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At least 829 records · Page 46Linked to original sources
PubMed1993

Modulatory effects of tamoxifen and recombinant human alpha-interferon on doxorubicin resistance.

Doxorubicin (DOX) resistance is frequently due to the multidrug resistance gene product P-glycoprotein. This study examined the effects of two biochemical modulators, recombinant human alpha-interferon (IFN-alpha) and tamoxifen (TAM), on the DOX sensitivity, DOX retention, and P-glycoprotein expression of the multidrug-resistant Chinese hamster ovary cell line ChR C5 and the parent AuX B1 cell line. In the absence of either modulator, the 50% inhibitory concentration for DOX after 1-h incubation as determined using a microculture tetrazolium assay was 8.3 microM in ChR C5 cells and 0.4 microM in AuX B1 cells. In ChR C5 cells, IFN-alpha (500 units/ml) for 24 h had no affect on DOX cytotoxicity, but tamoxifen (1.0 microM) for 24 h enhanced DOX cytotoxicity with the 50% inhibitory concentration decreased by 2-fold to 4.2 microM. A combination of IFN-alpha (500 units/ml) for the initial 24 h followed by TAM (1.0 microM) for another 24 h was even more effective in ChR C5 cells with the DOX 50% inhibitory concentration decreased by 4-fold to 2.1 microM. The combination IFN-alpha and TAM dramatically increased DOX accumulation in the resistant ChR C5 cells without significantly affecting P-glycoprotein expression as measured using flow cytometric analysis. IFN-alpha and/or TAM had no effect on DOX cytotoxicity or accumulation in parent DOX-sensitive AuX B1 cells. Both cell lines were estrogen and progesterone receptor negative. These data indicate that synergism between IFN-alpha and TAM may partially reverse DOX resistance and may potentially be useful in enhancing the clinical effectiveness of DOX.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

[A comparative study among ftorafur, ftorafur plus tamoxifen, and tamoxifen in adjuvant therapy for breast cancer. The Chubu Cooperative Study Group of Adjuvant Chemoendocrine Therapy for Breast Cancer, Japan].

A randomized study assessing the efficacy of three treatment of ftorafur (FT), ftorafur plus Tamoxifen (TAM), and Tamoxifen in patients diagnosed as having stage II (N1b) or stage III breast cancer was carried out at 90 institutions in the Chubu district of Japan. After 10 mg of MMC administration on the day of surgery and the next day, patients were allocated to one of three treatments: FT 600 mg/day for 2 years, FT 600 mg/day plus TAM 20 mg/day for 2 years, or TAM 20 mg/day for 2 years. A total of 647 cases were analyzed. No significant differences were observed in the 5-year disease-free survival rates or in the 5-year survival rates. In the stratified analysis, however, a beneficial effect of adding FT to TAM was observed in the patients with ER-positive tumors in the 5-year survival rate, and FT plus TAM treatment was favorable compared with the other two treatments for postmenopausal patients with ER-positive tumors.

Adult↗
PubMedDate not supplied

Effects of tamoxifen and the derivative (TAT) on cell cycle of MCF-7 in vitro.

The growth inhibitory activity and influences on cell-cycle progression of tamoxifen (TAM) and its derivatives [toremifene(NK), droloxifene (FK) and TAT-59 (TAT) against MCF-7, cells, an estrogen respondent human breast cancer cell line were investigated. TAM and its derivatives exhibited a dose-dependent growth inhibitory activity against MCF-7 cells in the order of TAT > FK > TAM > NK at 48 and 120 hours in vitro. 10(-6) M TAT reduced growth of MCF-7 to 25% of that of control after 120 hours incubation in the presence of 10(-8) M estradiol; however, in the case of TAM the growth of MCF-7 was 73%. FACS analysis showed that 82.7% of the cells were accumulated at G0/1 phase after 120 hours incubation with TAT and its accumulative activity was higher than that of TAM. Moreover, when TAT was used in combination with 5-FU, the accumulative effect was significantly increased. Thus it is suggested that TAT or TAT in combination with 5-FU may be a useful adjuvant treatment against breast cancer.

Administration, Oral↗
PubMedDate not supplied

Different chemo- and endocrino-sensitivity of MCF-7 cells with or without estradiol supplement in vitro.

The sensitivity of MCF-7 cells to tamoxifen (TAM) and mitomycin C (MMC) was assessed in rapidly and slowly growing cells with or without estradiol supplementation, respectively. The growth of MCF-7 was inhibited by MMC in a concentration-dependent manner with or without estradiol (E2) supplementation. Preincubation with MMC suppressed subsequent E2 stimulated growth of MCF-7. TAM inhibited the growth of MCF-7 supplemented with E2 and preincubation with TAM prevented subsequent E2 stimulated growth of MCF-7. However, TAM did not inhibit the growth of MCF-7 cells in E2 free medium. These results suggested that MMC may be more effective than TAM on breast cancer cells in the dormant or slow-growth phase.

Breast Neoplasms↗
PubMed1996

[Establishment of an estrogen receptor positive 3'-methyl-4-dimethylaminoazobenzene induced hepatoma cell line of rat and investigation of hormonal therapy].

An estrogen receptor (ER) positive cell line was newly established from a Wistar King Aptekman (WKA) rat, 3'-methyl-4-dimethylaminoazobenzene (DAB) induced hepatoma cell lines. The impact of hormonal therapy on cell growth was investigated. This cell line produced alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and ferritin in the conditioned medium. Progesterone receptors (PgR) were positive but androgen receptors (AR) were not detected. This cell line's doubling time was about 10.5 hours in a routine medium and 12.2 hours in the endogenous estrogen removed medium (exponential phase). The morphological features of the cell were of a hepatocellular type as observed by light microscopy. The modal chromosome number was 56 and the DNA ploidy pattern was aneuploid as observed by flow cytometry. The addition of 17 beta-estradiol (E2) did not increase cell growth but tamoxifen (TAM) in vitro inhibited cell growth in the lag phase. Surgical castration or oral administration of E2 or TAM in vivo inhibited tumor growth in the early phase. There were no additional effects between surgical castration and the administration of E2. Surgical castration plus the administration of TAM were not effective when combined. The administration of TAM caused the physiological effect of castration eg., diminished blood testosterone level same as E2 administration. TAM also decreased the maximal binding capacity (Bmax) of ER. A morphological change to the cholangiocell carcinoma type was noticed. These results that this cell line was ER dependent in the early phase of tumor growth.

Animals↗
PubMed1996

[Inhibitory effect of tamoxifen on the breast cancer risk induced by exogenous estrogen in rat].

In order to investigate the inhibitory effect of tamoxifen (TAM) on breast cancer risk induced by exogenous estrogen, female rats were randomly allocated into three groups, namely DES (diethylstilbestrol) group, DES + TAM group and blank control group. We found that in DES + TAM group the levels of estradiol (62.14 pg/ml) and progesteron (15.02 ng/ml) in serum were obviously higher than those in DES group (52.69 pg/ml, 10.38 ng/ml) individually (P < 0.05, P < 0.01), the incidence (28.57%) of mammary hyperplasia was significantly lower than that in DES group (73.33%) (P < 0.025), the degree of hyperplasia markedly slighter than that in DES group (P < 0.025), and the AgNOR count (1.93%), DNA content (80.24%) and ER positive rate (36.46%) were obviously lower than those in DES group (2.43%, 95.60%, 71.71%) individually. The results indicated that TAM could increase the levels of estradiol and progesterone in serum, also could decrease the ER contents, AgNOR counts and DNA contents in mammary epithelium. It suggested that the TAM could interfere the effect on the breast carcinogenesis induced by exogenous estrogen.

Animals↗
PubMed1998

Transforming growth factor-beta stimulates urokinase expression in tumor-associated macrophages of the breast.

Recent studies have shown that urokinase (uPA) is an independent prognostic marker in breast cancer. uPA plays a key role in the degradation of tumor matrix and promotes tumor progression. Macrophage expression of uPA appears to be important in this context. Our objective in the present study was to provide evidence that tumor growth factor-beta (TGF-beta) released from breast cancer cells markedly up-regulates uPA expression in tumor-associated macrophages (TAMs). TAMs from 32 breast carcinomas were cultured. Blood monocytes from healthy donors and breast cancer patients as well as tissue macrophages from patients with fibrocystic changes of the breast were also examined. After TGF-beta incubation, uPA levels were tested by ELISA, and uPA mRNA levels were determined by Northern blot analysis. TGF-beta receptor and uPA cell surface fluorescence intensities were determined by flow cytometry; TGF-beta receptors were determined by Western blot analysis. Protein kinase-C dependence was also examined, and immunohistochemical stainings for uPA and TGF-beta were performed. We have demonstrated that TGF-beta markedly up-regulates basal uPA expression (mRNA and protein) in TAMs but only modestly increases uPA production in blood monocytes and tissue macrophages. Exposure of macrophages to TGF-beta1 led to a rapid and sustained increase in uPA mRNA levels, which was independent of de novo protein synthesis and completely inhibited by actinomycin D. H7 markedly reduced the ability of TGF-beta to stimulate uPA expression. Likewise, okadaic acid potentiated the ability of TGF-beta to up-regulate macrophage uPA expression. We suggest that TAMs are more responsive to TGF-beta stimulation than are blood monocytes and tissue macrophages because of different TGF-beta receptor densities. TGF-beta stimulates transcription of the uPA gene, increases uPA-mRNA stability, and activates uPA expression via protein kinase-C-dependent mechanisms. The ability of TGF-beta to induce macrophage uPA expression may provide an indirect mechanism by which this growth factor stimulates angiogenesis. It may be, therefore, that TAMs promote tumor progression and tumor angiogenesis.

Breast Neoplasms↗
PubMed1998

Cholesterol biosynthesis from lanosterol: differential inhibition of sterol delta 8-isomerase and other lanosterol-converting enzymes by tamoxifen.

The fact that administration of tamoxifen (Tam) to humans and laboratory animals (e.g., rats and monkeys) results in both a drastic reduction in cholesterol and a marked accumulation of certain sterol intermediates in their serum led us to undertake more direct biochemical studies on the mechanism of Tam's inhibitory action on the cholesterogenic enzymes. Of the five rat hepatic lanosterol-converting enzymes examined, the enzyme most sensitive to inhibition by Tam was sterol delta 8-isomerase (delta 8-SI) (a 208-fold inhibition relative to lanosterol 14 alpha-methyl demethylase), followed by sterol delta 24-reductase (13-fold) and sterol delta 14-reductase (5.2-fold). The inhibition patterns of all four affected enzymes were found to be noncompetitive, despite widely different inhibition constants (Ki) of 0.21 to 23.5 microM. The inhibitory activity of Tam on delta 8-SI was not affected by detergent-mediated solubilization of the microsomes. In Chinese hamster ovary cells, inhibition of delta 8-SI activity (IC50 = 0.15 microM) was paralleled by a decreased rate of [14C]-mevalonate incorporation into cholesterol (IC50 = 0.70 microM). Our results should provide more insight into an underlying mechanism of Tam's cardioprotective role by interfering the operation of the pathway of cholesterol biosynthesis from lanosterol in mammals.

Animals↗
PubMedDate not supplied

Antagonistic effects of styrylpyrone derivative (SPD) on 7,12-dimethylbenzanthracene-induced rat mammary tumors.

Early studies reported that a styrylpyrone derivative (SPD) purified from the Goniothalamus sp. acts as a non-competitive antiestrogen in early pregnant mice (1). In the immature rat uterine wet weight test, we found that SPD markedly reduced uterine weight at doses 1 and 100 mg/kg, thus reflecting negative antiestrogenicity, probably attributed to low binding affinities towards ER. Tamoxifen (Tam) on the other hand exhibited partial antiestrogenicity at all doses (0.01-10 mg/kg BW) and dose-dependent estrogenicity. However, the estrogen antagonism: agonism ratio for SPD is much higher than Tam, which is indicative of the breast cancer antitumor activity as seen in compounds such as MER-25. Pretreatment assessment on 1 mg/kg BW SPD and Tam showed that SPD is not a very good, estrogen antagonist compared to Tam, as it was unable to revert the estrogenicity effect of estradiol benzoate (EB) on immature rat uterine weight. Antitumor activity assessment for SPD exhibited significant tumor growth retardation in 7,12-dimethyl benzanthracene (DMBA) induced rat mammary tumors at all doses employed (2, 10 and 50 mg/kg) compared to the controls (p < 0.01). This compound was found to be more potent than Tam (2 and 10 mg/kg) and displayed greater potency at a dose of 10 mg/kg. It caused complete remission of 33.3% of tumors but failed to prevent onset of new tumors. However, SPD administration at 2 mg/kg caused 16.7% complete remission and partial remission. It also prevented the onset of new tumors throughout the experiment.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Comparison of microvessel density with tumor associated macrophages in invasive breast carcinoma.

Neovascularization, the growth and formation of capillary blood vessels, is an essential component of solid tumor growth and a critical step in metastasis. Tumor associated macrophages (TAMs) have several functions related to tumor biology including growth, proliferative rate, stroma formation and dissolution, and neovascularization. The aim of this study was to define the TAM and microvessel density (MD) in human invasive breast carcinoma NOS and to correlate their values with lymph node status, tumor size, tumor grade and mitotic activity index (MAI), and, finally, to determine whether MD is connected with TAMs. A total number of 57 invasive breast carcinomas NOS were processed for immunohistochemical analysis using mAb to F-VIII to visualize endothelial cells and mAb to CD68 antigens for macrophages. Statistical analysis showed only a positive correlation between TAMs and MAI (p = 0.004). These results support the notion that intensity of tumor angiogenesis does not provide additional prognostic significance, while TAMs may play a positive role in breast cancer micro system since they regulate tumor proliferation.

Biomarkers↗
PubMed1997

Effects of tamoxifen, an antiestrogen, on rat prostate carcinogenesis by 3,2'-dimethyl-4-aminobiphenyl and testosterone do not support an estrogen role in testosterone promotion.

BACKGROUND: Our previous data suggest that estrogen plays an important role in rat prostate carcinogenesis, particularly in promotion by testosterone. Therefore, in the present experiment, effects of an antiestrogen, tamoxifen (TAM), were investigated. METHODS: Male F344 rats initially received 3,2'-dimethyl-4-aminobiphenyl (DMAB) at 50 mg/kg bw every 2 weeks for 20 weeks and then TAM in Silastic tubes was subcutaneously given alone or together with testosterone propionate (TP) for 40 weeks. RESULTS: TAM significantly suppressed prostate weights, suggesting an estrogenic action, but the development of preneoplastic and/or neoplastic lesions of the prostate or seminal vesicles in rats given DMAB alone or DMAB and TP was not altered. TAM reversed the suppression of development of ventral atypical hyperplasias by TP. CONCLUSIONS: These findings suggest that estrogen, which is derived from testosterone by the action of aromatase, is not involved in the strong promotion by TP of DMAB prostate carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
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↗
PubMed1998

Cytokine repertoire during maturation of monocytes to macrophages within spheroids of malignant and non-malignant urothelial cell lines.

Terminal maturation of human blood monocytes to macrophages (MAC) in vivo is believed to be important for the morphology, antigen expression and functional activity of the resulting MAC population. This process is modulated by the specific tissue micro-environment to which blood monocytes migrate upon leaving the vasculature. Tumor-associated macrophages (TAM) are a special type of MAC, and little is known about the modulating capacity of the tumor environment on monocyte-to-MAC differentiation. By co-culturing 3-dimensional multicellular spheroids (MCS) of the urothelial-bladder-carcinoma cell lines J82 and RT4 with human monocytes/MAC we generated TAM in vitro. For comparison, monocytes/MAC were co-cultured with the non-tumorigenic urothelial cell line HCV29. The effects on monocyte differentiation were analyzed, particularly with respect to cytokine release. Monocyte maturation was modulated within the tumor spheroid dependent upon the tumor cell type. Monocytes co-cultured with MCS of the poorly differentiated J82 carcinoma spontaneously produced high amounts of IL-1beta and IL-6, but only low amounts of TNF-alpha, which could be further increased by the addition of LPS. This cytokine pattern is characteristic for monocytes and remained constant for up to 8 days in J82-MCS co-cultures. However, in RT4-MCS and HCV29-MCS co-cultures, the initial cytokine pattern changed and after 8 days corresponded well to that of MAC differentiated in vitro without tumor contact. In addition to functional parameters, we analyzed the morphology of J82-MCS-TAM and found that they displayed a monocyte-like morphology. Our data indicate that (1) tumor cells can influence monocyte-to-MAC differentiation, giving rise to TAM with monocyte-specific phenotypic properties; and (2) this capacity is dependent on the type of tumor cell.

Cell Differentiation↗
PubMed1998

Thoracoabdominal motion in newborns during ventilation delivered by endotracheal tube or nasal prongs.

Preterm infants have asynchronous thoracoabdominal motion (TAM) secondary to a highly compliant chest wall and different lung mechanics compared to term infants. We compared TAM during continuous positive airway pressure (CPAP) administered through an endotracheal tube (ETT-CPAP) or nasal prongs (nasal-CPAP), and during synchronized intermittent mandatory ventilation administered by nasal prongs (nasal-SIMV) in 14 preterm newborn infants. Asynchrony of TAM was quantified by measuring relative motion of chest wall and abdomen with strain gauges and calculating phase angles (theta). Phase angles were lower during nasal-SIMV compared to nasal-CPAP or ETT-CPAP (P < 0.05), and lower during nasal-CPAP compared to ETT-CPAP (P < 0.05). The reduced TAM asynchrony during nasal-SIMV and nasal-CPAP may be due to elimination of resistance of the ETT and/or effective stabilization of the chest wall. These data suggest that nasal-SIMV may be an effective mode of respiratory support for preterm infants requiring minimal ventilatory support.

Abdomen↗
PubMed1990

The effects of estrogen, progesterone, and tamoxifen alone and in combination with cytotoxic agents against human ovarian carcinoma in vitro.

The effects of estradiol (E), medroxyprogesterone acetate (MPA), and tamoxifen (TAM) on the growth of a human ovarian carcinoma cell line, BG-1, were evaluated using a tumor clonogenic assay (HTCA). BG-1 contains significant quantities of estrogen and progesterone receptors. Growth inhibition by TAM and growth stimulation by MPA were demonstrated using continuous drug exposure. Estradiol resulted in a marginal increase in colony formation. With each of these three drugs, the greatest response occurred in the larger colonies (generally greater than or equal to 60 microns). Combinations of each of these three steroidal agents with three different cytotoxic drugs were studied in the HTCA. Synergistic activities were produced with TAM combined with either cisplatin or doxorubicin. Additive effects were seen with TAM and cyclophosphamide. Although predominantly additive or synergistic, the effects were variable with MPA and all three cytotoxic agents. Combinations of estradiol with cytotoxic agents were no more active than the cytotoxics alone. These findings indicate a biological rationale for hormonal manipulation as therapy in ovarian cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2007

One-pot synthesis of amino-alcohols using a de-novo transketolase and beta-alanine: pyruvate transaminase pathway in Escherichia coli.

Biocatalysis continues to emerge as a powerful technique for the efficient synthesis of optically pure pharmaceuticals that are difficult to access via conventional chemistry. The power of biocatalysis can be enhanced if two or more reactions can be achieved by a single whole cell biocatalyst containing a pathway designed de-novo to facilitate a required synthetic sequence. The enzymes transketolase (TK) and transaminase (TAm) respectively catalyze asymmetric carbon--carbon bond formation and amine group addition to suitable substrate molecules. The ability of a transaminase to accept the product of the transketolase reaction can allow the two catalysts to be employed in series to create chiral amino-alcohols from achiral substrates. As proof of principle, the beta-alanine: pyruvate aminotransferase (beta-A:P TAm) from Pseudomonas aeruginosa has been cloned, to create plasmid pQR428, for overexpression in E.coli strain BL21gold(DE3). Production of the beta-A:P TAm alongside the native transketolase (overexpressed from plasmid pQR411), in a single E.coli host, has created a novel biocatalyst capable of the synthesis of chiral amino alcohols via a synthetic two-step pathway. The feasibility of using the biocatalyst has been demonstrated by the formation of a single diastereoisomer of 2-amino-1,3,4-butanetriol (ABT) product, in up to 21% mol/mol yield, by the beta-A:P TAm, via transamination of L-erythrulose synthesized by TK, from achiral substrates glycolaldehyde (GA) and beta-hydroxypyruvate (beta-HPA). ABT synthesis was achieved in a one-pot process, using either whole cells of the dual plasmid strain or cell lysate, while the dual alcohol-amine functionality of ABT makes it an excellent synthon for many pharmaceutical syntheses.

Amino Alcohols↗
PubMed1993

Quantitative measurement of 4-hydroxy tamoxifen in human plasma and mammary tumours by combined gas chromatography/negative chemical ionization mass spectrometry.

A highly sensitive and specific assay was developed for the quantitative measurement of 4-hydroxy tamoxifen (4-OH Tam) at the femtomole level in human plasma and mammary tumours. The drug and deuterated internal standard (4-OH Tam D4) were measured by gas chromatography/negative chemical ionization mass spectrometry with methane as the reactant gas. The two compounds of interest were isolated from the complex biological matrices using a solid-phase extraction procedure with Extrelut 1 columns. Soft operating conditions were required to convert 4-OH Tam to the fluorinated derivatives with pentafluorobenzyl chloride. The mass spectrometer was tuned to monitor the abundant and stable molecular ions at m/z 581 and 585 which were generated in the ion source by an electron capture process. This assay required only 0.5 ml of plasma or 0.5 g of mammary tissue, and the quantification limits of the method were 20 pg ml-1 for the body fluids or 100 pg g-1 for the tissue samples. The very low relative standard deviation and mean percentage error calculated during the different within-day or day-to-day repeatability assays have clearly demonstrated the ruggedness of the technique for routine analysis of 4-OH Tam.

Antineoplastic Agents↗
PubMed2004

Selective estrogen-receptor modulators (SERMs) in the cyclopentadienylrhenium tricarbonyl series: synthesis and biological behaviour.

A series of organometallic antiestrogens based on the OH-tamoxifen (OH-Tam) skeleton and bearing the (eta(5)-C(5)H(4))Re(I)(CO)(3) unit has been prepared by using McMurry coupling for the purpose of studying their biological behaviour. The cyclopentadienylrhenium tricarbonyl moiety is indeed stable in biological media, compact, lipophilic and easy to handle. Furthermore, this study allowed us to select the best candidates for subsequent use as radiopharmaceuticals either for imaging or therapy by using appropriate radionucleides, namely (99m)Tc and (188)Re. In these molecules the beta-phenyl group of OH-Tam has been replaced by the (eta(5)-C(5)H(4))Re(CO)(3) moiety, and the length of the dimethylamino side chain --O(CH(2))(n)N(CH(3))(2) was varied (n=2, 3, 4, 5 and 8). The compounds 7 a-7 e were obtained as mixtures of their Z and E isomers, which could be separated by semipreparative HPLC. Unlike their ferrocene homologues, the compounds do not isomerise in solution. Structural identification was carried out with NMR spectroscopy by using the HMBC and NOE techniques and was confirmed by the X-ray structural determination of (E)-7 a (n=2). These molecules were more lipophilic than OH-Tam (log P(o/w)=4.5-6.3) and they were all reasonably well recognized by the two forms of the estrogen receptor (ERalpha and ERbeta). For example, (Z)-7 b (n=3) has high relative binding affinity (RBA) values of 31 % for ERalpha and 16.8 % for ERbeta. The antiproliferative effects of two pairs of isomers, (Z)- and (E)-7 b (n=3) and (Z)- and (E)-7 d (n=5), were studied at a molarity of 1 microM on two breast-cancer cell lines, MCF7 (ERalpha positive) and MDA-MB231 (ERalpha negative). These molecules had an antiproliferative effect on MCF7 cells slightly higher than that of OH-Tam and no effect on MDA-MB231 cells. Thus, the antiproliferative effect observed on the MCF7 cells seemed essentially to be linked to an antiestrogenic effect. Molecular modelling studies have allowed us to rationalise these effects and select the best compounds for future development of a radioactive series.

Cell Line, Tumor↗