Disease relevance of TOREMIFENE CITRATE

• PURPOSE: Our aim was to investigate the effect of a new antiestrogen, toremifene, on human breast cancer cells grown either in culture or as tumors in nude mice [1].
• Effects of the antiestrogens tamoxifen, toremifene, and ICI 182,780 on endometrial cancer growth [2].
• Toremifene prevents prostate cancer in the transgenic adenocarcinoma of mouse prostate model [3].
• High-grade prostatic intraepithelial neoplasia was observed in animals in the placebo group, but not in animals treated with toremifene [3].
• The chemopreventive efficacy of toremifene, an antiestrogen, was evaluated in the transgenic adenocarcinoma of mouse prostate (TRAMP) model [3].

High impact information on TOREMIFENE CITRATE

• The steady-state level of pS2 mRNA in the tumor cells dropped in response to either toremifene treatment or estrogen withdrawal [1].
• Apoptosis in toremifene-induced growth inhibition of human breast cancer cells in vivo and in vitro [1].
• Elevated levels of TRPM-2 and TGF beta 1 mRNAs were observed in in vitro or in vivo grown tumor cells treated with 5-10 microM toremifene [1].
• In contrast, the dehalogenated TAM derivative toremifene (TOR) did not inhibit MM cell proliferation [4].
• TAM, ICI, and, to a lesser extent, 4HTAM and TOR triggered apoptosis in both ER-alpha-positive as well as ER-alpha-negative MM cell lines and patient MM cells, evidenced both by fluorescence-activated cell sorting (FACS) analysis using propidium iodide staining and the TUNEL assay [4].

Chemical compound and disease context of TOREMIFENE CITRATE

• Therefore, it is possible that toremifene, like tamoxifen, may be associated with an increased incidence of endometrial cancer [2].
• 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 [3].
• Two ongoing large randomized placebo-controlled studies will prospectively define fracture outcomes in men with prostate cancer and assess the efficacy of novel pharmacologic interventions (AMG162, toremifene) during GnRH agonist treatment [5].
• New SERMs currently under development for use in the treatment and prevention of osteoporosis and breast cancer include ospemifene, a derivative of toremifene, and arzoxifene, a compound very similar in structure to raloxifene [6].
• To determine how toremifene, an anti-oestrogen triphenylethylene derivate, reduces tumour mass, we investigated its modulation of TGF-beta1 and TNF-alpha in fibroma fibroblasts [7].

Biological context of TOREMIFENE CITRATE

• CONCLUSION: Due to the paucity of long-term clinical data on toremifene, important unresolved questions remain, which include its effects on bone mineral density, the frequency of cardiac events, and the risk for endometrial cancer [8].
• The 24-mg/kg dose of toremifene exerted an inhibiting effect on foci of hepatocellular alteration in rat liver detectable by glutathione S-transferase immunohistochemistry at 3 months and by conventional histology at 12 months [9].
• OBJECTIVES: The pharmacokinetics of toremifene was investigated in an open study with four parallel groups of 10 subjects each [10].
• The AUC of toremifene was reduced by 87% (P < .001), Cmax by 55% (P < .001), and t1/2 by 44% (P < .01) with rifampin [11].
• We hypothesise that increased TGF-beta1 gene expression and TGF-beta1 secretion in fibroma fibroblasts as well as the subsequent rise in TNF-alpha production by monocytes may facilitate fibroma growth and that toremifene inhibits autocrine and paracrine growth factor production [7].

Anatomical context of TOREMIFENE CITRATE

• Effects of chronic administration of tamoxifen and toremifene on DNA adducts in rat liver, kidney, and uterus [12].
• Effects of transforming growth factor-beta1 and tumour necrosis factor-alpha on cultured fibroblasts from skin fibroma as modulated by toremifene [7].
• 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 [13].
• Tamoxifen (35 mg/kg per os) and toremifene (36.3 mg/kg per os) were dosed to rats for 4 weeks and chromosomal spreads made from hepatocytes [14].
• Toremifene reduced TGF-beta1 secretion by fibroma fibroblasts and TNF-alpha secretion by monocytes, thus downregulating cell proliferation, ECM macromolecule accumulation and angiogenic progression [7].

Associations of TOREMIFENE CITRATE with other chemical compounds

• In randomized controlled trials, bisphosphonates (pamidronate and zoledronic acid) and selective estrogen receptor modulators (raloxifene and toremifene) increased bone mineral density in GnRH agonist-treated men [5].
• Ethanol increased the expression of CD14 and tumor necrosis factor- (TNF) alpha mRNA and also the production of TNF-alpha by isolated Kupffer cells, but toremifene had no significant counteracting effect [15].
• In the presence of increasing concentrations of AAG, there was a dose-related reversal of the effect of toremifene on Adriamycin cytotoxicity in both cell lines [16].
• In the present study, the non-steroidal triphenylethylene toremifene selectively increased doxorubicin accumulation in multidrug resistant estrogen receptor negative MDA A-1 human breast cells compared to the MDA 231 wild type cells [17].
• Uterine weights and luminal epithelium cell heights were significantly increased by toremifene on PND 5 but returned to control levels by PND 26 [18].

Gene context of TOREMIFENE CITRATE

• Forty-seven elderly (> or =65 years old) women with nonmetastatic, ER-alpha-positive (by immunohistochemistry) primary breast cancers (> 2 cm in diameter) entered a neoadjuvant hormone therapy protocol (60 mg/day toremifene for 3 months) [19].
• We conclude that in this elderly patient population with ER-alpha-positive tumors, ER-beta mRNA was neither predictive of response to preoperative toremifene nor provided additional information to the knowledge of ER-alpha mRNA levels, which, conversely, were directly correlated with likelihood of response [19].
• In addition, the antiestrogens tamoxifen and toremifene also increased VEGF expression [20].
• The antiestrogens, tamoxifen, and toremifene, may moderate P-gp-related drug resistance in vitro [21].
• The effect of toremifene on P-glycoprotein-mediated multidrug resistance (MDR) in breast and head and neck cancer cell lines was measured in vitro and in vivo [22].

Analytical, diagnostic and therapeutic context of TOREMIFENE CITRATE

• RESULTS: Time-lapse video microscopy of the cell cultures indicated that treatment with 7.5 microM toremifene for 3 days caused approximately 60% of the cells to exhibit morphologic characteristics typical of cells undergoing programmed death, or apoptosis [1].
• Different combinations of castration, transplantation of ovarian or testicular fragments, and administration of antiestrogenic toremifene were used in controls [23].
• After oral administration, EM-800 exerted maximal 83% and 88% inhibitions of uterine and vaginal weight, respectively, whereas maximal inhibitions limited to 51% and 67% were achieved with toremifene [24].
• A population-based case-control study was performed to evaluate the risk of endometrial cancer related to tamoxifen or toremifene treatment [25].
• Their growth was inhibited by toremifene, but estradiol was able to abrogate this effect, which might have interesting clinical implications concerning the use of postmenopausal hormone replacement therapy [26].

References