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PubMed2001

Findings from recent National Surgical Adjuvant Breast and Bowel Project adjuvant studies in stage I breast cancer.

Before 1989, credible information about the treatment of breast cancer was derived mainly from randomized clinical trials that enrolled women with either metastatic (stage IV); locally advanced (stage III); or primary, operable, axillary lymph node-positive (stage II) disease. This report provides information from six recent National Surgical Adjuvant Breast and Bowel Project (NSABP) trials involving lymph node-negative (stage I) patients. Findings from NSABP B-13 demonstrated, through 14 years of follow-up, improvements in disease-free survival (DFS) and overall survival from methotrexate and fluorouracil (MF), regardless of age, in women with estrogen receptor (ER)-negative tumors. Results from NSABP B-19, which was conducted with similar patients, demonstrated, through 8 years, a greater overall DFS and survival advantage with cyclophosphamide and MF (CMF) than that observed with MF. Findings from NSABP B-23, in which patients similar to those in B-13 and B-19 were randomly assigned to receive CMF plus placebo, CMF plus tamoxifen (TAM), doxorubicin (Adriamycin) and cyclophosphamide (AC) plus placebo, or AC plus TAM, demonstrated no difference in relapse-free survival (RFS) or overall survival among the four groups through 5 years, either for all patients or relative to age. NSABP B-14, which was carried out in women with ER-positive tumors, compared the outcomes of those who received either placebo or TAM. Through 14 years, superior DFS and overall survival advantages, as well as a reduction in contralateral breast cancer, were observed with TAM. No additional benefit resulted from TAM administration beyond 5 years. Findings from NSABP B-20, a second study conducted in patients with ER-positive tumors, showed, after 8 years, both a DFS and an overall survival advantage from TAM plus either MF or CMF over that achieved with TAM alone. A recent meta-analysis in women with negative lymph nodes and either ER-negative or ER-positive tumors of less than or equal to 1 cm in size was conducted using patients from five NSABP trials. After 8 years, the RFS in women with ER-negative tumors was greater in the group treated with surgery and chemotherapy than in those who underwent surgery alone. In women with ER-positive tumors, RFS and overall survival advantages were observed from the addition of chemotherapy to TAM when that treatment regimen was compared with TAM alone. In addition, evidence has been presented from NSABP B-21, a trial evaluating radiation therapy (XRT) and/or TAM for the prevention of ipsilateral breast tumor recurrence (IBTR) after lumpectomy in women with tumors less than or equal to 1 cm. Findings have shown that XRT is superior to TAM and that XRT + TAM is superior to XRT alone for preventing IBTR. The findings demonstrate that chemotherapy and/or hormonal therapy is effective for the management of women with negative axillary lymph nodes and either ER-negative or ER-positive tumors. Because it also has been proven effective in women with tumors less than or equal to 1 cm, such therapy might also be considered in the treatment of that patient population.

Breast Neoplasms↗
PubMed2002

Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less.

PURPOSE: This trial was prompted by uncertainty about the need for breast irradiation after lumpectomy in node-negative women with invasive breast cancers of </= 1 cm, by speculation that tamoxifen (TAM) might be as or more effective than radiation therapy (XRT) in reducing the rate of ipsilateral breast tumor recurrence (IBTR) in such women, and by the thesis that both modalities might be more effective than either alone. PATIENTS AND METHODS: After lumpectomy, 1,009 women were randomly assigned to TAM (n = 336), XRT and placebo (n = 336), or XRT and TAM (n = 337). Rates of IBTR, distant recurrence, and contralateral breast cancer (CBC) were among the end points for analysis. Cumulative incidence of IBTR and of CBC was computed accounting for competing risks. Results with two-sided P values of.05 or less were statistically significant. RESULTS: XRT and placebo resulted in a 49% lower hazard rate of IBTR than did TAM alone; XRT and TAM resulted in a 63% lower rate than did XRT and placebo. When compared with TAM alone, XRT plus TAM resulted in an 81% reduction in hazard rate of IBTR. Cumulative incidence of IBTR through 8 years was 16.5% with TAM, 9.3% with XRT and placebo, and 2.8% with XRT and TAM. XRT reduced IBTR below the level achieved with TAM alone, regardless of estrogen receptor (ER) status. Distant treatment failures were infrequent and not significantly different among the groups (P =.28). When TAM-treated women were compared with those who received XRT and placebo, there was a significant reduction in CBC (hazard ratio, 0.45; 95% confidence interval, 0.21 to 0.95; P =.039). Survival in the three groups was 93%, 94%, and 93%, respectively (P =.93). CONCLUSION: In women with tumors </= 1 cm, IBTR occurs with enough frequency after lumpectomy to justify considering XRT, regardless of tumor ER status, and TAM plus XRT when tumors are ER positive.

Aged↗
PubMed2001

Effects of tamoxifen and melatonin on mammary gland cancer induced by N-methyl-N-nitrosourea and by 7,12-dimethylbenz(a)anthracene, respectively, in female Sprague-Dawley rats.

Chemopreventive effects were analysed of antioestrogen TAM and of MEL on NMU- or DMBA-induced mammary gland cancer, respectively, in female Sprague-Dawley rats. NMU was administered intraperitoneally in two doses each of 50 mg/kg b.w. between 46th-57th postnatal days. DMBA was given by gavage in one dose (20 mg per animal) between 50th-54th postnatal days. The treatment with MEL began 12 days and the treatment with TAM 10 days before carcinogen administration; both chemopreventive substances were administered until the end of the experiment (24 weeks after carcinogen application). TAM was administered subcutaneously twice a week in a dose 2.5 mg/kg b.w. MEL was given in tap water (20 mg/ml) daily between 3 p.m. to 8 a. m. The tumour incidence, tumour frequency per group and animal, latency period, tumour volume, body weight gain in the rats and weight of uterus (in the experiment with NMU) were evaluated. TAM suppressed carcinogenesis to 0% incidence like TAM+MEL in both the NMU and DMBA models. In NMU-induced mammary carcinogenesis MEL lowered the tumour volume (although statistically non-significantly) by 30% in comparison with the control group; in DMBA-induced mammary carcinogenesis it lowered the tumour volume (2.70 +/- 0.81 cm3 vs. 0.90 +/- 0.33 cm3) and lengthened (non-significantly) the latency period (by 12 days). The weight gain of animals in both NMU and DMBA models and relative uterus weight in the NMU model were significantly lower in the groups treated with TAM and TAM+MEL as compared to the control group and the group treated with MEL. Evaluation of the combined effect of TAM+MEL was not possible due to total suppression of carcinogenesis by TAM. TAM and TAM+MEL are highly effective agents in rat mammary carcinogenesis prevention, but the side effects of TAM in humans limits its use in clinical oncology.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1999

Tamoxifen in the treatment of metastatic malignant melanoma: still a controversy? (Review).

This review attempts to summarize the available preclinical and clinical evidence supporting the inclusion of tamoxifen (TAM) in the treatment of malignant melanoma, in the attempt to identify what role, if any, the antiestrogen could have in the present and future therapeutic approach to this disease. Emphasis has been given to the biological basis of the potential TAM mechanisms of action, as well as to the rational basis underlying the study design of the reported clinical experiences. Results to date show that TAM has no useful activity as a single agent in melanoma patients, most published response rates reaching less than 10%. A still controversial question is the inclusion of the antiestrogen in different active chemotherapy regimens, since clinical investigations on the role of TAM in combination therapy of advanced melanoma have produced inconclusive results. While several early trials suggested that TAM may improve the response rates when combined with different cytotoxic agents, the majority of subsequent reports, including recent randomized studies, did not show a significant benefit stemming from TAM addition to various single-agent or multi-agent combinations. Only one controlled trial showed a significant improvement in both response rate and survival for patients receiving dacarbazine plus TAM, an effect primarily noted in women, and confirmatory studies have not been reported. From a biological standpoint, why the activity of this poorly effective single-agent is potentiated when given in combination with some cytotoxic agents is not clearly understood, although preclinical and clinical experiences support a possible synergistic effect of TAM combined with cisplatin, particularly when the former is added at high doses. Of major interest is a body of experimental studies producing confirmatory data that induction of apoptosis, probably through the inhibition of protein kinase C, as well angiogenesis inhibition, at least in part mediated by TGF-beta stimulation, are alternative ways through which TAM suppresses tumor cell growth, independently of the expression of estrogen receptors. These findings also provide a model and rationale for combining TAM with agents which are able to modify cell biology in melanoma. The investigation on TAM-containing biological combinations appears to be a promising avenue to be explored in the near future. To this end, clinical research should incorporate biological studies to allow the selection of subgroups of patients who are most likely to benefit from TAM-based treatment.

Antineoplastic Agents, Hormonal↗
PubMedDate not supplied

The influence of tamoxifen on the secretion of transforming growth factor-beta2 (TGF-beta2) in glioblastomas: in vitro and in vivo findings.

BACKGROUND: Only a minority of patients with malignant gliomas respond to continuous high-dose tamoxifen (TAM) treatment. Therefore a method to predict the efficiency of TAM-treatment would be desirable. Analogous to previous studies in breast cancer patients, we investigated whether the dynamics of TGF-beta2 plasma levels allow the prediction of response to TAM-treatment in glioblastoma patients as well. MATERIALS AND METHODS: TGF-beta2 plasma levels of glioblastoma patients treated with 200 mg TAM/day on a continuous basis and of control patients not treated with TAM were measured by using an ELISA. In addition, the effect of TAM and 4-OH-TAM on the secretion of TGF-beta2 by established glioma cell lines as well as the effect of TGF-beta2 itself on cell proliferation were investigated in vitro. RESULTS: The effect of TAM on TGF-beta2 plasma levels did not correlate with the clinical response to TAM-therapy in glioblastoma patients. The in vitro experiments showed that TAM and 4-OH-TAM stimulate established glioma cell lines to increase their secretion of TGF-beta2. Externally added TGF-beta2 (nM) had no effect on cell proliferation of the same cell lines. CONCLUSION: In contrast to breast cancer patients, the clinical response to TAM in glioblastoma patients is not reflected by changes of TGF-beta2 plasma levels. It has to be assumed that, despite an increase of TGF-beta2 production by glioblastoma cells in response to TAM in vitro, such elevated production in vivo does not reach the plasma due to either the lower tumor burden in glioblastoma disease compared to breast cancer patients or due to some local sequestration process.

Antineoplastic Agents, Hormonal↗
PubMed2002

[Assessment of post-administration body distribution of toremifene and tamoxifen, and their administration regimens].

Toremifene is an anti-estrogenic drug like tamoxifen. We assessed the body distributions after administration of toremifene and tamoxifen in order to evaluate their treatment regimens by measuring the concentrations in tissues. It is known that, after toremifene (TOR) or tamoxifen (TAM) is consecutively administered to breast cancer patients, TOR or TAM and their main active N-desmethyl-metabolites (TOR-1 or TAM-1) are detected in sera, tumor tissues, and lymph nodes. Accordingly, after we administered toremifene or tamoxifen to primary breast cancer patients previous to surgery, we measured the concentrations of TOR, TOR-1, TAM, TAM-1 in sera, tumor tissues, and lymph nodes. We found that the concentrations of TOR and TOR-1 in sera, tumors, and lymph nodes reached a peak about 2 weeks after administration of toremifene 40 mg. Likewise, the concentrations of TAM and TAM-1 in sera, tumors, and lymph nodes reached a peak about 2 weeks after administration of tamoxifen, although the peak levels were lower than those of TOR or TOR-1. The concentrations of TAM-1 in lymph nodes were significantly and positively correlated to the duration of administration of TAM, and it was predicted that the concentration of TAM-1 in lymph nodes would reach a steady state at more than 4 weeks after administration of tamoxifen. The concentrations of TOR and TOR-1 were higher in tumors and lymph nodes than in sera. Furthermore, the concentrations of TOR and TOR-1 were significantly higher than those of TAM and TAM-1 in sera and tumors, respectively. Moreover, the concentration in tissue increased in a dose-dependent manner with administration of toremifene 120 mg. There were no significant differences between breast cancers positive and negative for estrogen receptors, with regard to the concentrations of TOR and TOR-1 in either sera, tumors, or lymph nodes. In conclusion, it would be expected that treatment with toremifene might be more effective for breast cancer than that with tamoxifen.

Adult↗
PubMed2003

Twenty-year results of the Naples GUN randomized trial: predictive factors of adjuvant tamoxifen efficacy in early breast cancer.

PURPOSE: Tamoxifen (TAM) is increasingly administered to new early breast cancer patients. Because it is not devoid of toxic effects, we studied factors potentially predictive of its efficacy. EXPERIMENTAL DESIGN: From 1978 to 1983, 433 patients were enrolled in the GUN randomized trial: 206 were assigned to TAM versus 227 controls (no-TAM). Premenopausal patients with axillary lymph node involvement (60 TAM versus 65 no-TAM) also received nine CMF cycles. Eight biological markers were retrospectively assayed for most patients: estrogen; progesterone; prolactin receptors (PrlRs); microvessel count (MVC); S-phase fraction; tumor ploidy; epidermal growth factor receptor (EGFR); and HER2. We performed a multivariate test of the TAM/covariate interactions to establish whether these variables predicted for TAM efficacy. Estimates of the TAM effect were expressed as hazard ratio (HR) of death of TAM over no-TAM patients with 95% confidence intervals (95% CIs). RESULTS: At a median follow-up of 15 years, PrlRs, MVC, S-phase fraction, ploidy, and EGFR did not influence TAM efficacy. Differently, HER2 had an overall significant predictive effect: HR = 0.59 (95% CI: 0.40-0.87) in HER2-negative subjects versus HR = 1.09 (95% CI: 0.63-1.87) in HER2-positive subjects (interaction test: P = 0.04). The predictive effect of HER2 was also evident in the subgroup of patients with steroid receptor-positive tumors (HER2 positive: HR = 1.33, 95% CI: 0.70-2.51; HER2 negative: HR = 0.73, 95% CI: 0.47-1.14). CONCLUSIONS: With the statistical power of the present randomized trial, S-phase, ploidy, EGFR, PrlR, and MVC do not seem to predict for TAM efficacy. Conversely, our data support the hypothesis that tumors overexpressing HER2 might not benefit from adjuvant TAM.

Adolescent↗
PubMed2006

The regulatory effect of tamoxifen on fibronectin expression in estrogen-dependent MCF-7 breast carcinoma cells.

We investigated the regulatory effect of tamoxifen (TAM) on fibronectin (FN) expression in estrogen-dependent MCF-7 breast carcinoma cells both in vitro and in vivo. in vitro, MCF-7 cells were cultured with 17beta-estradiol (E2) and/or TAM. In the animal experiment in vivo, MCF-7 tumors were grown in ovariectomized athymic mice by implanting a sustained release E2 pellet. The E2 pellets were removed after 3 weeks of E2 treatment. Animals were then divided into four groups: 1) an E2 (0.72 mg/pellet) pellet [E2(+)]; 2) an E2 and a TAM (5 mg/pellet) pellet [E2(+)TAM]; 3) no treatment [E2(-)] and 4) a TAM pellet [E2(-)TAM]. Following each treatment for 4 weeks, all animals were sacrificed and tumors were removed. Specimens, cells (in vitro) or tumors (in vivo), were homogenized and assayed for FN by Western blots. In the in vitro experiment, FN expression in MCF-7 cells decreased by incubating with 10(-9) M E2 and increased with 10(-6) M TAM. The effect of TAM increasing FN expression was inhibited by incubation accompanied with 10(-9) M E2 or 1 microg/ml transforming growth factor-beta (TGF-beta) neutralizing antibody. In the in vivo animal experiment FN expression in the tumors of E2(+) mice was lower than that of E2(-) mice. However, TAM increased FN expression in the tumors regardless of E2 pellet. These results suggest that TAM increases FN expression of MCF-7 breast carcinoma cells and that these regulatory effects of TAM on FN expression are partly mediated by TAM-induced TGF-beta.

Animals↗
PubMed1990

Effects of tamoxifen and somatostatin analogue on growth of human medullary, follicular, and papillary thyroid carcinoma cell lines: tissue culture and nude mouse xenograft studies.

The knowledge that (1) the normal thyroid contains somatostatin, (2) polypeptide growth factors influence thyroid cell function, and (3) thyroid cells contain steroid hormone receptors prompted us to add somatostatin analogue No. 201-995 (SMS) (5 ng/ml) and/or tamoxifen citrate (TAM) (5 mumol/L) to 7-day monolayer cultures (50,000 cells/well) of three separate human thyroid carcinoma cell lines: DR081 (medullary), WR082 (follicular), and NPA'87 (papillary). Results, tabulated as cell numbers/well (X10(5) on day 7, revealed that TAM inhibited growth of medullary and follicular cells and that TAM plus SMS inhibited growth of papillary cells. In vivo studies of subcutaneous tumor cell xenografts in nude mice have documented that TAM (5 mg subcutaneous pellet) significantly inhibits the growth of medullary implants. Flow cytometric DNA studies of medullary cell cultures demonstrated a reduced G2 + M phase with TAM treatment. For papillary cell implants, TAM plus SMS (5 micrograms subcutaneously, twice daily) did not suppress tumor growth. All three cell lines were negative for estrogen receptor; addition of estradiol (5 ng/ml) to medullary cell cultures neither stimulated replication nor reversed the inhibitory effects of TAM in vitro. We conclude that (1) TAM slowed the growth of a cell line of human medullary carcinoma, both in vitro and in vivo; (2) this effect was not reversed by estradiol; (3) TAM plus SMS inhibited replication of a papillary carcinoma cell line in vitro, but not in vivo; and (4) TAM alone and TAM plus SMS inhibited replication of cultures of a human follicular thyroid carcinoma cell line. TAM and SMS may be useful in treatment of some human thyroid carcinomas.

Adenocarcinoma↗
PubMed1990

Chemoendocrine therapy in DMBA-induced rat mammary carcinoma.

In the present study, chemotherapy with 5-fluorouracil(5-Fu), endocrine therapy with tamoxifen (TAM), and chemoendocrine therapy with concominant use of 5-FU and TAM were performed and compared for DMBA-induced rat mammary carcinoma, a hormone-dependent tumor. The study was designed to assess the usefulness of chemoendorine therapy based on the antitumor effects and changes in hormone receptor levels. The response rates in the groups treated with 5-Fu or TAM alone and the combination of 5-Fu and TAM were 60%, 50% and 62%, respectively. There was no difference in these response rates. The tumor regression rates in these treatment groups were 22 +/- 69%, 20 +/- 54% and 46 +/- 37%; again there was no difference among the three groups. After treatment, the estrogen receptor (ER) and progesterone receptor (PgR) levels decreased significantly in the groups treated with TAM alone and the combination of 5-FU and TAM but remained unchanged in the group treated with 5-FU alone. The decreases in the ER and PgR levels in responsive tumors after treatment were considerably greater in the groups greated with TAM alone and the combination of 5-FU and TAM than in the group treated with 5-FU alone. However, the changes in the receptor levels in nonresponsive tumors did not differ among the three treatment groups. Moreover, there were no differences in the antitumor effects and changes in receptor levels between the groups treated with TAM alone and the combination of 5-FU and TAM. These results suggest that the antitumor effect observed in the combination therapy with 5-FU and TAM was mainly due to the action of TAM. In brief, the expected additive effects of chemoendocrine therapy were not observed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

Differential ability of antiestrogens to stimulate breast cancer cell (MCF-7) growth in vivo and in vitro.

We have previously described an MCF-7 breast cancer cell variant, MCF-7TAM, which is stimulated to grow in athymic mice by tamoxifen (TAM) (M. M. Gottardis and V. C. Jordan, Cancer Res., 48:5183-5187, 1988). Earlier experiments have shown that TAM exhibits some profound estrogen-like effects in mice whereas TAM is less estrogenic in the rat. The aim in these studies was to compare the ability of MCF-7TAM to grow in different host environments and to determine whether the TAM-stimulated phenotype could be maintained in vitro. Ovariectomized athymic mice and rats were implanted with 1-mm3 pieces of MCF-7TAM tumor and treated with estradiol, TAM, or control silastic capsules. After 9 weeks of growth in either species, TAM or estradiol-treated groups both had sustained growth of MCF-7TAM compared with the control groups. To determine the effects of estradiol and TAM on immune function in athymic mice, splenocytes from treated or control athymic mice, challenged with poly(I:C), were assayed for natural killer (NK) cell activity against 51Cr-labeled YAC1 target cells. Both estradiol and TAM abolished lytic activity by 12 weeks of treatment. To evaluate the role of a decrease in NK-cell activity in the host on growth of MCF-7TAM xenografts we compared the growth effects in athymic and NK-cell deficient, ovariectomized beige mice. TAM stimulated MCF-7TAM in both beige and athymic mice; however, the tumor grew more rapidly in control beige mice than in control athymic mice. This study demonstrated that TAM-stimulated growth could occur in vivo. However, TAM or 4-hydroxytamoxifen did not cause a stimulation of MCF-7TAM compared with wild-type MCF-7 cells when experiments were conducted in vitro. These studies demonstrate that a suppression immune function can facilitate the growth of MCF-7TAM in athymic animals. However, additional components of the host environment contribute to TAM-stimulated growth in vivo.

Animals↗
PubMed1987

Endocrine effects of adjuvant chemotherapy and long-term tamoxifen administration on node-positive patients with breast cancer.

Ovarian and pituitary hormones were determined in pre- and postmenopausal breast cancer patients before and at intervals during adjuvant chemotherapy or chemotherapy plus tamoxifen (TAM). Chemotherapy did not affect gonadotrophin levels in postmenopausal patients; however, inclusion of TAM in the regimen produced a partial (approximately 50%) reduction in circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone. Gonadotrophin levels remained reduced as long as TAM therapy continued, at which time they rose to postmenopausal values. Chemotherapy (6-12 months) caused ovarian failure in premenopausal patients with decreases in estrogen (estrone plus estradiol) and rises in gonadotrophin levels to postmenopausal levels. Inclusion of TAM in the regimen caused an initial 3-fold rise in peak circulating estrogen levels before ovarian failure (6-9 months of therapy). Some younger patients (approximately 40 years of age) who had a short course (4 months) of chemotherapy plus TAM followed by continuous TAM therapy alone resumed ovulatory menstrual cycles. Estrogen, progesterone, and follicle-stimulating hormone levels were increased compared with control subjects. Those patients who experienced ovarian failure with adjuvant chemotherapy plus TAM only had a partial rise in gonadotrophins compared with patients receiving chemotherapy alone. TAM maintained the levels of gonadotrophins for as long as therapy was administered, at which time they rose to postmenopausal levels. Although TAM exhibited estrogen-like effects on gonadotrophins there was no estrogen-like increase in circulating prolactin levels in either pre- or postmenopausal patients. One patient experienced an estrogen receptor-positive recurrence during long-term tamoxifen therapy. Serum levels of tamoxifen and metabolites declined in the year prior to the recurrence and this was associated with a rise in gonadotrophins. This indicated noncompliance by the patient. Compliance can be monitored either directly with serum levels of TAM or by serial gonadotrophin determinations. We suggest that the optimal antitumor activity of TAM will be achieved in a low estrogen environment with continuous high levels of the drug in the serum. We recommend that patients undergoing long-term TAM therapy be monitored for complete ovarian failure and drug compliance.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

[Effects of antiestrogens and medroxyprogesterone acetate on the clonogenic growth of tamoxifen-sensitive and resistant human breast cancer cells].

Effects of tamoxifen (TAM), nafoxidine (NFA), 4-hydroxytamoxifen (4-OH-TAM), 3-hydroxytamoxifen (3-OH-TAM), and medroxyprogesterone acetate (MPA) on the clonogenic growth of a hormone-responsive human breast cancer cell line (MCF-7) and its tamoxifen-resistant variant (R-27) were studied. TAM, (10(-6)M) showed an inhibitory effect on the colony formation in a plastic dish of MCF-7 cells only in medium containing DDC-treated FCS (E2(-) medium). With the presence of E2 (10(-8)M) in the medium (E2(+) medium), TAM did not show any effect on cell growth. Irrespective of the presence or absence of E2 in the medium, there was no inhibitory effect of TAM on the clonogenic growth of R-27 cells. The ID50 values, expressed as the suppression of plating efficiencies, obtained by adding NFA, 4-OH-TAM, 3-OH-TAM, and MPA to the MCF-7 cells were shown to be 2 X 10(-7)M, less than 10(-8)M, 1 X 10(-7)M, and 4 X 10(-7)M, respectively in the E2 (-) medium, and 2 X 10(-6)M, 2 X 10(-7)M, 2 X 10(-6)M, and 4 X 10(-8)M respectively in the E2 (+) medium. For the R-27 cells, ID50 values obtained by adding NAF, 4-OH-TAM, 3-OH-TAM, and MPA were 7 X 10(-7)M, 5 X 10(-8)M, 4 X 10(-7)M, and 6 X 10(-8)M, respectively in the E2(-) medium, and 2 X 10(-6)M, 2 X 10(-6)M, greater than 5 X 10(-6)M, and 1 X 10(-8)M, respectively in the E2(+) medium. These results suggest that the antiestrogens used produce their suppressive effects on cell growth depending on the E2 concentration in the medium in these estrogen-responsive cell lines, and that the monohydroxytamoxifens are more potent than TAM in suppressing cell growth. The effects of MPA are shown to be different from the antiestrogen used in that MPA inhibited the growth of both TAM-sensitive and-resistant cells, independent of the presence or absence of E2 in the medium. The R-27 cell line, a variant of the MCF-7 cell line, appears to be a good model for studying antiestrogen resistance and for evaluating the effectiveness of agents against endocrine-resistant breast cancer cells.

Breast Neoplasms↗
PubMed1988

Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse.

The effects of the antiestrogen tamoxifen (TAM) on the growth of two hormone-sensitive human tumors have been examined in athymic mice. The endometrial tumor, EnCa101, was stimulated to grow by TAM either alone or when combined with estradiol. This contrasted with the nonstimulation of the breast tumor, MCF-7, by TAM alone and the antagonist action of TAM on estradiol-stimulated growth of MCF-7 tumors. The individual tumor responses were observed even when the two tumor types were implanted on opposite sides of the same animal. This suggests that host metabolism of TAM does not dictate tissue response. The conclusion is supported by the finding of very similar patterns of metabolites in the two tumors after administration of [ring-3H]TAM. Tissue metabolism therefore is unlikely to be involved. Progesterone receptor levels were higher in estradiol (376 +/- 35 fmol/mg cytosol protein)- or TAM (317 +/- 37 fmol/mg cytosol protein)-stimulated EnCa101 tumors than control (42 +/- 5 fmol/mg cytosol protein) and increased further with combined treatment (485 +/- 75 fmol/mg cytosol protein). Estrogen receptor levels, however, were lower in estradiol (45 +/- 11 fmol/mg cytosol protein)-treated tumors than control (92 +/- 13 fmol/mg cytosol protein) but higher than control in TAM (200 +/- 15 fmol/mg cytosol protein)-treated tumors. Tumors grown with estradiol and TAM had lower estrogen receptor levels (130 +/- 7 fmol/mg cytosol protein) than tumors grown with TAM alone. Estrogen receptor levels indicate that TAM may not be acting exactly as estradiol in the EnCa101 tumor. Overall, these findings suggest that the disparate pharmacology of TAM is a tissue-specific phenomenon.

Animals↗
PubMed1987

Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model.

We have compared the antitumor activities of the antiestrogens, keoxifene (LY 156758) and tamoxifen (TAM), using the N-nitrosomethylurea (NMU) rat mammary carcinoma model. To establish an effective antitumor dose of TAM in this model, rats were treated 2 wk after initiation with NMU for 8 wk with s.c. daily injections of 6.25 micrograms, 25 micrograms, or 100 micrograms of TAM in peanut oil. At the 25-micrograms and 100-micrograms daily doses, TAM completely inhibited tumor appearance during the therapy period. An effective antitumor dose of TAM (100 micrograms daily) was compared to 20-, 100-, or 500-micrograms daily doses of keoxifene 7 wk after NMU initiation. None of the keoxifene-treated groups prevented the appearance of tumors as effectively as TAM during 13 wk of therapy. When keoxifene was compared to TAM at equivalent daily doses of 100 and 500 micrograms daily starting 2 wk after NMU injection, the keoxifene groups again failed to prevent the appearance of all tumors during 10 wk of therapy. TAM, however, completely suppressed any tumor formation. In the same experiment, animals treated with 500 micrograms of TAM had therapy stopped after 10 wk, and tumors started to appear 6 wk later. No tumors appeared when animals (n = 25) were treated continuously for 23 wk with 100 micrograms of TAM. In separate experiments, keoxifene (500 micrograms daily) and TAM (500 micrograms and 100 micrograms daily) administered for 1 wk blocked the binding of [3H]-estradiol in NMU tumors and in uteri. The effect lasted for up to 5 wk after antiestrogen therapy was stopped. These experiments demonstrate that keoxifene is not as effective in its antitumor action as TAM in the NMU model.

Animals↗
PubMed1984

Induction of neovascularization in vivo and endothelial proliferation in vitro by tumor-associated macrophages.

The role of macrophages in neovascularization of tumors was investigated by examining the ability of tumor-associated macrophages (TAM) and their conditioned culture media to induce neovascularization in the cornea of syngeneic rats and proliferation of bovine aortic endothelial cells in culture. TAM were isolated from a 3-methycholanthrene-induced fibrosarcoma propagated in F344 male rats by enzymatic dissociation and were purified by centrifugation through continuous Percoll density gradients, followed by adherence to fibronectin-coated dermal collagen gels. The angiogenic potential of (a) TAM and their 72-hour conditioned culture media, (b) whole tumor cell suspensions (WTCS), (c) tumor cell suspensions depleted of TAM (TCS), and (d) macrophage-depleted tumor cell suspensions reconstituted with TAM (TCS + TAM) were compared. Cells were injected directly; conditioned media were concentrated 10-fold, incorporated into slow-release Hydron pellets, and implanted intracorneally. Stimulation of bovine aortic endothelial cell growth by TAM was assayed in culture with TAM-conditioned media and compared with responses induced by conditioned media from peptone-elicited rat peritoneal exudate macrophages. TAM and their conditioned media induced neovascularization in 38 of 40 corneas (95%) and 15 of 17 corneas (88%), respectively. Maximal vessel ingrowth occurred by the 5th day of implantation. Neovascular responses induced by WTCS (24 of 26 corneas, 92%) and TCS (17 of 24 corneas, 71%) occurred on the 7th and 10th day, respectively. TCS + TAM induced neovascular responses comparable to those elicited by WTCS (19 of 20 corneas, 95%). Addition of TAM-conditioned media to bovine aortic endothelial cell cultures stimulated a 10-fold increase in cell number within 10 days. This growth stimulatory effect was comparable to or greater than responses induced by conditioned media from rat peritoneal macrophages. Our results demonstrate that TAM are potent stimulators of neovascularization and endothelial cell proliferation and that depletion of macrophages from tumor cell suspensions significantly decreased their angiogenic potential. This suggests that neovascularization of this tumor is mediated in part by macrophages.

Animals↗
PubMed1982

Progress report on two clinical trials in women with advanced breast cancer. Trial I: tamoxifen versus tamoxifen plus aminoglutethimide. Trial II: aminoglutethimide in patients with prior tamoxifen exposure.

A progress report is presented on two on-going clinical trials in women with advanced breast cancer. In Trial I to date, 56 patients have been randomized to tamoxifen (TAM) alone or TAM plus aminoglutethimide (AG) (plus hydrocortisone). Patients failing TAM can then receive AG. The two groups are reasonably well balanced with respect to prior hormonal therapy exposure (TAM, 19%; TAM plus AG, 17%), age, disease-free interval, performance score, and estrogen receptor status. The TAM plus AG group has a higher incidence of visceral dominant disease (41 versus 26%) and prior chemotherapy exposure (41 versus 33%). Responses have been observed in 7 of 27 (26%) patients on TAM and 11 of 28 (39%) on TAM plus AG. Median times to treatment failure (defined as disease progression, unacceptable toxicity, or patient refusal) are 211 and 123 days, respectively (log-rank on time to treatment failure, p = 0.87). Toxicity is greater for TAM plus AG with a higher incidence of skin rash, lethargy, and dizziness. Thrombotic events were seen in one patient on TAM and two patients on TAM plus AG. One patient on TAM plus AG developed leukopenia and sepsis. The data are too preliminary for one to draw firm conclusions regarding relative efficacy. In TRial II to date, 35 patients with prior tamoxifen exposure have received AG. The mean number of prior systemic therapies is 3.2 (range, 1 to 7). The response rate is 20% and similar with (21%) or without (19%) prior chemotherapy exposure. The median time to treatment failure is 92 days. One patient developed leukopenia and sepsis. Additional patient accrual is necessary to allow characterization of potential efficacy within prognostically important subsets.

Adult↗
PubMed1982

Tamoxifen and metabolites in MCF7 cells: correlation between binding to estrogen receptor and inhibition of cell growth.

The binding of [3H]tamoxifen ([3H]Tam), a nonsteroidal antiestrogen, and of 4-[3H]hydroxytamoxifen ([3H]OH-Tam), a metabolite accumulated in vivo in target cell nuclei, was characterized in soluble extracts of human breast cancer MCF7 cells growing in a medium depleted in estrogens. Saturation analysis indicated a much higher affinity for OH-Tam (Kd = 0.15 nM) than for Tam (Kd = 4.8 nM). The binding of [3H]Tam and [3H]estradiol was competitive and mutually exclusive, and the binding site concentration (0.16 to 0.47 pmol/mg total protein) was similar for both ligands, strongly suggesting that antiestrogens were binding to the estrogen receptor (ER) in these cells. The ability of Tam and of some of its metabolites or derivatives to prevent the MCF7 cell growth was found to be correlated with their affinity for ER as determined by direct interaction or by binding competition with [3H]estradiol on the uterine and MCF7 cytosol ER. OH-Tam was the highest-affinity compound and was 100-fold more active than Tam. The inhibitions observed were actually due to Tam and OH-Tam, respectively, since we did not detect any significant metabolism of these two labeled compounds by the MCF7 cells. N-desmethyltamoxifen, the other Tam metabolites found in high concentration in human plasma, was as effective as Tam while cis-tamoxifen appeared less effective. Compound E, which has no lateral chain, was the only tested compound having a good affinity for ER and a poor efficiency in preventing cell growth. These results support the hypothesis that antiestrogens control the growth of breast cancer by acting directly on the ER located in cancer cells.

Biotransformation↗