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PubMed2000

Nonsteroidal anti-estrogens inhibit the functional differentiation of human monocyte-derived dendritic cells.

Dendritic cells (DC) are professional antigen-presenting cells with a unique capacity to initiate and regulate immune responses. Immature CD1a(+) DC can be cultured from CD14(+) monocytes in the presence of interleukin (IL)-4 and granulocyte macrophage colony-stimulating factor in vitro. Results of this study show that the nonsteroidal anti-estrogens toremifene and tamoxifen inhibit this differentiation. In the presence of anti-estrogens the cells lose CD14 expression, but remain CD1a(-) and clearly have less dendritic processes than immature DC. Functionally, anti-estrogen-treated cells are inferior to immature DC in inducing proliferation of allogeneic T cells and in producing IL-12 p70 protein after CD40 ligation. The expression of the costimulatory molecules CD80 and CD86 is differentially regulated by anti-estrogens during DC differentiation. Furthermore, anti-estrogens are also able to inhibit the terminal maturation of DC. By inhibiting the functional differentiation of DC, anti-estrogens may have a role in the treatment and prevention of autoimmune diseases. (Blood. 2000;95:2875-2882)

Antigens, CD↗
PubMed2000

[A case of far advanced breast cancer with distant metastases which had mostly disappeared after chemoendocrine therapy].

We report a case of far advanced breast cancer showing an excellent response to chemo-endocrine therapy. A 40-year-old female with a huge ulcerated tumor on her left anterior chest visited our hospital. Distant metastases were found in the lymph nodes, liver and bone. Therefore, endocrine therapy (toremifene and medroxyprogesterone acetate) and chemotherapy (cyclophosphamide, Therarubicin and 5-fluorouracil) were started as a combination treatment. As a result, the main tumor and metastatic lesion were remarkably reduced, and extended mastectomy with resection of right axillary lymph nodes was performed. Histologically, cancer cells in the primary lesion mostly disappeared, and only one lymph node in the left axillary lesion showed metastasis. No recurrence was found for 16 months after the surgical treatment. The combined therapy in the present case was extremely effective.

Adult↗
PubMedDate not supplied

Antiestrogens affect both pathways of killer cell-mediated oncolysis.

BACKGROUND: Our previous studies indicate that antiestrogenic drugs tamoxifen (TX) and toremifene (TO) augment immune oncolysis induced by various killer cells. The underlying mechanism(s), however, have not been fully elucidated. MATERIALS AND METHODS: Ovarian carcinoma cells freshly isolated from cancer patients and the human erythroleukemia cell line, K562 were used as targets for killer cells and/or the anti-Fas monoclonal antibody, CH-11 in 51Cr release assays. In a number of experiments, extracellular Ca++ was chelated by EGTA/MgCl2 to distinguish Ca(++)-dependent perforin/granzyme pathway from Fas/FasL pathway. Fas expression was studied by flow cytometry. RESULTS: Ovarian carcinoma cells were sensitized by antiestrogens towards enhanced cytolysis mediated by autologous cytotoxic lymphocytes. Antiestrogens also significantly augmented the killing of ovarian carcinoma cells triggered by anti-Fas monoclonal antibody. Flow cytometry analyses showed an upregulation of Fas (CD 95/Apo-1) upon TX or TO treatment in a number of cases. By contrast, antiestrogen treatment did not induce Fas expression in the Fas-negative K562 cells; yet, natural killer cell-mediated cytotoxicity against K562 was augmented by antiestrogens and maximal lysis was achieved when both target and effector cells were treated. The presence of Ca++ chelator (EGTA/MgCl2) in the assay abrogated killing of K562 and its antiestrogen--mediated augmentation. This indicates the involvement of the perforin/granzyme pathway. CONCLUSION: Antiestrogens can influence both Fas/FasL and perforin/granzyme pathways of killer cell--mediated oncolysis.

Endopeptidases↗
PubMedDate not supplied

Antiestrogens sensitize human ovarian and lung carcinomas for lysis by autologous killer cells.

BACKGROUND: The antiestrogens tamoxifen (TX) and toremifene (TO) were shown previously to enhance the lysis of target cells by natural killer cells (NK), lymphokine activated killer (LAK) cells, and by cytotoxic T lymphocytes (CTL). MATERIALS AND METHODS: CTL were cultured from lung cancer tissue and from ascites fluid of ovarian carcinoma patients with the aid of human recombinant interleukin-2 (hrIL-2). The target, effector or both cell populations were pretreated by TX, TO and/or with human recombinant interferon-alpha (IFN-alpha). RESULTS: Significant enhancement of cytotoxicity occurred when the tumor targets or both the target and effector cells were treated with TX, TO or when these drugs were used in combination with IFN-alpha. The lytic activity of CTL cultured from draining lymph nodes of lung cancer patients, was also observed after similar treatment. The lytic effect of autologous LAK cells derived from peripheral blood was increased to a lesser extent, which could be amplified by additional treatment with IFN-alpha. CONCLUSIONS: The antiestrogens TX and TO and IFN-alpha enhance the lysis of autologous tumor cells by CTL and LAK effectors.

Antineoplastic Agents, Hormonal↗
PubMed2000

Cross-resistance of triphenylethylene-type antiestrogens but not ICI 182,780 in tamoxifen-stimulated breast tumors grown in athymic mice.

The triphenylethylene antiestrogens, idoxifene (Idox) and toremifene (Tor), are structurally related analogues of tamoxifen (Tam) and were developed to improve the therapeutic index for advanced breast cancer patients. However, the issue of cross-resistance with Tam for these new agents is critical for clinical testing because the majority of breast cancer patients have already received or failed adjuvant Tam. The goal of this study was to determine the effectiveness of Idox as an antitumor agent in three models of Tam-stimulated breast cancer in athymic mice and compare the results with the actions of Tor and ICI 182,780 in a Tam-stimulated MCF-7 tumor model. We first compared the activities of Tam and Idox in the 17beta-estradiol (E2)-stimulated MCF-7 tumor line MT2:E2. Tam and Idox reduced E2-stimulated growth by 65-70% (week 9: P = 0.0009 for Tam, P = 0.0005 for Idox versus E2 alone). However, Tam (1.5 mg daily) and Idox (1.0 mg daily) both produced T47D breast tumors in athymic mice during 23 weeks of treatment (12 tumors/22 sites and 15 tumors/18 sites, respectively). Tam and Idox stimulated tumor growth equally in two different Tam-stimulated MCF-7 models and in a T47D model. Tor was completely cross-resistant with Tam in the MCF-7 tumor model, which implied that neither Idox nor Tor would be effective as a second-line endocrine therapy after Tam failure and may offer no therapeutic advantages over Tam as adjuvant therapies. In contrast, ICI 182,780, a pure antiestrogen currently being tested as a treatment for breast cancer after Tam failure, had no growth-stimulatory effect on the MCF-7 Tam-stimulated breast tumor line. This agent may provide an advantage as an adjuvant therapy and increase the time to treatment failure.

Animals↗
PubMedDate not supplied

Breast-conservation treatment for bilateral breast cancer in five Japanese women.

Between August 1989 and September 1999, breast-conservation treatment (BCT) was performed in 250 of 256 breast cancer patients. Five of the 250 patients had bilateral breast cancer, and 4 with synchronous bilateral breast cancer of the 5 were concomitantly treated by chemo-endocrine therapy before simultaneous breast-conservation surgery for bilateral breast cancer. Chemotherapy was performed using cyclophosphamide, pirarubicin, and 5-fluorouracil, while endocrine therapy was performed using an antiestrogen agent (tamoxifen or toremifene). All patients were also treated by radiotherapy. Since no severe side effects or complications were induced by these therapeutic approaches, bilateral breast cancer may be successfully treated by BCT as in unilateral breast cancer. However, of the 5 patients with bilateral breast cancer, cancer recurrence in the axillary lymph nodes was detected only in 1 patient with T2N1 cancer 78 months after simultaneous breast-conservation surgery for bilateral breast cancer.

Adult↗
PubMed2002

[Antiestrogen therapy in the treatment of breast neoplasms].

During recent years the development of hormone therapy for the treatment breast neoplasms has seen, in addition to classic aspecific antiestrogens (AE) like tamoxifen (TAM) and to a lesser extent toremifen, a major development of new molecules divided into two groups: the first is the so-called selective estrogen receptor modulators (SERMs), the most important of which is Raloxifen, which mediate estrogen-agonist effects in some tissues and estrogen-antagonist effects in others; the second group includes the aromatase inhibitors (AI), important enzymes for peripheral estrogen conversion. Some studies compare or associate classic AE with the new SERMs and AI, both in adjuvant therapy and in treatment for advanced forms. Other trials assess the anti-osteoporotic activity of some SERMs which present concomitant inhibitory activity on the breast and endometrium.

Adult↗
PubMed1988

Antiestrogen therapy for breast cancer: current strategies and future prospects.

The antiestrogen tamoxifen has had an enormous impact upon the therapy of breast cancer. It is the most widely used antihormonal therapy. The success of tamoxifen has stimulated broader applications of the drug (long-term adjuvant therapy and chemosuppression) and has spurred the development of toremifene, droloxifene, and zindoxifene. However, the clinical evaluation of tamoxifen as a chemosuppressive agent is not sufficiently advanced to be able to provide any conclusion about the success of this strategy. It may be a decade before a randomized clinical study can be analyzed and the value of chemosuppression assessed. In the near future, the clinical evaluation of new antiestrogens will provide additional information about the potential value of these drugs and will perhaps challenge our ideas about the mode of action of antiestrogens as antitumor agents.

Breast Neoplasms↗
PubMed1995

[Adjuvant endocrine therapy for breast cancer].

As reported by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) in Lancet (1992), the 10-year relapse-free survival or overall survival was significantly better in the tamoxifen (TAM) treatment group than in the control group in both node-positive and -negative groups. Adjuvant TAM treatment works better on patients over 50 years of age. Adjuvant TAM treatment for over 2 years is more effective than less than that time. Some reports demonstrated that long-term TAM treatment caused an increase in the circulating estrogen levels of premenopausal patients. This increase blocked the antitumor effect of TAM in a dose dependent fashion in our animal models. Similar results were obtained in toremifene or TAT-59 in our animal models. These results show that antiestrogens are more effective for postmenopausal than premenopausal women. LH-RH agonist or aromatase inhibitor may be a promising adjuvant endocrine agent of breast cancer. Combination therapy of TAM and LH-RH agonist, or LH-RH agonist and aromatase inhibitor will be an effective new adjuvant endocrine therapy for breast cancer. The combination of endocrine therapy and biological response modifiers, or of endocrine therapy with vitamin D3 will be clinically used in the future.

Animals↗
PubMed1995

[Circumvention of cisplatin resistant ovarian cancer cells by antiestrogens].

Antiestrogens (AEs) have been considered to elicit antitumor effects via estrogen receptor. However, recent reports have demonstrated that AEs had an antitumor effect even in cases without estrogen receptor, and that AEs caused various kinds of biological behavior such as a chemosensitizing effect. We therefore investigated the possibility of circumvention of cisplatin (CDDP) resistance due to the chemosensitizing effect of AEs by using 5 ovarian cancer cell lines. They were named KF, MH, KK, KFra and KFrb cell lines. KF and MH were derived from serous cystadenocarcinomas, and KK from a clear cell carcinoma. KFra and KFrb were CDDP-resistant cell lines developed from the KF cell line. MCF-7 cell line derived from breast cancer was used as a control. The study of a 50% inhibitory concentration (IC50) revealed that clomiphene (CLO) had the most potent antiproliferative effect among the AEs used, and was followed by tamoxifen (TAM) and toremifene (TOR) with a similar effect. On the whole, the degree of CDDP sensitivity was not correlated with the degree of AE sensitivity. KFra cell line which had the highest CDDP-resistance among the 5 ovarian cancer cell lines used was the most sensitive to AEs, especially to CLO. In the study on the combined administration of CDDP and AEs, 1 microM of CLO significantly reduced the IC50 of CDDP to KFrb, KK and MCF-7 cell lines. Similarly, 1 microM of TAM significantly reduced the IC50 of CDDP to KF, KFra and MCF-7 cell lines, and 1 microM of TOR significantly reduced it to KFra, KK and MCF-7 cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)

Cisplatin↗
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

Modulation of biological responses of normal human mononuclear cells by antiestrogens.

The effect of three non-steroidal antiestrogens, Tamoxifen, Toremifene and ICI 164, 384, on various aspects of the immune response was studied in cultures of normal peripheral mononuclear blood cells. The drugs differ somewhat in their effect on the functions tested (pokeweed mitogen-induced immunoglobulin synthesis and cell proliferation, mixed lymphocyte reaction, Interleukin 2 (IL 2) synthesis, IL 2 receptor expression and Tumor Necrosis Factor (TNF alpha) synthesis). However, all three are immunosuppressive. On the other hand, ICI 164, 384 and Tamoxifen were stimulatory for TNF alpha production by adherent cells which may prove as an additional feature in antiestrogen treatment.

Adult↗
PubMed1997

Tamoxifen causes gene mutations in the livers of lambda/lacI transgenic rats.

Tamoxifen, a rat liver carcinogen, was administered to female lambda/lacI transgenic rats at a dose of 20 mg/kg body weight by gavage for 6 weeks, and the animals were sacrificed 2 weeks later. Tamoxifen induced liver DNA adducts and caused a significant increase in mutation frequency (MF) of approximately 3-fold at the lacI gene in liver DNA. Liver DNA from animals dosed with tamoxifen at 10 mg/kg also showed a similar increase in MF. The mutations were characterized by a raised proportion of: (a) G:C to T:A transversions; (b) insertions of base pairs; and (c) deletions of pairs of G:C base pairs. These observations indicate that tamoxifen induces a distinct spectrum of mutations compared with that found in controls. Toremifene, a noncarcinogenic analogue of tamoxifen with similar estrogenic/antiestrogenic properties examined at 20 mg/kg body weight using the same dosing regime as tamoxifen was not mutagenic. A single oral dose of the rat liver carcinogen aflatoxin B1 (0.5 mg/kg) also significantly raised the MF. In conclusion, although tamoxifen is not mutagenic in regulatory short-term tests, it is a gene mutagen in the rat liver.

Aflatoxins↗
PubMedDate not supplied

Anti-estrogens potentiate the immunotherapy of the P815 murine mastocytoma by cytotoxic T lymphocytes.

Many animal and human tumors are infiltrated with killer cells. Recent studies have shown that the stimulation of such killer cells with interleukin-2 improves their tumor rejecting capacity. In this paper we demonstrate that the anti-estrogens, tamoxifen (TX) and toremifene (TO), enhance host resistance by sensitizing the tumor target to killer cell mediated lysis. The P815 mastocytoma syngeneic to DBA/21 mice was used. Cytotoxic T lymphocytes (CTL) were detected in the spleens of mice 12-14 days after tumor inoculation. In vitro target, effector, or both cell types were treated with either TX (1 microM) or TO (5 microM) for 4 hours prior to cytotoxicity testing by 51Cr release. Mice bearing P815 mastocytomas, 5 mm in diameter, were treated orally with TX or TO and were given CTL isolated from the spleens of tumor bearing donors i.p. Tumor growth, mortality, and immunological memory in cured animals were monitored. Both TX and TO treatment sensitized P815 target cells to lysis by CTL isolated from tumor bearing animals. The transfer of killer cells from the spleens of tumor bearing mice produced tumor suppression in the recipients, which could be enhanced by additional oral treatment by TX or TO. Complete cure was achieved in a significant number of animals, showing partial or complete resistance to a subsequent lethal dose of P815 cells. These experiments indicate that killer cells isolated from mice bearing progressive tumors can have an immunotherapeutic effect in syngeneic tumor bearing recipients and that the antiestrogens, TX and TO, may be used to potentiate the immunotherapy of this tumor.

Adoptive Transfer↗
PubMed1997

Reliability of estrogen receptors in predicting response to antiestrogens.

In postmenopausal women, about 65% to 80% of breast cancers contain estrogen receptors (ERs) and 50% to 65%, progesterone receptors (PRs). Receptor-positive breast cancer is somewhat less common in premenopausal patients. Recently, the biochemical dextran-coated charcoal (DCC) assay for ERs has been replaced in many laboratories by immunohistochemical and immunocytochemical methods, which are not disturbed by endogenous estrogen or antiestrogen treatment. Receptors now can also be assayed from fine-needle biopsy and paraffin-embedded tissue specimens. The ER has been shown to be a prognostic factor for overall and disease-free survival in newly diagnosed and relapsed breast cancer. The value of the ER in predicting response to both surgical and medical endocrine treatment of breast cancer has been demonstrated. Ample evidence supports the predictive value of the ER in the treatment of breast cancer with the antiestrogen tamoxifen (Nolvadex). The first studies of a new antiestrogen, toremifene (Fareston), support the value of the ER in predicting breast cancer treatment results.

Antineoplastic Agents, Hormonal↗
PubMedDate not supplied

Combination therapy of the H2712 murine mammary carcinoma with cytotoxic T lymphocytes and anti-estrogens.

BACKGROUND: The triphenylethylene antiestrogenic agents, tamoxifen (TX) and toremifene (TO), are currently being used for the therapy of estrogen dependent breast carcinomas and for some other estrogen receptor positive tumors. Some observations indicate that these drugs may have a beneficial effect on estrogen receptor negative tumors as well. MATERIALS AND METHODS: The H2712 mammary carcinoma of C3H/HeJ mice was studied in combination immunotherapy experiments using cytotoxic T lymphocytes (CTL) and TX or TO. The effect of TX and TO on the in vitro lysis of H2712 cells by CTL was also investigated. Finally, the H2712 cells were examined for the presence of estrogen receptors. RESULTS: Both TX and TO potentiated the lysis of H2712 cells by CTL in vitro, and exerted a growth inhibitory and therapeutic effect on H2712 mammary carcinomas in vivo. The therapeutic effect of CTL isolated from tumor bearing mice was improved on H2712 carcinomas when the animals were also treated orally by TX or TO. Using the dextran-coated charcoal assay, H2712 cells were found to be negative for classical estrogen receptors. CONCLUSIONS: These results indicate that the anti-estrogens, TX and TO, have the ability to suppress the growth of the estrogen receptor negative mammary carcinoma and to amplify target cell lysis by tumor-reactive CTL. By this mechanism these drugs enhance host immunity to an estrogen receptor negative tumor.

Animals↗
PubMedDate not supplied

Combination immunotherapy of the P815 murine mastocytoma with killer cells, IL-2 and anti-estrogens.

BACKGROUND: Lymphokine activated killer (LAK) cells, cytotoxic T lymphocytes (CTL) and interleukin-2 (IL-2) all are being tested in cancer immunotherapy with modest success. The anti-estrogenic drug, toremifene (T0), was found earlier to amplify cancer immunotherapy with killer cells in mice. Here T0 is examined in combination with CTL and IL-2 in immunotherapy experiments. MATERIALS AND METHODS: The P815 mastocytoma of DBA/2 mice was treated with combinations of CTL, LAK cells and T0 and combinations of CTL, IL-2 and T0 along with control groups. Tumor growth rate and mortality has been recorded. RESULTS: Combined treatment with CTL and LAK cells cured 25% of tumor bearing animals, as did treatment with tamoxifen (TX) or T0 alone. When killer cells were given in conjunction with anti-estrogens the cure rate was 75% with both TX and T0. Human recombinant IL-2 significantly inhibited tumor growth but no cures occurred. CTL alone cured 25% of the animals. When CTL and IL-2 treatment was given jointly with T0 75% of tumor bearing animals were cured. CONCLUSIONS: The results indicate that treatment with anti-estrogens increased the efficiency of immunotherapy by killer cells. This was true also when CTL therapy was supplemented with IL-2 treatment.

Animals↗
PubMed1998

Status of antiestrogen breast cancer prevention trials.

Various ongoing double-blind clinical trials are evaluating the use of tamoxifen (Nolvadex) as chemoprevention for breast cancer. A total of over 24,000 healthy women have been randomized to these trials, and it should be possible, by the year 2000, to detect any preventive effect of tamoxifen in healthy women. Furthermore, with the large numbers of women involved, it should be possible to evaluate prevention in subgroups of participants according to risk of the disease, particularly those women carrying high-risk genes, such as BRCA1 and BRCA2. Adverse effects of tamoxifen have been identified, including a transient bone loss in premenopausal women and uterine effects, including polyps, cysts, and endometrial cancer, in postmenopausal women. Although the potential benefit of tamoxifen in preventing breast cancer in healthy women is likely to outweight any potential long-term risks, the use of other tamoxifen-like drugs, such as raloxifene (Evista) and toremifene (Fareston) is now being investigated.

Antineoplastic Agents, Hormonal↗