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PubMed2003

Epidermal growth factor-responsive laryngeal squamous cancer cell line Hep2 is more sensitive than unresponsive CO-K3 one to quercetin and tamoxifen apoptotic effects.

Epidermal growth factor receptor (EGFR) plays a role in laryngeal squamous cell carcinoma (SCC) development and progression. The flavonoid quercetin (Q) and the antiestrogen tamoxifen (TAM) inhibit proliferation of both primary laryngeal SCC and laryngeal carcinoma cell lines, through still uncharacterized mechanisms. We studied Q and TAM inhibitory effect on epidermal growth factor (EGF)-stimulated Hep2 and CO-K3 laryngeal squamous cell lines. Q and TAM (0.1-1.0 microM) induced more apoptosis in EGF growth-stimulated than in unstimulated Hep2 cells. EGF neither stimulated CO-K3 cell growth nor enhanced Q and TAM-induced apoptosis. Mitogen-activated protein kinase (MAPK) analysis revealed that in Hep2 cells, but not in CO-K3 cells, EGF induced a time-dependent phosphorylation of p42, p44, p38, and p46. In Hep2 cells, but not in CO-K3 cells, Q and TAM produced, upon EGF treatment, a twofold increase of p38 and p46 and an enhancement of p42 and p44 dephosphorylation, suggesting a requirement of EGFR. The enhancing effect was due to a p38 and p46 dephosphorylation delayed kinetics. An antiphosphorylated p38 antibody prevented Q and TAM inhibitory effect on p42 and p44 phosphorylations, suggesting that the EGF-dependent increase in Q and TAM apoptotic effect on Hep2 cells could depend on the p38 inhibition of the survival kinases p42 and p44. In SCC, EGFR overexpression is an early event from dysplasia to neoplasia. We conclude that the capacity of Q and TAM to increase apoptosis in EGFR-activated cells makes these compounds possible chemopreventive drugs in subjects at risk of developing laryngeal cancer.

Anticarcinogenic Agents↗
PubMed2005

Tamoxifen can reverse multidrug resistance of colorectal carcinoma in vivo.

AIM: To investigate the effect of tamoxifen (TAM) on multidrug resistance (MDR) of colorectal carcinoma in vivo and its relationship with estrogen receptor (ER). METHODS: Multidrug resistance was determined by means of semi-quantitative retro-transcription polymerase chain reaction (RT-PCR) to test mdr1 gene mRNA and ER expression was studied by immunohistochemistry. Tumor tissues from three cases of human colon carcinoma, which had mdr1(+)/ER(+), mdr1(+)/ER(-), mdr1(-) expressions, were planted subcutaneously in the neck of nude mice to establish three xenograft models. These models were subdivided into four subgroups randomly: Doxorubicin (DOX)-treated group, TAM-treated group, DOX and TAM group and control group. The dimensions of these xenografts were measured after each course of treatment and the xenografts were removed at the end of the experiments for measurements of weight and the variation of mdr1 mRNA level with RT-PCR. In each course, TAM (15 mg/(kg/d)) was administrated orally per day in the first seven days and DOX (3.6 mg/kg) was injected peritoneally on the first day. Data was evaluated by q and t tests. RESULTS: In the animal models with mdr1(-) tumor, the weights and volumes of the planted tumor in DOX group ((39.1+/-2.29) mg, (31.44+/-1.61) mm(3)) and TAM and DOX group ((38.72+/-2.56) mg, (31.31+/-1.74) mm(3)), which were lesser than that of control group ((45.48+/-3.92) mg, (36.42+/-2.77)mm(3), P = 0.037, P = 0.016 respectively) significantly. In the animal models with mdr1(+)/ER(+) tumor, the weights and volumes of planted tumor were not affected by DOX or TAM treatment; however, in TAM and DOX group ((425.5+/-28.58) mg, (340.35+/-22.28) mm(3)), they were significantly less than that of control group ((634.23+/-119.41) mg, (507.45+/-93.34) mm(3), P = 0.022, P = 0.045 respectively), which are similar to that in the models with mdr1(+)/ER(-) tumor. No significant changes were found in the expressive level of mdr1 mRNA following these treatments. CONCLUSION: The expression of mdr1 gene corresponds to the sensitivity of colon cancer to anti-tumor drugs in vivo. TAM can reverse the MDR of colorectal carcinoma in nude mice, which is independent of the expression of ER; however, no change was observed in the expressive level of mdr1 mRNA.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

The mature form of adrenomedullin correlates with brain natriuretic peptide in plasma of chronic hemodialysis patients.

AIM: Adrenomedullin (AM), a hypotensive and natriuretic peptide, consists of an amidated mature form (mAM) and an intermediate form in human plasma, of which only mAM exerts biological activity. Like atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), plasma levels of mAM are reported to be significantly elevated in hemodialysis (HD) patients, suggesting that mAM may be stimulated partly by increased body fluid volume in a manner similar to the natriuretic peptides. Here, we examined the relationship between mAM levels and ANP or BNP levels and the effect of HD on plasma mAM in HD patients. PATIENTS AND METHODS: We measured plasma levels of mAM, total AM (tAM), ANP and BNP before and after HD in patients on long-term HD (n = 22, mean age 56.3 +/- 3.2 years) using radioimmunoassay. RESULTS: Baseline mAM (2.7 +/- 0.3 fmol/ml) and tAM (23.6 +/- 2.0 fmol/ml) were significantly higher in HD patients than in healthy subjects (1.1 +/- 0.2 fmol/ml, 9.0 +/- 2.1 fmol/ml, respectively). HD significantly reduced the levels to 1.2 +/- 0.2 fmol/ml and 13.8 +/- 1.4 fmol/ml, respectively, although tAM levels were still elevated compared to healthy subjects. Similar plasma ANP and BNP levels were obtained in HD patients. There were significant correlations between mAM and tAM levels before and after HD and between HD-induced changes in mAM and tAM levels. In the pre-HD state, levels of both mAM and tAM correlated significantly with BNP levels, but the correlation of BNP with mAM was closer than that with tAM. In contrast, no correlations were observed between the 2 forms of AM and ANP. Changes in mAM levels during HD also correlated significantly with BNP but not ANP levels, although the changes in tAM did not correlate with those of the 2 natriuretic peptides. CONCLUSION: Our results suggest that the secretion/metabolism of mAM may be regulated in a manner similar to that of BNP in HD patients.

Adrenomedullin↗
PubMed1976

Evaluation of tamoxifen dose in advanced breast cancer: a progress report.

The results of an ongoing trial randomizing patients with progressive, metastatic breast carcinoma between tamoxifen (Tam, NSC-180973) and Tam plus fluoxymesterone (Flu) (7 mg/m2 bid) are reported. Each patient received a single dose level of Tam in the range of 2-100 mg/m2 bid. The combination had a higher response rate overall (45% vs 28%) and when only the patients' soft tissue sites were analyzed (54% vs 9%, P=0.04). The time to treatment failure was longer for the combination among those patients with a response or disease stabilization (P=0.08). Response rates with Tam doses less than 12 mg/m2 bid were also higher than with doses greater than or equal to 12 mg/m2 for all patients in the study (62% vs 30%, P=0.025) and for those where only soft tissue sites were evaluable (43% vs 29%, P=0.07). Side effects were mild and consisted primarily of transient hematologic suppression, nausea, masculinization, hepatic enzyme elevations, and edema. The latter three were observed only with the Flu regimen. Leukopenia and thrombocytopenia were more frequent at Tam doses less than 12 mg/m2 bid whereas nausea was more common at higher doses. Tam doses as high as 100 mg/m2 bid were well tolerated. Tam amy be more effective at low doses, has only mild side effects, and is well tolerated at doses up to 100 mg/m2 bid. Combining Tam with Flu appears to enhance the therapeutic effectiveness.

Adult↗
PubMed1999

Significance of thymidine phosphorylase as a marker of protumor monocytes in breast cancer.

Tumor-associated monocytic cells (TAMs) are a major component of the stroma responsible for tumor formation. TAMs generate various kinds of mediators for their function, one of which is thymidine phosphorylase (TP). TP is an angiogenic enzyme that is known to be up-regulated in tumor tissues. Here, we focused on the clinical implication of TP expression in TAMs by studying 229 primary breast carcinoma tissues. Immunohistochemical analysis demonstrated that monocytic TP+ tumors had a significantly worse prognosis than did monocytic TP- tumors (P < 0.01, log-rank test). A multivariate analysis confirmed that monocytic TP status provided an independent prognostic value (P < 0.0001). Furthermore, of interest was that monocytic TP status could categorize the CD68+ patients, who had an extensive accumulation of CD68+ TAMs, into two subgroups with strikingly contrasting prognoses: a good prognostic monocytic TP- group and a poor prognostic monocytic TP+ group. This indicates that there are both antitumor and protumor types of TAM. Subanalysis showed that microvessel density was significantly increased in CD68+/monocytic TP+ tumors compared with CD68+/monocytic TP- tumors. Experimentally, TAMs are known to function in diverse manners, antitumor and protumor; however, little is known about clinically recognizable markers to characterize the TAMs in histological sections. TP might be such a marker, which would be useful for identifying the character of TAMs, particularly the protumor phenotype.

Adult↗
PubMed1999

Tamoxifen-induced apoptosis in breast cancer cells relates to down-regulation of bcl-2, but not bax and bcl-X(L), without alteration of p53 protein levels.

Tamoxifen (TAM) has been shown to induce apoptosis in breast cancer cells. bcl-2 family genes, which can interact with each other, have been shown to interfere with apoptosis after various stimuli. In this study, we investigated the effects of TAM on bcl-2 family gene products bcl-2, bax, and bcl-X(L) and on p53 levels in estrogen receptor-positive MCF-7 breast cancer cells. We found that TAM induced time- and concentration-dependent down-regulation of bcl-2 at both the mRNA and protein level. Down-regulation of bcl-2 correlated with TAM-induced apoptosis. In addition, estradiol treatment significantly increased bcl-2 protein expression and blocked the reduction of bcl-2 by TAM. TAM did not, however, affect bax, bcl-X(L), or p53 expression at the mRNA or protein level. Our results demonstrate that TAM can induce apoptosis in a time- and dose-dependent manner by modulating bcl-2 levels in breast cancer cells, and down-regulation of bcl-2 induced by TAM was not accompanied by alterations in p53 levels.

Antineoplastic Agents, Hormonal↗
PubMed2001

[Endocrine therapy for advanced or recurrent breast cancer].

Endocrine therapy of advanced or recurrent breast cancer was described. The presence of ER or PgR in primary breast tumors is the best-established marker for response to endocrine therapy. However, ER-positive breast tumors overexpressing EGF-R and/or HER-2 (Erb B2) are resistant to endocrine therapy. Recently it was suggested that an elevated level of the circulating extracellular domain of HER-2 could be a predictor for poor response to endocrine therapy. LH-RH agonist is used as a first-line therapy for premenopausal patients. And LH-RH agonist plus tamoxifen (TAM) has shown a higher response rate and more prolonged survival than LH-RH agonist or TAM alone. As two new aromatase inhibitors, anastrozole (ANA) and letrozole, have shown an equal or higher response rate and a prolonged time to progression than TAM as a first-line therapy, these could be used as a first-line therapy instead of TAM. In a cross-over trial of ANA and TAM, the response rate of ANA after TAM failure was equal to that of TAM after ANA failure. As these drugs showed an equal or higher response rate and longer survival than progestin in TAM resistant cases, these drugs could also used as a second-line therapy. In addition, the trend of recent studies regarding the mechanisms of hormone resistance is also described.

Antineoplastic Agents, Hormonal↗
PubMed2002

A dominant negative c-jun specifically blocks okadaic acid-induced skin tumor promotion.

Okadaic acid (OA) is a prototypical non-phorbol ester skin tumor-promoting agent that works by inhibiting protein phosphatases, leading to an increase in protein phosphorylation. Increased protein phosphorylation can lead to stimulated signaling through various signal transduction pathways. One or more of the pathways affected by OA leads to increased signaling via the activator protein 1 (AP-1) transcription factor. Because AP-1 signaling has been shown to be required for skin tumor promotion by phorbol ester, studies were undertaken to determine whether AP-1 signaling is also required for 7,12-dimethylbenz(a)anthracene (DMBA)-initiated/OA-promoted skin tumorigenesis. Transgenic mice expressing a dominant negative c-jun (TAM-67) controlled by the keratin 14 promoter in ICR mice were used to determine the effects of OA on AP-1 signaling. By crossing the TAM-67 mice with mice expressing an AP-1-responsive luciferase, it was shown that TAM-67 decreases AP-1 activation in response to OA treatment by 95%. After 7,12-dimethylbenz(a)anthracene initiation, the TAM-67 mice and nontransgenic littermates were promoted with twice weekly applications of OA. These experiments showed that TAM-67 expression decreased tumor multiplicity by 90%. Additional experiments with TAM-67 mice showed that the hyperplastic response to OA is not impaired in these mice, nor were there differences in OA-induced transcription of various genes known to be AP-1 responsive under other conditions. This result suggests that only a subset of AP-1-regulated genes is targeted by TAM-67 when it prevents tumor promotion by OA. A determination of the mechanism by which TAM-67 can block tumor promotion without affecting hyperplasia will be important.

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

Immunohistochemical expression of steroid receptors and glycodelin A in isolated proliferative human endometrial glandular cells after stimulation with tamoxifen and phytoestrogens (genistein and daidzein).

INTRODUCTION: The aims of this study were an evaluation of the distribution patterns of steroid hormone receptors (ER, PR) and glycodelin A (GdA) expression of proliferative endometrial glandular cells after stimulation with tamoxifen (TAM) and phytoestrogens (PE) (genistein, daidzein). MATERIALS AND METHODS: Human endometrium was obtained from 4 premenopausal women. Glands were stimulated after isolation with single doses of TAM, genistein and daizein (0.1, 1 and 10 mumol/l) and characterised with ER, PR and GdA after 9 days of culture. RESULTS: ER showed a significant decline with the highest TAM and genistein concentration (p < 0.05), whereas PR increased significantly with TAM and genistein concentrations of 1 mumol/l and 10 mumol/l (p < 0.05). GdA did not show any significant expression under TAM and genistein stimulation. Stimulation with daidzein resulted in no statistically relevant alterations in ER, whereas the PR significantly increased with all three concentrations (p < 0.05) and GdA also showed a significant increase with 1 mumol/l (p < 0.05). DISCUSSION: TAM showed anti-estrogenic properties in premenopausal endometrium. PE showed a similar ER, PR expression pattern as TAM, so therefore PE (genistein and daidzein) could also act as antiestrogens. GdA marked a cell transformation from proliferative to secretory status or the antiestrogen effects of TAM and PE.

Adult↗
PubMed1992

[Aminoglutethimide and aminoglutethimide+tamoxifen treatment for advanced breast cancer].

Twenty-eight and 24 patients with advanced breast cancer were treated with Aminoglutethimide (AG) or AG + Tamoxifen (AG + TAM) from June 1984 to June 1989, respectively. Evaluated cases were 25 and 21 treated with AG or AG+TAM, respectively. Objective response was seen in 5/25 (20.0%) for AG treatment with 9, 13, 16, 20 and 31 months remission and 4/21 (19.1%) for AG + TAM treatment with 6, 7, 12 and 26 months remission. Response rate according to dominant site of metastases were 1/10 in soft tissue, 2/7 in bone, 2/7 in lung and pleura treated with AG, 1/9 in soft tissue, and 3/5 in lung treated with AG + TAM treatment. Two of the 5 responding patients in AG treatment group had prior tamoxifen treatment and 3 out of 4 responding patients in AG + TAM treatment group had prior chemoendocrine therapy with tamoxifen and FAC chemotherapy. Main toxic side effects were lethargy and/or rash, and drug discontinuation was required in 3 cases of AG treatment group and 2 cases of AG + TAM treatment group. Serial determination of serum hormone levels during AG or AG + TAM treatment revealed a decrease in estrone and an increase in androstenedione in many cases of both treatment groups. This data suggested that AG treatment may be favorable for endocrine treatment for advanced breast cancer patients, but the response to AG was not augmented by adding TAM.

Administration, Oral↗
PubMed1992

Effect of tamoxifen on preneoplastic cell proliferation in N-nitroso-N-methylurea-induced mammary carcinogenesis.

N-Nitroso-N-methylurea (NMU) is an effective carcinogen for the induction of mammary carcinoma in the rat. Tamoxifen (TAM), used as a chemopreventive agent to reduce tumor incidence, has been well studied using this model. We have utilized the rat mammary carcinoma model to assess the effect of TAM on preneoplastic changes. Fifty-day-old virgin female Sprague-Dawley rats were randomized by weight and divided into the following five groups: Group 1, normal controls (n = 24); Group 2, TAM (n = 20); Group 3, NMU-short term (n = 24); Group 4, NMU-short term + TAM (n = 26); and Group 5, NMU-long term (n = 23). Seven weeks after the exposure to NMU, rats in Groups 1, 2, 3, and 4 were given injections of [3H]thymidine and sacrificed 4 h later for autoradiographic determination of thymidine labeling index (TLI). The rats from Group 5 were observed for 30 weeks after NMU exposure to confirm mammary tumor development. TLI in both terminal ducts and terminal end buds was modulated by treatment with TAM. Carcinogen administration induced higher TLI relative to the normal controls [18.3 +/- 1.8% (SD) versus 15.5 +/- 2.1%, P less than 0.001] in terminal end buds. The effect of carcinogen on TLI was also apparent in the terminal ducts (15.8 +/- 1.1% versus 9.5 +/- 1.1%, P less than 0.001). TAM administration was able to suppress both constitutive and NMU-induced TLI increases in terminal end buds (15.5 +/- 2.1% versus 2.8 +/- 1.1% and 18.3 +/- 1.8% versus 6.8 +/- 1.4%, respectively, P less than 0.001). Similar effects were observed in terminal ducts. In addition to its antiproliferative effect on nontransformed mammary tissue, TAM was effective in suppressing NMU-induced mammary tumor incidence and frequency. NMU-induced hyperproliferation is an intermediate stage in NMU carcinogenesis in the rat and is suppressed by TAM. Mammary epithelial hyperproliferation may provide a useful quantitative intermediate end point to evaluate chemopreventive efficacy.

Animals↗
PubMed1997

[In vitro reversal of homoharringtonine resistance by the combination of tamoxifen and verapamil].

OBJECTIVE: To investigate the reversal of homoharringtonine (HHT)-resistance by tamoxifen (TAM) or verapamil (VER) alone or in combination. METHODS: The drug-sensitivity test was performed with semisolid agar culture. RESULTS: The cytotoxicity of HHT to K562/S cells was not enhanced by TAM or VER alone or in combination,but HHT resistance in HHT resistant cells (K562/H20) was reversed by VER and TAM at nontoxic doses (4micromol/L or 8micromol/L). The IC50 of K562/H20 for HHT decreased from 446.8 +/- 0.08microg/L to 45.1 +/- 0.02microg/L in the presence of 4micromol/L of VER, to 22.4 +/- 0.03microg/L in 8micromol/L of VER, to 85.1 +/- 0.03microg/L in 4micromol/L of TAM and to 26.4 +/- 0.02microg/L in 8micromol/L of TAM. In the presence of combinations of 2micromol/L VER and 4micromol/L TAM and of 2micromol/L VER and 8micromol/L TAM, IC50 of K562/H20 decreased to 30.4 +/- 0.02microg/L and 4.3 +/- 0.04microg/L, respectively. CONCLUSION: HHT-resistance could be reversed by VER or TAM alone, and the combination of the two drugs showed a synergistic effect.

Animals↗
PubMed1990

[Experimental combined chemo- and endocrine therapy with UFT and tamoxifen in human breast carcinoma xenografts serially transplanted into nude mice].

We have investigated the experimental combined chemo- and endocrine therapy of UFT and tamoxifen (TAM) on two human breast carcinoma xenografts, R-27 and Br-10 with estrogen receptors (ER) serially transplanted into nude mice. When sc inoculated tumor started the exponential growth, the treatments were initiated in four groups which were control, UFT 20 mg/kg (as tegafur) po daily for 18 times, TAM 5 mg/kg im twice a week for 6 times and UFT + TAM groups. The antitumor activity of the agents were assessed by the growth curves, the lowest T/C ratios of the relative mean tumor weight and the actual tumor weights at the end of the experiments. TAM alone was effective on both R-27 and ineffective on Br-10, while UFT alone was ineffective on R-27 and Br-10. The combination antitumor activity was observed in R-27 but not in Br-10. When 5 mg of TAM per kg and 20 mg of UFT per kg as tegafur was administered daily po for 2 wk, there were no statistically significant differences between the concentration of 5-FU in UFT alone and UFT + TAM groups for the two strains. By the assay of ER and progesterone receptors using the same specimen, it was observed that ER was stable by the treatment of UFT, while ER was suppressed by the treatment of TAM in both tumor strains. In addition, this suppression of ER by TAM alone was enhanced by the combined treatment with UFT in both the strains.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Regulation of estrogen and progestin receptor concentrations in an experimental rat prostatic carcinoma by estrogen, antiestrogen, and progesterone.

In order to assess prostatic tissue as a target for receptor-mediated estrogen action, we have examined the regulation of estrogen (ER) and progestin receptors (PgR) by estrogen, antiestrogen, and progesterone in cytosolic and nuclear fractions of the R3327H (Dunning) prostatic adenocarcinoma of the rat. Twenty micrograms diethylstilbestrol (DES) with or without 800 micrograms tamoxifen (Tam) were injected s.c. in oil 5 times weekly for 2 weeks. Controls were given oil only. Estrogen receptor assays were carried out using [3H]estradiol and a hydroxylapatite exchange method. Progestin receptors were assayed using [3H]R5020 and dextran-coated charcoal to separate free and bound steroid. All binding data were evaluated by using Scatchard analysis. Treatment with DES depleted cytosolic ER, promoted association of ER with the nuclear fraction, and concomitantly increased PgR concentrations in amounts proportional to nuclear ER. Treatment with Tam alone resulted in higher nuclear ER concentrations than treatment with DES, but induced only one-fifth the amount of PgR. Treatment with DES plus Tam resulted in similar nuclear ER concentrations as with Tam alone, but PgR concentrations were intermediate between those observed with DES alone and Tam alone. Thus Tam exhibited both estrogenic and antiestrogenic properties. In this experiment, the same cytosolic and nuclear extracts were also assayed for ER by using monoclonal antibodies to the receptor in an enzyme immunoassay. No significant differences were observed between the results obtained by the radioligand and enzyme immunoassay methods in the cytosol and nuclear fractions from the control and DES-treated tumors. However in both Tam-treated groups, the ER values obtained by the enzyme immunoassay method were significantly higher than those obtained by the radioligand method in both cytosolic and nuclear fractions. This confirms the observations made by others in female target organs, that monoclonal antibody to ER reacts differently with the Tam-bound ER complex than with the estradiol-bound ER complex. In a separate experiment, administration of progesterone with DES decreased the concentration of nuclear ER to less than one-half that observed after administration of DES alone, with proportional decreases in both cytosolic and nuclear PgR. All these observations indicate that the control of ER and PgR concentrations in this prostatic tumor is identical to that observed in female rat target organs. Use of an immunohistochemical method for the detection of ER in frozen sections indicated that the receptor was localized in the glandular epithelium in both control and DES-treated tumors.

Animals↗
PubMedDate not supplied

Some chemical and biochemical aspects of liver microsomal metabolism of tamoxifen.

The triarylethylene antiestrogen tamoxifen (TAM) has been shown to undergo N-demethylation, 4-hydroxylation, and N-oxidation in animals and man. We have studied the effects of drug metabolism inhibitors metyrapone and SKF 525-A, and an inducer (phenobarbital), on these processes and on overall TAM metabolism, in the presence of rat and rabbit liver microsomes. In the rabbit, metyrapone had no significant inhibitory effects. In the rat, it inhibited N-demethylation by 40% at a concentration of 1 microM, while overall TAM metabolism and 4-hydroxylation were unaffected. SKF 525-A markedly inhibited all of these processes in both species. Enzymatic N-oxidation of TAM in the rat was unaffected by either inhibitor, suggesting this to be independent of cytochrome P-450. In the rat, phenobarbital pretreatment increased N-demethylation by 105% and decreased 4-hydroxylation by 48% compared to corresponding rates in untreated animals. Together with the results obtained with the inhibitors, these findings implicate participation of alternative isoenzymatic forms of cytochrome P-450 in N-demethylation and 4-hydroxylation of TAM. In the rat, the sum of the amounts of the three metabolites found was less than the amount of TAM metabolized, implying the existence of additional biotransformation routes. Radiochromatographic analysis of extracts of incubation mixtures showed the presence of the three known metabolites, plus two additional ones. The more polar of these was spectrally and chromatographically identical to authentic 4'-hydroxytamoxifen. The other one, which was slightly less polar than TAM, was tentatively identified as TAM epoxide.

Animals↗
PubMed1984

Estrogen-like effects of tamoxifen on human endometrial carcinoma transplanted into nude mice.

The effect of tamoxifen (TAM) on human endometrial carcinoma was investigated in nude mice bearing an estrogen receptor-positive or estrogen receptor-negative tumor. The receptor-negative tumor grew rapidly, and the rates of tumor growth of 17 beta-estradiol or TAM-treated animals were identical to the rate of controls. The estradiol receptor and progesterone receptor (PR) concentrations in the tumor cytosol remained undetectable under all experimental conditions. In contrast, the rate of growth of steroid receptor positive tumor was significantly accelerated in the presence of TAM compared to controls (p less than 0.02). The increased tumor growth rate was, however, significantly lower (p less than 0.01) than that observed in animals receiving 17 beta-estradiol. The PR concentration in these tumors was elevated in response to TAM treatment. That the TAM-induced PR was indeed functional was evident from (a) increased activities of the progestin-sensitive enzyme, 17 beta-estradiol hydroxysteroid dehydrogenase and (b) histological appearance of subnuclear vacuolization in these tumors after progestin administration. These studies indicate that continuous, short-term administration of TAM to nude mice results in an estrogen-like effect on endometrial carcinoma. Based on the finding that TAM induces functional PR, we predict that steroid receptor-positive endometrial carcinoma may show a greater response rate to combined, long-term treatment with TAM and progestin.

Animals↗
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↗
PubMed1995

[Effects of long-term administration of tamoxifen on vaginal epithelium and complications of endometrial lesions in breast cancer patients].

The effects of tamoxifen (TAM) on 56 postoperative breast cancer patients who were orally administered TAM and followed up at Cancer Institute Hospital from 1989 to 1992 were studied retrospectively. The maturation index (MI) and karyopyknotic index (KPI) were employed to investigate the effects of TAM on vaginal epithelial cells cytologically, and the patients were also monitored for complications. The results were as follows. (1) The relationship between the duration of TAM therapy and the changes in MI and KPI were analyzed. It was found that, for the MI, intermediate cells (IMT) increased and superficial cells (ST) decreased during TAM administration for up to 4 years, but when the TAM therapy was continued for longer than 4 years, IMT showed a gradual decrease and ST increased gradually. The KPI values showed similar changes. (2) Studies of the endometrium (26 cases) revealed a tendency for few of the long-term administration cases to show a picture of atrophy. Of the total of 56 patients, endometrial lesions were observed in five cases (8.9%), consisting of endometrial cancer in three and cystic glandular hyperplasia in two. The mean duration of TAM administration to these five patients was 54 (+/- S.D.26.8) months. These data indicate that long-term oral administration of TAM involves the possibility of having an estrogenic effect on the vaginal epithelium and the uterine endometrium.

Administration, Oral↗