positive subgroup is encouraging, but a longer follow-up is needed to confirm this.

Antineoplastic Agents, Hormonal↗
PubMed1997

Toremifene. A review of its pharmacological properties and clinical efficacy in the management of advanced breast cancer.

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.

Animals↗
PubMed1998

Genotoxicity studies with the antiestrogen toremifene.

Toremifene, a second-generation triphenylethylene antiestrogen used clinically in the chemotherapy of breast cancer and some other cancers, differs in its nonclinical toxicology from its first-generation congener tamoxifen. Tamoxifen produces DNA adducts and tumors in rat liver, whereas assays for DNA adduct formation with toremifene have been negative to weakly positive, and toremifene does not produce liver tumors in rats. To evaluate further toremifene for possible genotoxicity, it was tested in three standard, in vitro assay--reversion of bacterial point mutations, unscheduled DNA synthesis in cultured hepatocytes from two rat strains, and cytogenetics of human lymphocytes in primary culture--and in one in vivo assay, the mouse, erythrocyte micronucleus assay. The three in vitro assays were conducted with toremifene at up to the limit of cytotoxicity (100 to 250 micrograms/ml, depending on the system). The bacterial mutagenicity and lymphocyte chromosome aberration assays were performed both in the presence and absence of metabolic activation by Araclor-induced, rat liver S-9, while the hepatocyte unscheduled DNA synthesis assay provides intrinsic bioactivation. To test for chromosome damage in vivo, mice were administered up to 2g/kg toremifene once by gavage, and bone marrow was harvested daily, for three days. Normochromatic and polychromatic bone marrow erythrocytes were examined for micronuclei. Toremifene lacked genotoxicity or myelotoxicity detectable by any of the above assays. These findings, together with the reported absence of DNA binding in rat liver, provide evidence that toremifene is not genotoxic.

Animals↗
PubMed2000

Toremifene-induced fatty liver and NASH in breast cancer patients with breast-conservation treatment.

We have described fatty liver, diagnosed by computed tomography scanning (CT) in more than 30% of patients with breast cancer who received tamoxifen. Therefore, it is urgent to elucidate the frequency and the degree of fatty liver induced by toremifene, an analogue of tamoxifen, which is also used in breast cancer. We enrolled 52 breast cancer patients who were treated with breast-conservation treatment and administered oral toremifene for 3-5 years as adjuvant endocrine therapy. We evaluated the degree of fatty liver by abdominal CT performed annually. CT demonstrated toremifene-induced fatty liver in four (7.7%) of 52 breast cancer patients. Toremifene-induced fatty liver did not correlate with abnormal levels of AST, ALT, GGT or total cholesterol. One patient who demonstrated moderate fatty liver by CT was histologically diagnosed as non-alcoholic steatohepatitis (NASH) by liver biopsy. The incidence of toremifene-induced fatty liver was significantly lower than that induced by tamoxifen. Accordingly, in terms of fatty liver and NASH, toremifene is considered to be more appropriate agent than tamoxifen. Though toremifene is less likely to induce fatty liver, the possibility remains that toremifene-induced steatohepatitis occurs. Because the diagnosis of fatty liver or NASH can be easily missed if only a blood test is performed, it is necessary to screen fatty liver by annual CT examination for patients who receive an antiestrogen agent.

Alanine Transaminase↗
PubMedDate not supplied

Toremifene as a substitute for adjuvant tamoxifen in breast cancer patients.

BACKGROUND: Toremifene is a new antiestrogen, which in nonclinical studies appears less carcinogenic than tamoxifen. Clinical trials of adjuvant toremifene vs. tamoxifen in breast cancer patients are ongoing. This study aimed to evaluate the short-term effects of changing from adjuvant tamoxifen to toremifene. PATIENTS AND METHODS: Twenty postmenopausal breast cancer patients receiving adjuvant tamoxifen, 20 mg/day, were switched to toremifene 60 mg/day. The effects on the uterus were evaluated prospectively by transvaginal ultrasound; tolerability was assessed clinically. RESULTS: In 14 patients who had uterine abnormalities (endometrial thickening or polyps) under tamoxifen, no significant changes occurred during a median of 18 months (range 7-24) of toremifene treatment. Out of six patients who had entered the study due to intolerance to tamoxifen, however, 3 tolerated toremifene well. CONCLUSION: Toremifene does not modify previous uterine changes induced by tamoxifen. For some patients who do not tolerate tamoxifen, however, switching to toremifene may allow the continuation of adjuvant antiestrogenic therapy.

Aged↗
PubMed2004

[Activity of toremifene plus mitomycin, vindesin and cisplatin regimen in unresectable non-small cell lung cancer].

OBJECTIVE: To investigate the activity and clinical efficacy of toremifene plus mitomycin, vindesin and cisplatin regimen (MVP) in non-small cell lung cancer (NSCLC). METHODS: A549 cells were seeded into 96 wells at the concentration of 10 x 10(4)cells/well and exposed to different agents. Seventy-two hours later, the cytotoxicity of the agents were evaluated with the method of MTT. The clinical trial included 63 patients with chemtherapy-naive NSCLC and 30 patients who had received chemotherapy (Pre-treatment arm). The chemotherapy-naive patients were randomly divided into the toremifene-treatment arm and the control arm. Each patient was given MVP chemotherapy. Five days before the chemotherapy, those in the toremifene-treatment group and pre-treatment arm started toremifene 420 mg daily orally for 7 days. The response was evaluated after two cycles of chemotherapy and toxic side effects and the survival of the patients were followed up. RESULTS: Toremifene decreased the IC(50) of chemotherapeutic agents and increased their cytotoxicity. In the clinical trial, the response rate and median survival were 47% and 11 months in the toremifene-treatment arm and 32% and 9 months in the control arm, respectively. The difference between the two arms was not significant. The response rate and median survival were 17% and 7 months in the pre-treatment arm, respectively. The toxicity among the three groups was not significantly different. CONCLUSIONS: Toremifene can improve the cytotoxicity of cisplatin, mitomycin and vindesin. Toremifene plus MVP regimen is safe and effective in the treatment of NSCLC.

Aged↗