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PubMed2005

K-ras mutation in the endometrium of tamoxifen-treated breast cancer patients, with a comparison of tamoxifen and toremifene.

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.

Adult↗
PubMed1999

In vitro release behavior of toremifene citrate from sol-gel processed sintered silica xerogels.

Factors affecting the adsorption and desorption of toremifene citrate (TC) on sintered silica xerogels were investigated in vitro. TC was attached onto sol-gel processed sintered silica xerogel grains or disks by adsorption. The adsorption of TC on the surface of silica was pH dependent. The results support the conclusion that large pore size results in highest drug adsorption. Adsorption of TC was most effective in xerogels sintered at 700 degrees C and containing the largest pores and lowest specific surface area of the silica xerogels studied in the adsorption tests. The release of TC from the xerogel matrix was linear with respect to the square root of time. The release of TC from the grains was very rapid for the first 5 hr, followed by a slower release. All drug was released from the grains, and 60% to 80% was released from the disks in 24 hr. All drug-silica xerogel formulations showed sustained in vitro release profiles.

Adsorption↗
PubMed2000

Lack of evidence for tamoxifen- and toremifene-DNA adducts in lymphocytes of treated patients.

Tamoxifen (TAM) is used for the adjuvant treatment of women with breast cancer and has also been recommended as a chemopreventive agent. Among unwanted side effects, TAM was shown to increase endometrial cancer in treated women by mechanisms that are not yet clearly understood. We studied DNA adducts in lymphocytes of female breast cancer patients treated with TAM or toremifene (TOR), a TAM analogue and compared them with adducts formed by TAM in rat liver, where the drug induces tumours. DNA adducts were measured by TLC-(32)P-post-labelling assays. After TLC, all DNA samples including DNA from untreated healthy women showed a faint radioactive zone, where the positive control DNA adducts isolated from the liver of rats treated with TAM migrated. The relative adduct levels were calculated from the radioactivity present in this zone. Means +/- SD of adduct levels per 10(8) nucleotides (associated with this area) were for untreated volunteers (control) 1.83 +/- 1.41 (n = 13), for TAM treatment 2.17 +/- 3.04 (n = 25) and for TOR treatment 1.18 +/- 1.05 (n = 8). Most of the human samples were further analysed by HPLC after labelling with (32)P in order to compare adducts in human DNA with those in liver DNA isolated from TAM-treated rats. None of the human samples showed any peaks at retention times where putative TAM-DNA adducts were eluted. In conclusion, lymphocyte DNA from female patients treated at therapeutic levels did not show evidence of the formation of TAM- or TOR-DNA adducts.

Adult↗
PubMed2004

Effects of neonatal exposure to diethylstilbestrol, tamoxifen, and toremifene on the BALB/c mouse mammary gland.

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.

Aging↗
PubMed1998

Intratumoral toremifene therapy and tissue distribution in the baboon.

The purpose of the present study was to evaluate the tissue distribution of toremifene (TOR) in baboons following intra-tissue injections and to examine the effectiveness of intratumoral TOR therapy of baboons with various spontaneous neoplasms. Five healthy baboons (Papio sp.) were used to examine the distribution of TOR following intra-tissue injections. Twenty-three different tissue specimens were collected for HPLC analysis. In addition, four baboons with various spontaneous neoplasms (myxoma, squamous cell carcinoma, lymphosarcoma and adenocarcinoma) were treated with intratumoral TOR and their responses were evaluated. Tissue TOR distribution was also examined in these animals. In the tissue distribution study, target tissue/serum TOR concentration ratios ranged from 138 to 8873 and the target tissue/other tissue ratios ranged from 1.2 to 2428. The distribution of TOR was very favorable, with the highest concentrations outside the injection sites noted in adjacent organs. A marked response was observed in the myxoma and partial responses were observed in the other three cases. Drug level analysis data from these four animals revealed tissue concentrations similar to those seen in the TOR tissue distribution study. Intratumoral administration of TOR can achieve effective local tumor and tissue concentrations, while systemic distribution via circulation to other organs is limited.

Adenocarcinoma↗
PubMed1999

Treatment of mesenteric desmoid tumours with the anti-oestrogenic agent toremifene: case histories and an overview of the literature.

Desmoid tumours are histologically benign but due to their infiltration and compression of surrounding structures potentially life-threatening fibromatous lesions of unknown aetiology. The annual incidence rate is 2-4 per million people. The mesenteric variant constitutes about 10% of all desmoid tumours, although in familial adenomatous polyposis (FAP) patients this may be up to 70%. Due to the small number of patients with mesenteric desmoids the therapy is mainly empirical. This report describes the rationale as well as the value of the short- and long-term treatment (up to 6 years) with the anti-oestrogenic agent toremifene in combination with sulindac in two patients suffering from such a mesenteric desmoid tumour. These patients did not respond to sulindac alone and previous treatment with tamoxifen together with this non-steroidal anti-inflammatory drug had also failed. An overview of the literature on the management of these dismal tumours is presented.

Adult↗
PubMed2002

Inhibitory effects of toremifene on N-methyl-N-nitrosourea and estradiol-17beta-induced endometrial carcinogenesis in mice.

Short- and long-term experiments were designed to determine the effects of toremifene (TOR) on estrogen-related endometrial carcinogenesis in mice. In the short-term experiment, a single low dose of TOR (0.2 mg / 30 g body weight) decreased expression of c-fos, interleukin (IL)-1alpha, estrogen receptor (ER)-alpha mRNAs and corresponding proteins induced by estradiol-17beta (E(2)), in the uteri of the ovariectomized mice. Expression of ER-beta mRNA was increased by the TOR treatment, compared with the control. In the long-term experiment, 106 female ICR mice were given N-methyl-N-nitrosourea (MNU) into their uterine corpora. The animals were divided into four groups as follows: group 1, E(2) diet (5 ppm) plus TOR (0.2 mg / 30 g body weight, subcutaneously, every four weeks); group 2, E(2) diet alone; group 3, basal diet plus TOR. Group 4 served as the control. TOR treatment decreased the incidence of MNU and E(2)-induced endometrial adenocarcinoma and atypical hyperplasia at the termination of the experiment (30 weeks after the start). These results suggest that TOR exerts preventive effects against estrogen-related endometrial carcinogenesis in mice, through the suppression of c-fos as well as IL-1alpha expression induced by E(2). Such suppressive effects of TOR may be related to the decreased ER-alpha and increased ER-beta expressions.

Animals↗
PubMed1991

The effect of toremifene therapy on serum immunoglobulin levels in breast cancer.

Estrogens and anti-estrogens enhance the number of immunoglobulin (Ig)-secreting cells in pokeweed mitogen (PWM)-stimulated lymphocyte cultures. Lymphocytes from patients who have received anti-estrogen therapy show similar enhancement of Ig-secreting cells after PWM stimulation. In this study the effect of anti-estrogen (toremifene) therapy on serum immunoglobulin (IgA, IgM, IgG) levels in breast cancer patients was investigated. Serum Ig levels were followed up to two years after or during the therapy. An unexpected finding was that the Ig levels decreased during the follow-up period. This decrease was seen in patients who responded to the therapy as well as in those who did not.

Aged↗
PubMedDate not supplied

The proliferation in uterine compartments of intact rats of two different strains exposed to high doses of tamoxifen or toremifene.

Uterine Cell proliferation was studied in intact Sprague-Dawley (SD) and Fischer 344 (F344) rats exposed to the antiestrogens tamoxifen (TAM; 5, 10, 20, or 40 mg/kg) and toremifene (TOR: 21.2 or 42.4 mg/kg). The antiestrogens were administered to animals via gavage daily for 2 or 12 wk. Uterine proliferation was assessed using markers for the proliferating cell nuclear antigen (PCNA) and by the bromodeoxyuridine (BrdU) method. Diethylstilbestrol (DES) was used as an estrogenic reference compound. The antiestrogens either reduced or prevented changes of myometrial and stromal proliferation indices (PI). TAM and TOR caused a time-dependent reduction of endometrial glands without an associated decrease in cell proliferation. In the luminal columnar epithelium, the antiestrogens depressed PCNA PI but enhanced BrdU PI, indicating a low continuous DNA synthesis in otherwise quiescent cells. The antiestrogens induced focal hyperplastic multilayered epithelia with PCNA-positive basal cells along segments of the luminal uterine epithelium. We suggest that this hyperplastic epithelium represents remnants from the glandular epithelium. DES was less efficient in inducing these changes but induced squamous metaplasias in the F344 rats. Uterine effects of the 2 antiestrogens were comparable with the exception of I TAM-exposed (40 mg/kg) SD rat that showed squamous metaplasia. F344 rats were more sensitive to the estrogenic action of DES than were the SD rats.

Animals↗
PubMed2005

Human desmoid fibroblasts: matrix metalloproteinases, their inhibitors and modulation by Toremifene.

BACKGROUND: Desmoid tumour is a benign, non metastasising neoplasm characterised by an elevated deposition of organic macromolecules in the extracellular matrix (ECM). The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of ECM macromolecules. The MMPs and their natural inhibitors (TIMPs) have been implicated in tumour growth, invasion and metastasis. In this study we provide evidence that the in vitro cultured cell line from desmoid tumour accumulates more collagen fibres in the ECM than healthy fibroblasts. METHODS: We investigated collagen accumulation by 3H-thymidine incorporation, MMP expression by substrate gel zymography and TIMP expression by Western blot analysis. RESULTS: Desmoid fibroblasts showed a reduction in MMP activity and an increase of type I and III collagen and TIMPs compared to normal fibroblasts. CONCLUSION: The increase in collagen in desmoid fibroblasts was due to inhibited collagen degradation (reduction of MMP activity) rather than to increased collagen synthesis. Adding toremifene, an anti-estrogen triphenylethylene derivate, to desmoid fibroblasts reduced collagen accumulation by decreasing mRNA expression and increasing collagen degradation.

Antineoplastic Agents, Hormonal↗
PubMed1995

Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer.

PURPOSE: To perform a randomized three-arm comparison of tamoxifen (TAM; 20 mg/d) and two separate doses of toremifene (TOR; 60 mg/d [TOR60] and 200 mg/d [TOR200]) in postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer. MATERIALS AND METHODS: Six hundred forty-eight patients with hormone receptor-positive or -unknown metastatic breast cancer were randomly assigned to receive TAM (n = 215), TOR60 (n = 221), or TOR200 (n = 212). RESULTS: The combined response rates (by intent to treat) were as follows;: TAM, 44%; TOR60, 50%; and TOR200, 48%. Complete and partial response rates were as follows: TAM, 19%; TOR60, 21%, and TOR200, 23% (not statistically different). Median times to progression and overall survival were not significantly different. Adverse events (lethal, serious but nonlethal, and important but non-life-threatening) were similar in all three arms, except that patients in the TOR200 arm had a statistically significantly increased rate of nausea (37% v 26% and 26% for TOR200, TAM, and TOR60, respectively; P = .027). Quality-of-life assessments were not different among the three arms. CONCLUSION: The activity, toxicity, and side effects of TOR in postmenopausal women with hormone receptor-positive or -unknown metastatic breast cancer are similar if not equivalent to those of TAM. We detected no clear evidence of a dose-response effect for TOR. TOR60 is an effective and safe agent for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer and can be considered an alternative to TAM as first-line treatment for such patients.

Adult↗
PubMed2003

The effects of tamoxifen and toremifene on bone cells involve changes in plasma membrane ion conductance.

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.

Animals↗
PubMed2006

Toremifene--a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy.

Deregulation of the estrogen axis in humans prompts a series of tissue-specific events. In the breast and prostate, alterations in estrogen signalling lead to genotypic and phenotypic molecular alterations that result in dysplastic cellular appearance, deregulated cell growth and carcinoma. In bone, decreased estrogen leads to increased osteoclastogenesis and bone resorption, decreased bone mineral density and a significant fracture risk. Toremifene is a selective estrogen receptor modulator that exerts pharmacological activity in the breast, bone and prostate. An intense interest in developing this agent for prostate cancer chemoprevention is based on the reduction of premalignant and malignant prostate lesions in a transgenic model of prostate cancer. Biological and clinical activity was demonstrated in Phase II trials by the prevention of progression to prostate cancer in men with high-grade prostate intraepithelial neoplasia and through suppression of bone turnover biomarkers and increased bone mineral density in men on androgen deprivation therapy for prostate cancer.

Androgen Antagonists↗
PubMed2001

[A breast cancer patient with recurrence in the thoracic wall in whom a high-dose of toremifene was effective].

The patient was a 53-year-old female who presented with a primary complaint of reddening of the left precordial skin. She had undergone mastectomy for cancer of the left breast 12 years and 4 months earlier and had received endocrine chemotherapy including TAM as a postoperative adjuvant therapy. A diagnosis of thoracic wall recurrence was made by chest CT and pathological examination of skin biopsy specimens. Toremifene (TOR) was administrated at 120 mg/day, and PR was maintained for 8 months. Even after the condition became PD, the patient has retained adequate QOL with combination therapies including radiotherapy, and is still treated on an outpatient basis 3 years after the beginning of the treatment.

Antineoplastic Agents, Hormonal↗
PubMed2001

Mechanism of lower genotoxicity of toremifene compared with tamoxifen.

An increased incidence of endometrial cancer has been reported in breast cancer patients taking tamoxifen (TAM) and in healthy women participating in the TAM chemoprevention trials. Because TAM-DNA adducts are mutagenic and detected in the endometrium of women treated with TAM, TAM adducts are suspected to initiate the development of endometrial cancer. Treatment with TAM has been known to promote hepatocarcinoma in rats, but toremifene (TOR), a chlorinated TAM analogue, did not. TAM adducts are primarily formed via sulfonation of the alpha-hydroxylated TAM metabolites. To explore the mechanism of the lower genotoxicity of TOR, the formation of DNA adducts induced by TOR metabolites was measured using (32)P-postlabeling/ high-performance liquid chromatography analysis and compared with that of TAM metabolites. When alpha-hydroxytoremifene was incubated with DNA, 3'-phosphoadenosine 5'-phosphosulfate, and either rat or human hydroxysteroid sulfotransferase, the formation of DNA adducts was two orders of magnitude lower than that of alpha-hydroxytamoxifen. alpha-hydroxytoremifene was a poor substrate for rat and human hydroxysteroid sulfotransferases. In addition, the reactivity of alpha-acetoxytoremifene, a model activated form of TOR, with DNA was much lower than that of alpha-acetoxytamoxifen. Thus, TOR is likely to have lower genotoxicity than TAM. TOR may be a safer alternative by avoiding the development of endometrial cancer.

Animals↗
PubMed2001

[Antiangiogenic and antimetastatic effects of toremifene citrate].

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.

Angiogenesis Inhibitors↗
PubMed2001

[A case of breast cancer with bone marrow and liver metastases responding completely to low-dose weekly paclitaxel combined with toremifene].

A 36-year-old woman was admitted to our hospital because of general malaise in October 1999. She was diagnosed with bilateral breast cancer with bone marrow and liver metastases. Low-dose weekly paclitaxel (60 mg/body/week) combined with toremifene (120 mg/day) was started in December 1999. Myelofunction was recovered after 2 weeks of chemotherapy (CT), and the primary tumors and cervical/axillary lymphadenopathy disappeared after 4 weeks of CT. Bone marrow and liver metastases was no longer detected after 16 weeks of CT, and the case was evaluated as a complete response (CR). The same therapy has been performed for eight months and no evidence of recurrence has been observed.

Adult↗
PubMed2002

[Combined chemoendocrine therapy using adriamycin, cyclophosphamide and high dose toremifene in patients with recurrent breast cancer].

We studied a new chemoendocrine therapy against recurrent breast cancer in order to evaluate its efficacy and toxicity. Sixteen eligible patients were treated with the therapy consisting of adriamycin/cyclophosphamide (AC) plus toremifene (TOR). Adriamycin (20 mg/m2) was administered intravenously on days 1 and 8, and cyclophosphamide (100 mg/body) was given orally on days 1 to 14 every 4 weeks. TOR (120 mg/day) was given orally daily. The median age of the patients was 52 years; 6 were premenopausal and 10 postmenopausal. As post-operative adjuvant therapy, anthracycline chemotherapy and tamoxifen were given to 4 and 9 patients, respectively. AC therapy was administered for 8.5 cycles (median). Four complete responses (25%), 8 partial responses (37.5%), 4 no change (25%) (including 2 long NC), and 2 progressive disease (12.5%) were obtained, for an overall response rate of 62.5%. The median duration of time to progression and survival were 13.2 months (0.7-30.4 months) and 22.8 months (13.7-44.8 + months), respectively. The frequent toxicities were leukopenia, nausea/vomiting, and alopecia, but these were clinically well tolerated. Our results suggest that the addition of high dose TOR to AC therapy is useful in the treatment of recurrent breast cancer.

Administration, Oral↗