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PubMed2001

Comparisons of the effects of tamoxifen, toremifene and raloxifene on enzyme induction and gene expression in the ovariectomised rat uterus.

This study compares the actions of oestradiol, tamoxifen, toremifene and raloxifene on enzyme and gene expression in uterine tissues of ovariectomised rats over 72 h. The time-course for the induction of ornithine decarboxylase by the compounds showed a rapid biphasic response, while for creatine kinase brain type (BB) there was a continued increase over 72 h. The efficacy of induction showed that, with both markers, oestradiol gave the highest induction level, followed by tamoxifen or toremifene and then raloxifene. RT-PCR demonstrated that all compounds decreased oestrogen receptor (ER) alpha, ERbeta and ERbeta2 gene expression, 8-24 h after the first dose, suggesting that down-regulation of ER is not the primary cause of the difference in efficacy between these compounds. Using cDNA arrays, expression of 512 genes was examined in the uteri of oestradiol- or tamoxifen-treated rats. Both compounds resulted in the up-regulation of heat-shock protein 27, telomerase-associated protein 1 and secretin. However, most surprising was the marked down-regulation of Wilms' tumour and retinoblastoma genes. We speculate that this may result in a loss of regulation of the transition from the G1 to the S phase in the cell cycle and may make cells more vulnerable to the carcinogenic effects of tamoxifen in this tissue.

Animals↗
PubMedDate not supplied

Down-regulation of nitric oxide production by droloxifene and toremifene in human breast cancer cells.

We investigated the effect of tamoxifen, 4-OH tamoxifen, toremifene droloxifene, interferon-alpha2a, interferon-alpha2b and interferon-alpha2c, singly and in combination, for their effect on nitric oxide production by MCF-7 and ZR-75-1 human breast cancer cells. Tamoxifen and 4-OH tamoxifen singly had no effect on nitric oxide production by either cell line. However, treatment with droloxifene or toremifene significantly reduced nitric oxide production by both MCF-7 and ZR-75-1 human breast cancer cell lines. Combination treatment with anti-estrogens and interferon-alpha2a interferon-alpha2b or interferon-alpha2c had no synergistic or additive effect compared to each drug singly.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Antiestrogenic treatment of advanced and recurrent carcinoma corporis uteri--a phase II study of toremifene.

The antitumor efficacy and toxicity of a new anti-estrogenic substance--toremifene--were investigated in a phase II study. Twenty-six patients were eligible for final evaluation (6 primary and 20 recurrent disease). A daily dose of 200 mg toremifene was given orally. Treatment continued for at least 3 months, until progression or significant side-effects were encountered. The response rate was 35% (3 CR and 6 PR). Six patients had NC and 11 did not respond to the treatment. The median duration of responses for CR was 10+ months (range 3(+)-19) and for PR 4 months (range 3(+)-16). The treatment seems to be well tolerated and effective.

Aged↗
PubMed1995

Influence of different combinations of tamoxifen and toremifene on estrogen receptor-positive breast cancer cell lines.

Acquired tamoxifen (TAM) resistance is supposed to be the major cause of hormone therapy failure in estrogen receptor (ER)-positive breast cancer patients. Toremifene (TOR), a chlorinated TAM-related compound, has been found to be more effective and less toxic than TAM. Moreover 4-hydroxy-toremifene (OH-TOR), like 4-hydroxy-tamoxifen (OH-TAM), is the most effective metabolite in human. To better understand the relative role of TAM, TOR, OH-TAM, and OH-TOR, singly or in combination, we studied their effect on MCF7, ZR-75.1, and T47D cell lines, which, despite their positive receptor status, have a different responsiveness to estradiol and antiestrogenic compounds. The results may be summarized as follows; in MCF7 cells, all compounds, singly or in association, showed an inhibitory effect; ZR75.1 cells were resistance to TAM and OH-TAM, but partially sensitive to TOR and OH-TOR; in T47D cells, all compounds displayed their estrogenic activity and induced cell growth. These result suggest the inefficacy of these triphenylethylene derivatives as a hormone treatment even when given in a simultaneous or sequential combination.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Chemoprevention of MNU-induced mammary tumorigenesis by hormone response modifiers: toremifene, RU 16117, tamoxifen, aminoglutethimide and progesterone.

The effects of structurally different antiestrogens, progesterone and the aromatase inhibitor aminoglutethimide, were evaluated for chemopreventive activity in the N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis model. Treatment with either RU 16117, progesterone or aminoglutethimide resulted in a significant decrease in cancer multiplicity [> or = 50%; P < .05] when administered individually at doses 80% of the maximally tolerated dose [MID]. Toremifene was also remarkably effective in inhibiting MNU-induced mammary tumorigenesis although this inhibition was achieved at a dose which caused a significant decrease in body weight gain. Aminoglutethimide, RU 16117 and toremifene citrate, in addition to their effects on tumor multiplicity, caused significant increases in the latency period for tumor development. Combinations of aminoglutethimide, progesterone and/or a suboptimal dose of tamoxifen citrate also proved to be effective in inhibiting the development of MNU-induced mammary cancers; however, the combination regimen was no more effective than either aminoglutethimide or progesterone administered alone. These results suggested that agents altering the hormonal environment, regardless of their mechanism of action, may provide protection against the development of hormone responsive mammary cancer.

Aminoglutethimide↗
PubMed1993

Effect of Toremifene in patients with metastatic melanoma: a phase II study of the EORTC Melanoma Cooperative Group.

The EORTC Melanoma Cooperative Group conducted a phase II trial (study number 18891) to study the effect of Toremifene in 45 patients with advanced, metastatic melanoma. Male and female patients, median age 61 (range 23-88) years received a mean total dose of 11 g (4.3-62.6) orally for at least 6 weeks. No objective remissions were seen. Four patients (3 women and 1 man; 9%) experienced 3-6 months' disease stabilization. The toxicity of the drug, given at a dose of 240 mg daily, was negligible. Because of the minimal side-effects, Toremifene may be recommended for patients who have only a small number of slowly growing metastases, in particular to soft tissue and lung.

Adult↗
PubMedDate not supplied

The effect of toremifene on the expression of genes in a rat mammary adenocarcinoma.

Toremifene, apart from its partial estrogen antagonism, exerts multiple and varied effects on a variety of genes involved in the control of signalling and apoptosis. After three weeks of exposure of R3230AC hosting rats to therapeutical oral doses of toremifene distinct changes in steroid receptors, P-glycoprotein, p53 and Bc1-2 expression and protein S100 levels occurred, which may contribute to our understanding of the mechanisms of action of this antiestrogen.

Adenocarcinoma↗
PubMed1997

Open phase II study of high-dose toremifene as first-line therapy for advanced breast cancer.

In an open phase II study conducted in Finland and Latvia, 73 postmenopausal women were treated with 240 mg of toremifene (Fareston) as first-line therapy for advanced breast cancer. Among the 56 patients evaluable for responses, 59% achieved objective responses [complete response (CR) plus partial response (PR)], 29% showed no change (NC), and 12% had progressive disease (PD). When all treated patients were included, the objective response rate was 47%. Several very long durations of responses up to 86 months and survival durations up to 95 months were observed. In assessable patients, the best objective response rates were seen in those with soft-tissue (74%) and visceral (60%) disease. In 54% of patients with very large inoperable primary cancers, a PR was achieved. Half of patients reported side effects, about 60% of which were mild; 30%, moderate; and 5%, severe. Based on response rate and safety, high-dose toremifene is useful as first-line therapy for advanced breast cancer.

Adult↗
PubMed1998

[Toremifene sensitized the effect of adriamycin on human breast cancer cell lines].

A experimental study was reported here to clarify the chemosensitizing effect of Toremifene (Tor) on human breast cancer cell lines. MCF7, estrogen dependent adriamycin (ADM) resistant cell, and MDA-MB231, estrogen independent cell, were preincubated for 8 hours with Tor 0, 4 or 10 microM, then with ADM 0-10 micrograms/ml for one hour. After that, cells were cultured for 24 hours, and their cell cycle and growth were analyzed with flow-cytometry and MTT assay, respectively. Furthermore, the ADM concentrations of these cells were measured by high-performance liquid chromatographic assay (HPLC). Although flowcytometric analysis showed the enhancement of Gz block only in MCF7 at the ADM concentration with 5 micrograms/ml, the sensitizing effect was revealed by MTT assay, and the elevation of ADM concentration was found in HPLC assay in both cells. The chemosensitizing effect of Toremifene was observed in estrogen dependent and independent cell lines.

Antibiotics, Antineoplastic↗
PubMed1997

17beta-estradiol, diethylstilbestrol, tamoxifen, toremifene and ICI 164,384 induce morphological transformation and aneuploidy in cultured Syrian hamster embryo cells.

To examine the ability of estrogens and anti-estrogens to induce cellular transformation and genetic effects, Syrian hamster embryo (SHE) cells were treated with estrogens, 17beta-estradiol (E2) or diethylstilbestrol (DES), or with anti-estrogens, tamoxifen (TAM), toremifene (TOR) or ICI 164,384. Treatment with each substance for 1-3 days suppressed cellular growth in a dose-dependent manner. Colony-forming efficiency (CFE) increased following treatment of cells with E2 or DES for 48 hr at 3 or 10 microM but decreased at 20 or 30 microM. In contrast, CFE was increased by treatment with TAM, TOR or ICI 164,348 over the concentration range examined (1-30 microM). Treatment with each chemical at 1-30 microM for 48 hr caused morphological transformation of SHE cells in a dose-related fashion. The highest frequency was exhibited in SHE cells treated with DES at 20 microM and was 2 times higher than that induced by treatment with benzo[alpha]pyrene (B[alpha]P) at 4 microM. Transformation frequencies induced by other substances (E2, TAM, TOR and ICI 164,348) did not exceed that induced by the B[alpha]P treatment. TOR showed a higher transforming ability over all concentrations examined when compared to the other anti-estrogens (TAM and ICI 164,348). No significant increases in the frequencies of chromosomal aberrations were observed in SHE cells that were treated with any of the chemicals. However, treatment of SHE cells with each chemical induced a dose-dependent increase of aneuploid cells in the near diploid range. Our results indicate that the ability of the estrogens and anti-estrogens to induce numerical chromosomal abnormality may be involved in their cell transformation activity and potential carcinogenicity.

Aneuploidy↗
PubMed2002

Comparison of the effects of EM-652 (SCH57068), tamoxifen, toremifene, droloxifene, idoxifene, GW-5638 and raloxifene on the growth of human ZR-75-1 breast tumors in nude mice.

EM-652 exerts pure antiestrogenic activity in the mammary gland and endometrium, while tamoxifen, the antiestrogen most widely used for the treatment of breast cancer, exerts mixed antiestrogenic-estrogenic activity in these tissues. Our objective was to compare the agonistic and antagonistic effects of EM-652 with tamoxifen and 5 other antiestrogens on the growth of ZR-75-1 human breast xenografts in ovariectomized nude mice. During the 23 weeks of treatment at a daily oral dose of 50 microg, EM-652 was the only compound that decreased tumor size relative to pretreatment values, whereas the 6 other antiestrogens only decreased to various extents the progression rate stimulated by estrone. Under estrone stimulation, all groups of animals had more than 60% of their tumors in the progression category except for the EM-652-treated group, where only 7% of the tumors progressed. In the absence of estrone stimulation, progression was seen in 60%, 33%, 21% and 12% of tumors in the tamoxifen-, idoxifene-, toremifene- and raloxifene-treated groups, respectively, while only 4% of tumors progressed in the EM-652-treated group. The agonistic and antagonistic actions of each antiestrogen were also measured on endometrial epithelial cell thickness. Our present findings indicate that EM-652, in addition to being the most potent antiestrogen on human breast tumor growth, has no agonistic effect in breast and endometrial tissues. Since previous data have shown benefits of EM-652 on bone density and lipid profile, this compound could be an ideal candidate for chemoprevention of breast and uterine cancers, while protecting against osteoporosis and cardiovascular disease.

Animals↗
PubMed1998

Effect of chronic administration of mestranol, tamoxifen, and toremifene on hepatic ploidy in rats.

The nonsteroidal antiestrogen tamoxifen increases the incidence of rat liver cancer through a variety of mechanisms. To compare the effects of tamoxifen (TAM) and a structurally similar analog toremifene (TOR) on rat liver, we determined the ploidy distribution for hepatocytes isolated from rats treated for 18 months with these antiestrogens or the estrogenic compound mestranol (MS). Female Sprague-Dawley rats were subjected to a 70% partial hepatectomy and administered the solvent, trioctanoin, or diethylnitrosamine (10 mg DEN/kg). After a 2-week recovery from the surgery, the rats were administered a basal diet or one containing TAM (250 or 500 ppm), TOR (250, 500, or 750 ppm), or MS (0.2 ppm) for 18 months. Pathologic changes in the liver were examined in the 15-22 rats per treatment group at the 18-month time point. An increased incidence of hepatocellular carcinomas (HCC) was detected in the 500 ppm TAM group, but not with the other treatments that did not include DEN. Both TOR and TAM promoted formation of DEN-initiated HCCs. At sacrifice, four to five rats per group were perfused and the hepatocytes isolated and cultured. Karyotypic analysis was performed on colcemid-blocked cells after 2 days in culture. The hepatic ploidy distribution was characterized in Giemsa-stained metaphase spreads. These studies indicated that chronic treatment with TAM alone resulted in a shift from tetraploid to diploid, as was also observed for rats treated once with DEN. TOR and MS alone did not cause this change in hepatic ploidy at the doses examined. A shift toward an increased content of diploid hepatocytes occurred in all rats treated once with DEN followed by TAM, TOR, or MS. These results indicate that tamoxifen administration results in a shift toward growth of diploid hepatocytes, thus contributing to its carcinogenic action in the rat liver.

Animals↗
PubMed1993

Toremifene and tamoxifen in advanced breast cancer--a double-blind cross-over trial.

Toremifene (TOR) is a triphenylethylene derivative related to tamoxifen (TAM). TOR has antitumor activity, not dependent on estrogen receptors, and responses with TOR have been observed in patients with progressive disease during TAM-treatment. To elucidate possible cross-resistance between these two antiestrogens, we compared their anti-tumor activity in a randomized, double-blind, cross-over study. 66 postmenopausal women with advanced estrogen receptor positive or unknown breast cancer and a median age of 63 years (range 38-82) were included. Patients were randomized to TAM 40 mg/day or TOR 240 mg/day. Treatment continued until progressive disease, when cross-over to the alternative treatment was done. The response rate with first line TOR was 29% (95% confidence limits 10-41%) and with TAM 42% (95% confidence limits 25-61%). Response rates and response durations, survival and toxicity were not significantly different between the two treatments. 44 patients progressing on first line TAM or TOR were evaluable for second line TOR or TAM treatment. As no responses were observed, the possibility of over-looking a response rate of 20% or more is less than 1%. In conclusion, this study strongly indicates that TOR and TAM are clinically cross-resistant in patients with advanced breast cancer.

Adult↗
PubMed1990

A phase I study of toremifene.

A Phase I study of the new antiestrogenic drug toremifene was carried out in 27 Japanese women, using oral doses of 10-480 mg per day for one or five days. Serum concentrations reached a dose-dependent maximum 2-6 hours after each oral administration. Side effects were generally mild.

Administration, Oral↗
PubMed1990

High dose toremifene (240 mg daily) is effective as first line hormonal treatment in advanced breast cancer. An ongoing phase II multicenter Finnish-Latvian cooperative study.

The efficacy of high dose toremifene (240 mg daily) in postmenopausal women with advanced breast cancer is investigated in this ongoing study. At present, 38 patients are fully evaluable. Ten patients have CR (26%), 16 PR (42%) (objective response rate 68%), 8 NC (21%), and 4 PD (11%). Most objective responses are in soft tissue tumors (14/17, 82%). The response rate is equally high in patients with positive or unknown estrogen receptor (ER) status. Median duration of responses and survival are not yet evaluable. Of 48 patients evaluable for side-effects, 22 (46%) experienced some kind of toxicity, which was mild in 64% of cases, moderate in 29%, and mostly of estrogenic type. The study will continue to confirm the results thus far obtained.

Aged↗
PubMed1989

Rats with mammary cancer treated with toremifene and interferon: morphometry and needle aspiration biopsy for determination of ATP and 14C-fluorodeoxyglucose content.

The combined and separate action of the antiestrogen toremifene (TOR) and recombinant rat gamma interferon (RIF) was studied in rat mammary cancer induced by dimethylbenzanthracene (DMBA). The content of ATP and 14C-fluorodeoxyglucose (FDG) was also determined from fine needle aspiration biopsies (FNAB). RIF alone had no antitumor activity, when measured as the average number of new tumors appearing in RIF and control animals (2.4 vs 2.4 new tumors per animal), while TOR and TOR + RIF had a significant effect (1.2, P less than 0.05 and 0.6, P less than 0.01). Morphometrically, there was a significant decrease in the amount of epithelium in the tumors of the RIF + TOR animals (65% vs 82% in the controls, P less than 0.05); there was conversely an increase in the stromal component (25% vs 14%, NS). It appears that an increase of the stromal compartment is part of the healing process. The feasibility of the FNAB-technique was shown by the finding that there was a close correlation between FDG and ATP content in almost all the groups before and after treatment. Thus, FDG and ATP measure the same phenomenon, i.e., energy content. There was a large variation in the contents of ATP and FDG within and among the groups, which invalidated considerations regarding the predictive value of ATP and FDG content in tumors subject to treatment.

Adenosine Triphosphate↗
PubMed1997

Toremifene concentration and multidrug resistance in lung tumors.

In this pharmacokinetics study, concentrations of toremifene (TOR), a new antiestrogen, were measured after a 7-day oral treatment in serum, lung, and tumor tissue to determine the optimal dose of TOR for the modulation of clinical multidrug resistance in patients with lung cancer. Target levels of the antiestrogen were based on previous in vitro studies. Altogether, 18 patients with operable lung tumors were studied. TOR was given in an open, nonrandomized, phase I study at three different dose levels. The medication consisted of oral TOR given for 7 days at either 240, 480, or 600 mg/day before surgical removal of the tumor. At least five patients were scheduled to be included at each dose level, with all five receiving the full course of therapy before escalation of the dose. Blood samples for serum TOR concentration measurements were taken on days 0 and 7. Specimens of tumor and normal lung tissue of approximately 0.5 g were taken on day 7. The concentrations of TOR and its metabolites were determined in serum, lung, and tumor tissue at different dose levels. Altogether, 12 evaluable patients completed the scheduled treatment. The concentrations measured in serum, lung, and tumor tissue increased along with the dose used, such that the highest TOR values were achieved at 600 mg/day, with mean values being 4.9 mumol/l, 175.0 mumol/g, and 122.7 mumol/g, respectively. The concentrations of TOR and its metabolite N-demethyltoremifene were highest in lung tissue, but the values measured in tumor specimens were also well above the respective concentrations detected in serum samples. The TOR doses of 240 and 480 mg/day were well tolerated. One patient in the group treated at 600 mg/day had to discontinue the treatment because of headache and nausea. TOR given at doses ranging from 480 to 600 mg/day for 7 days will produce serum, lung, and tumor concentrations of the parent drug and its metabolites that have been shown to reverse multidrug resistance of cancer cells in vitro. As the 480-mg/day dose of TOR produced tumor concentrations high enough to reverse multidrug resistance without producing adverse drug reactions, the dose recommended for the foreseen clinical trials in the reversal of multidrug resistance would be 480 mg/day for 7 days.

Adult↗
PubMed2004

Effects of toremifene (TOR) and tamoxifen (TAM) on serum lipids in postmenopausal patients with breast cancer.

This study clarified the difference in the effects on serum lipids between toremifene (TOR) and tamoxifen (TAM). To remove influencing factors, we investigated adjuvant therapy for hormone receptor-positive patients with breast cancer without lymph node metastasis. The subjects were 65 patients who were enrolled in a multicenter randomized comparative study between April 1997 and March 2001. As adjuvant therapy, 20 mg of TAM or 40 mg of TOR was administered for 1 year. The levels of triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-1 (Apo A-1), apolipoprotein A(Apo B), and lipoprotein a (Lp(a)) were measured prior to administration and 3, 6, and 12 months after the start of administration. TC, LDL-C, Lp(a) and Apo B significantly decreased from the third month of administration compared with values before the start of administration in both the TOR and TAM groups. HDL-C significantly increased from the third month only in the TOR group. TG significantly increased in the TAM group but significantly decreased in the TOR group in the 12th month of administration. When these two groups were compared, HDL-C was significantly higher (p < 0.01) and TG was significantly lower (p < 0.01) in the TOR group in the 12th month. Improvement of abnormal values of TG, HDL-C and LDL-C was better in the TOR group than in the TAM group after administration for 12 months. The effect on lipid metabolism showed different profiles between the two selective estrogen receptor modulators (SERMs), and TOR gave better results than TAM.

Adult↗