Disease relevance of Triphenylethene

• If this pattern of cross-resistance occurs in some breast cancer patients, administering triphenylethylene antiestrogens as a first-line therapy with a cross-over to steroidal compounds upon recurrence may be advantageous [1].
• Okadaic acid-sensitive activation of Maxi Cl(-) channels by triphenylethylene antioestrogens in C1300 mouse neuroblastoma cells [2].
• This paper describes the use of the triphenylethylene tamoxifen, and a new chlorinated analogue, toremifene, in 20 patients with progressive desmoid disease [3].
• OBJECTIVES: Tamoxifen is a nonsteroidal triphenylethylene derivate with a predominant antiestrogen activity, used in the endocrine treatment of breast and endometrial cancer [4].

High impact information on Triphenylethene

• The triphenylethylene antiestrogen tamoxifen and its major metabolite N-desmethyltamoxifen at concentrations of 4-6 microM enhance the intracellular concentration of natural-product antineoplastics and augment the cytotoxicity of such drugs three-fold to 10-fold in a variety of human and murine cell lines [5].
• Other study results indicate that both progestins and triphenylethylene antiestrogens may be substrates for P-glycoprotein, the product of the MDR1 gene [6].
• Although the mechanism of inhibition of PKC by triphenylethylenes clearly involves nonspecific interactions between the antiestrogens and the lipid cofactor of PKC, we recently demonstrated that PKC itself has specific triphenylethylene-binding sites, suggesting that the inhibitory mechanism also involves specific drug-protein interactions [7].
• It is proposed that the double binding of Tam and OH-Tam to ER and ABS in estrogen target cells may be related to the complex double series of estrogenic and "antiestrogenic" activities displayed by nonsteroidal triphenylethylene derivatives [8].
• Induction of virus could be inhibited by the triphenylethylene anti-estrogen tamoxifen at concentrations that had minimal effects on cellular DNA synthetic responses and cell cycle kinetics [9].

Chemical compound and disease context of Triphenylethene

• Tamoxifen (TXF), a triphenylethylene antiestrogen, is the major therapeutic agent for breast cancer [10].
• Estradiol and triphenylethylene antiestrogen actions have been studied extensively in breast cancer cell lines [11].
• The triphenylethylene antiestrogens, idoxifene (Idox) and toremifene (Tor), are structurally related analogues of tamoxifen (Tam) and were developed to improve the therapeutic index for advanced breast cancer patients [12].
• The triphenylethylene antiestrogen trans-tamoxifen is an effective antitumor agent used in the treatment of human breast cancer [13].

Biological context of Triphenylethene

• The nonestrogen receptor-mediated antiproliferative action of antiestrogen binding site (AEBS) ligands, including triphenylethylene antiestrogens and phenothiazines, has been linked to their ability to inhibit protein kinase C (PKC) [14].
• We have observed that hydroxylation of the triphenylethylene molecule significantly decreases its ability to inhibit the calmodulin-dependent phosphodiesterase activity in vitro [15].
• The triphenylethylene antiestrogen tamoxifen has been shown previously to inhibit both calmodulin and protein kinase C activities, which are involved in the control of cell proliferation [15].
• These results indicate that the serum-free culture system presented here is suitable for studying the autocrine mechanisms of cell growth regulated by estrogens as well as triphenylethylene compounds [16].
• By using saturation and competitive binding analyses with [3H]tamoxifen as the radio-labeled ligand, we have determined that rat serum contains a relatively high affinity (Kd, 28 nM), protease-sensitive binding site that is specific for antiestrogens of the triphenylethylene type (clomiphene and nafoxidine) [17].

Anatomical context of Triphenylethene

• If a racemic brominated triphenylethylene, i.e., broparestrol, is administered, serum and pituitary prolactin decrease rapidly (10 ng/ml and 4 micrograms/mg of tissue, respectively), and prolactin receptors in the mammary gland are markedly reduced [18].
• We therefore examined the developmental effects of the triphenylethylene antiestrogen tamoxifen, which exhibits both estrogen agonist and antagonist properties, in the postnatal rat uterus [19].
• Disparate effects of triphenylethylene antiestrogens on estrogen and progestin biosyntheses by cultured rat granulosa cells [20].
• Screening of over 50 derivatives for inhibition of prostaglandin synthetase (PGS) activity in bovine seminal vesicle microsomes has revealed that many of the triphenylethylene derivatives are potent inhibitors of PGS [21].
• The triphenylethylene drug tamoxifen is a hepatocarcinogen in rats, has genotoxic potential and may produce carcinoma of the endometrium in humans, while the structurally closely related toremifene has no carcinogenic or genotoxic potential [22].

Associations of Triphenylethene with other chemical compounds

• We examined the chemosensitizing activity of a new triphenylethylene, toremifene, and its major metabolites in a doxorubicin-resistant human breast cell line, MCF-7/DOX [23].
• The influence of triphenylethylene antiestrogens on FSH-stimulated production of estrogen, progesterone, and 20 alpha-hydroxy-4-pregnen-3-one (20 alpha-OH-P) was examined in cultured rat granulosa cells [20].
• Selective estrogenic effects of a novel triphenylethylene compound, FC1271a, on bone, cholesterol level, and reproductive tissues in intact and ovariectomized rats [24].
• These data demonstrate that, in vitro, nuclear ER is cleaved into a smaller molecular form and that the receptor fragments can be held together by the triphenylethylene antiestrogen hydroxytamoxifen [25].
• Differential effects of ovarian steroids and triphenylethylene compounds on macromolecular uptake and thymidine incorporation in the mouse uterus [26].

Gene context of Triphenylethene

• This was demonstrated because D351 but not D351G ER activated the TGF-alpha gene with the TPE [27].
• The study was aimed to investigate the interaction of d,l-ormeloxifene (Orm), a triphenylethylene and its hydroxy derivative with estrogen receptor subtypes alpha and beta, its influence on ERE-driven transcriptional activation and progesterone receptor expression [28].
• We have shown previously that estrogen-independent and -responsive MCF7/LCC1 human breast cancer cells selected for resistance to the triphenylethylene tamoxifen produce a variant (MCF7/LCC2) that retains sensitivity to the steroidal antiestrogen ICI 182,780 (N. Brunner et al., Cancer Res., 53: 3229-3232, 1993) [1].
• Structure-activity relationships for GSTA1 suppression and CYPIIB2 induction were compared with previously published relationships for triphenylethylene: 1) estrogen receptor relative binding affinity; 2) calmodulin antagonism; 3) antiuterotrophic activity; and 4) antagonism of MCF-7 cell growth [29].
• Various steroids and triphenylethylene antiestrogens also efficiently induced the dissociation of estradiol from the estrogen receptor [30].

Analytical, diagnostic and therapeutic context of Triphenylethene

• Tamoxifen (TAM) is a triphenylethylene antiestrogen used for the treatment, and in clinical trials for the prevention, of breast cancer in women [31].
• The ability of several triphenylethylene antiestrogens to affect the modulation of gap junctions in rat uterine myometrial and serosal cells was examined in animals 60 days following hypophysectomy [32].
• MCF-7 human breast cancer cell homogenates and subcellular organelles were submitted to isopycnic centrifugation on Percoll gradients to investigate the subcellular localization of triphenylethylene antiestrogen specific binding sites (AEBS) [33].
• Estrogen receptor-positive (MCF7) and -negative (BT20) human breast cancer cell lines, which are frequently used for studies on cancer chemotherapy with triphenylethylene (TPE) anti-estrogens, express at least three protein kinase C subspecies [34].
• The procedure involves preparations of the silyl derivatives, addition of an internal standard (triphenylethylene), and use of a hydrogen flame-ionization detector [35].

References