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PubMed2005

Postoperative adjuvant therapy with tamoxifen, tegafur plus uracil, or both in women with node-negative breast cancer: a pooled analysis of six randomized controlled trials.

PURPOSE: This article reports the results of a pooled analysis of six randomized trials conducted to study the efficacy of uracil and tegafur (UFT) in the adjuvant treatment of node-negative breast cancer patients. PATIENTS AND METHODS: Six randomized controlled trials on node-negative breast cancer patients were conducted from 1992 through 1995 in Japan that included the three, three-arm trials (control [no adjuvant], UFT, and tamoxifen [TAM] groups) and the three, four-arm trials (control, UFT, TAM, and UFT plus TAM groups). Pooled analysis was performed on the data obtained from these six trials (involving 2,934 patients). RESULTS: Overall survival was compared between the UFT group (including both the UFT group and the TAM plus UFT group) and the non-UFT group (control group and TAM group). A significant difference (P = .04) was observed in 5-year survival rates between the UFT (95.9%) and the non-UFT (94.0%) groups. Overall survival was also compared between the TAM group (TAM group and TAM plus UFT group) and the non-TAM group (control group plus UFT group). The 5-year survival rate (95.2%) in the TAM group was not significantly different from that (93.9%) in the non-TAM group, but the subset analysis showed a significant (P = .01) improvement in the estrogen receptor-positive subset. CONCLUSION: Adjuvant UFT improves the overall survival of node-negative breast cancer patients. Given that UFT has milder adverse effects, it is suggested that UFT can be a useful alternative to doxorubicin and cyclophosphamide, or cyclophosphamide, methotrexate, and fluorouracil in the adjuvant treatment for node-negative breast cancer.

Aged↗
PubMed2003

Tamoxifen inhibits cell proliferation via mitogen-activated protein kinase cascades in human ovarian cancer cell lines in a manner not dependent on the expression of estrogen receptor or the sensitivity to cisplatin.

Although tamoxifen (TAM), which is widely used in the treatment of breast cancer, also has a beneficial effect on cisplatin-refractory ovarian cancer, the biological mechanism of this effect has remained obscure. TAM, besides its action as an antiestrogen, also inhibits cell proliferation of estrogen receptor (ER)-negative cells by an unknown mechanism. Therefore, we examined the roles of the MAPK family in the antiproliferative effect of TAM on cisplatin-resistant Caov-3, which expresses ER and cisplatin-sensitive A2780, which does not express ER. The number of viable cells was reduced by TAM dose-dependently. TAM induced the activation of ERK, c-Jun N-terminal protein kinase (JNK), and p38 with different time courses. PD98059 canceled the reduction of the number of viable cells by 1 microM TAM and inhibited the TAM-induced cell-cycle arrest at the G(1) phase and dephosphorylation of the retinoblastoma protein. Either expression of dominant-negative JNK or pretreatment with SB203580 canceled the reduction of the number of viable cells by 5 microM TAM and inhibited the apoptotic nuclear changes and the cleavage of poly (ADP-ribose) polymerase induced by TAM. These results provide evidence that whereas the ERK cascade is involved in the induction of cell-cycle arrest at the G(1) phase by lower concentrations of TAM, the JNK or p38 cascade is involved in the induction of apoptosis by higher concentrations of TAM in both types of cells.

Adenocarcinoma, Papillary↗
PubMed1992

The estrogenic and antiestrogenic properties of tamoxifen in GH4C1 pituitary tumor cells are gene specific.

We have examined the effects of the antiestrogen tamoxifen (TAM) and the estrogen 17 beta-estradiol (E2) on several estrogen-regulated responses in GH4C1 pituitary tumor cells. After 5 days of treatment with either TAM (1.0 microM) or E2 (1.0 nM), the level of PRL mRNA was markedly increased when measured by the cytosolic dot blot procedure. In contrast, only E2 was able to increase the levels of beta-actin mRNA and cytosolic protein, suggesting that this estrogen may stimulate cell proliferation over the course of treatment. This apparent difference in the abilities of TAM and E2 to stimulate GH4C1 cell proliferation was examined directly. TAM had no effect on cell proliferation as evidenced by its inability to increase cellular DNA or deoxythymidine triphosphate incorporation by nuclei isolated from treated cells. In contrast, E2 stimulated cell proliferation as evidenced by increases in cellular DNA and deoxythymidine triphosphate incorporation by isolated nuclei. The abilities of TAM and E2 to induce progesterone receptor (PR) and PR mRNA were also examined. TAM was unable to increase the levels of PR or PR mRNA, whereas E2 was effective in both of these regards. When added in combination with E2, TAM acted as a classical antiestrogen, partially blocking the induction of PR by E2. To determine whether the inabilities of TAM to stimulate cell proliferation and induce PR were a function of TAM concentration, dose-response experiments were performed. TAM at concentrations ranging from 10(-8)-10(-6) M was effective in inducing PRL mRNA, but at none of the tested concentrations was TAM effective in stimulating cell proliferation or inducing PR.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed2004

All trans-retinoic acid acts synergistically with hydroxytamoxifen and transforming-growth factor beta to stimulate apoptosis in MCF-7 breast cancer cells.

The anti-estrogen 4-hydroxytamoxifen (TAM) and vitamin A-related compounds, the retinoids, in combination act synergistically to inhibit growth of breast cancer cells in vitro and in vivo. To clarify the mechanism of this synergism, the effect of TAM and all trans-retinoic acid (AT) on proliferation of MCF-7 breast cancer cells was studied in vitro. TAM and AT acted synergistically to cause a time-dependent and dose-dependent inhibition of MCF-7 cell growth. In a temporally related manner, TAM+AT acted synergistically to downregulate Bcl-2 mRNA and Bcl-2 protein expression, and to stimulate apoptosis. TAM and AT each blocked cell cycle progression throughout 7 days of treatment but without any synergistic or additive effect on this process, indicating a selective synergism for apoptosis. The negative growth factor-transforming growth factor beta (TGFbeta) is secreted by these cells and was studied as a potential mediator of the synergistic effects of TAM+AT on apoptosis. TAM+AT acted synergistically to induce a fivefold increase in TGFbeta1 secretion over 72 h. TGFbeta1 alone had no apoptotic effects on these cells; however, TGFbeta1 in combination with AT acted synergistically to inhibit growth, to downregulate Bcl-2 mRNA and Bcl-2 protein expression, and to stimulate apoptosis of these cells in a manner comparable with that noted for TAM+AT. The synergism of both TAM+AT and TGFbeta1+AT for apoptosis was suppressed by estradiol. Co-incubation of TAM+AT with anti-TGFbeta antibody did not block down-regulation of Bcl-2 protein expression or stimulation of apoptosis. The synergistic effects of TAM+AT on apoptosis therefore occur independently of TGFbeta, although TGFbeta may interact with AT in a novel manner to provide another important anti-proliferative mechanism for breast cancer cells.

Apoptosis↗
PubMed2005

Prognostic significance of cell infiltrations of immunosurveillance in colorectal cancer.

AIM: To determine whether the mast cell (MCs) and tumor-associated macrophage (TAMs) counts have any correlation with clinical outcome in colorectal cancer, and to investigate whether MCs undergo phenotypic changes in colorectal cancer. METHODS: The MC and TAM counts were determined immunohistochemically in 60 patients with colorectal cancer and the depth of invasion, lymph node metastasis rate, distant metastasis rates, and survival rates were compared between patients with low (less than the mean number of positive cells) and high (more than the mean number of positive cells) cell counts. RESULTS: Both patients with a low MC count and patients with a low TAM count had significantly deeper depth of invasion than those with a high MC count and those with a high TAM count (P<0.01 and P<0.01 respectively). Patients with a high MC count and patients with a high TAM count were significantly higher showing significantly lower rates of lymph node metastasis, distant metastasis than those with a low MC count and those with a low TAM count. There were significant positive correlation between MC counts and TAM counts (r = 0.852, P<0.01). In both cancerous tissue and normal colorectal tissue, the predominant MC phenotype was MC(TC). The 5-year survival rate estimated was significantly lower in both patients with a low MC count and patients with a low TAM count than in those with a high MC count and those with a high TAM count (P<0.05 and P<0.01 respectively). CONCLUSION: There appears to be a direct relationship between the number of MCs and clinical outcome in patients with colorectal cancer, even though MCs exhibited no significant phenotypic changes. TAM count is of value to predict the clinical outcome or prognosis. It is more beneficial for estimating biological character of colorectal carcinoma to combine MC and TAM counts.

Aged↗
PubMed2001

Tamoxifen-induced antitumorigenic/antiestrogenic action synergized by a selective aryl hydrocarbon receptor modulator.

Tamoxifen (TAM) is a highly effective selective estrogen receptor (ER) modulator used extensively for the treatment and prevention of breast cancer. However, prolonged treatment of women with TAM may be a risk factor for endometrial cancer, and research in our laboratory is focused on the development of selective aryl hydrocarbon receptor modulators that can be used in combination with TAM to improve its efficacy in the breast and inhibit TAM-induced endometrial effects. This study investigated the effects of the selective aryl hydrocarbon receptor modulators 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF) alone and in combination with TAM in the carcinogen-induced mammary tumor model and in the ovariectomized uterotropic assay using female Sprague Dawley rats. The lowest effective dose of 6-MCDF that inhibited tumor growth was 50 microg/kg/day, and TAM was antitumorigenic at a dose of 100 microg/kg/day. In animals cotreated with TAM + 6-MCDF at doses of 100, 50, or 25 microg/kg/day of each compound, complete inhibition of mammary tumor growth was observed at all doses, and the results are consistent with a more than additive antitumorigenic response for the low dose group (25 + 25 microg/kg) and additive interactions at the 50 and 100 microg/kg doses. In a separate experiment, 6-MCDF (800 microg/kg) inhibited TAM-induced peroxidase activity and progesterone receptor binding in the ovariectomized rat uterus but did not affect TAM-induced bone growth in ovariectomized rats. This study also investigated the effects of TAM and 6-MCDF alone and in combination on ERalpha protein levels in MCF-7 human breast cancer cells as a model for studying interactions between these compounds. The results show that 6-MCDF decreased TAM-induced ERalpha levels in the absence or presence of 17beta-estradiol through proteasome activation, and these interactions may contribute to the observed combined antitumorigenic effects of these compounds.

Animals↗
PubMed2001

Mechanism of lower genotoxicity of toremifene compared with tamoxifen.

An increased incidence of endometrial cancer has been reported in breast cancer patients taking tamoxifen (TAM) and in healthy women participating in the TAM chemoprevention trials. Because TAM-DNA adducts are mutagenic and detected in the endometrium of women treated with TAM, TAM adducts are suspected to initiate the development of endometrial cancer. Treatment with TAM has been known to promote hepatocarcinoma in rats, but toremifene (TOR), a chlorinated TAM analogue, did not. TAM adducts are primarily formed via sulfonation of the alpha-hydroxylated TAM metabolites. To explore the mechanism of the lower genotoxicity of TOR, the formation of DNA adducts induced by TOR metabolites was measured using (32)P-postlabeling/ high-performance liquid chromatography analysis and compared with that of TAM metabolites. When alpha-hydroxytoremifene was incubated with DNA, 3'-phosphoadenosine 5'-phosphosulfate, and either rat or human hydroxysteroid sulfotransferase, the formation of DNA adducts was two orders of magnitude lower than that of alpha-hydroxytamoxifen. alpha-hydroxytoremifene was a poor substrate for rat and human hydroxysteroid sulfotransferases. In addition, the reactivity of alpha-acetoxytoremifene, a model activated form of TOR, with DNA was much lower than that of alpha-acetoxytamoxifen. Thus, TOR is likely to have lower genotoxicity than TAM. TOR may be a safer alternative by avoiding the development of endometrial cancer.

Animals↗
PubMedDate not supplied

Combined effects of lutenizing hormone-releasing hormone analogue with antiestrogen on rat mammary tumors.

The efficacy of luteining hormone-releasing hormone (LH-RH) analogue, buserelin, combind with tamoxifen (TAM) on 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors was investigated. Low-dose of TAM (L-TAM), 1 mg/kg daily, significantly suppressed the growth of tumors compared with no treatment group. High-dose of TAM (H-TAM), 10 mg/kg daily, suppressed growth considerably, and there was a significant difference in the antitumor effect between the L-TAM group and the H-TAM group. The combined treatment using buserelin and L-TAM significantly suppressed the tumor growth compared with the treatment using each single agent. LH-RH analogue actually reduced serum estradiol (E2) levels and enhanced the antitumor effect brought by a therapeutical dose of TAM. The reduction of serum cholesterol levels as a beneficial effect of TAM was reserved when combined with buserelin. Insulin-like growth factor 1 (IGF-1) expressions in tumors were significantly decreased in the buserelin and L-TAM group. These results support the usefulness of this combination in clinical use.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2001

Effects of the new selective estrogen receptor modulator LY353381.HCl (Arzoxifene) on human endometrial cancer growth in athymic mice.

PURPOSE: Arzoxifene (Arzox) is a novel benzothiophene analogue with selective estrogen receptor modulator activity similar to raloxifene. Arzox is being developed as a treatment for breast cancer and has a predominantly antiestrogenic effect on the rodent uterus. Our objectives were to verify whether the novel selective estrogen receptor modulator, Arzox, can be a good first-line agent and also be effective at controlling the growth of endometrial cancer after exposure to tamoxifen (Tam). EXPERIMENTAL DESIGN: We compared the effects of Tam and Arzox on the growth of estrogen responsive ECC-1 endometrial cancer cells in vitro, and we determined their antitumor effects on ECC-1 and EnCa101 endometrial carcinoma growth in athymic mice. RESULTS: We observed that estrogen receptor protein expression is down-regulated by Arzox to the same extent as raloxifene, whereas 4-hydroxytamoxifen, the active metabolite of Tam, does not affect estrogen receptor protein levels. Tam and Arzox inhibit the growth of Tam-naïve ECC-1 tumors in athymic mice. However when Tam-stimulated or estrogen-stimulated (which had been treated with Tam previously) EnCa101 endometrial tumors were treated with Tam or Arzox, we observed a stimulatory effect of both compounds in these models. CONCLUSIONS: The results indicate that Arzox may be a good first-line agent, but it may be ineffective at controlling the growth of endometrial cancer after exposure to Tam. Our data suggest that Arzox stimulates endometrial tumor growth to at least the same extent as Tam, thereby suggesting a limited role as a second-line agent for the patient on Tam who develops occult endometrial cancer.

Animals↗
PubMed2002

An antiangiogenic urokinase-derived peptide combined with tamoxifen decreases tumor growth and metastasis in a syngeneic model of breast cancer.

Expression of urokinase (uPA) and its receptor (uPAR) is associated with increased tumor-cellinvasion and metastasis in several malignancies including breast cancer. An 8-mer peptide derived from the nonreceptor-binding domain of urokinase (A6) has been shown to have antiangiogenic and proapoptotic effects to block the progression of breast cancer in vivo. In the present study, we evaluated the effects of A6 and the antiestrogen tamoxifen (TAM) alone and in combination on estrogen-receptor-positive Mat B-III rat breast cancer cells in vitro and in vivo. Treatment of Mat B-III cells with A6 and TAM resulted in a dose-dependent decrease in tumor-cell invasion through Matrigel; these effects were more marked when A6 and TAM were tested in combination. In addition, treatment of Mat B-III cells with either A6 or TAM resulted in a significant reduction of vascular endothelial growth factor receptor (flk-1) expression and in transforming growth factor beta activity, effects that were significantly higher after combined treatment with A6 and TAM. For in vivo studies, female Fischer rats were inoculated with Mat B-III cells (1 x 10(6)) into the mammary fat pad. These orthotopic tumors were staged to 30-40 mm(3) in volume and then treatment was initiated with A6 (75 mg/kg/day) and TAM (3 mg/kg/day) alone or in combination. Both A6 and TAM caused a significant reduction in tumor volume; however, these antitumor effects were significantly greater in animals receiving both A6 and TAM, which demonstrated a 75% reduction in tumor growth as compared with control animals. The number of macroscopic tumor foci was significantly reduced in A6-treated animals, whereas TAM failed to exhibit any antimetastatic effects. Histological analysis of primary tumors from different groups showed a decrease in new blood-vessel density and increased tumor-cell death in A6- and TAM-treated animals, and these effects were greater in experimental animals receiving A6 and TAM in combination. Collectively, these studies demonstrate that the addition of novel antiangiogenic/antimetastatic agents like A6 to hormone therapy can enhance the antitumor effects of hormone therapy through increased inhibition of angiogenesis and induction of tumor-cell death.

Adenocarcinoma↗
PubMed1992

Modulation of cisplatin resistance in human malignant melanoma cells.

Previous studies have shown that the combination of dacarbazine, carmustine, cisplatin (DDP), and tamoxifen (TAM) produced a 53% overall response rate in patients with disseminated melanoma. Deletion of TAM from the regimen resulted in a fall in the response rate to 10%, and reincorporation of TAM returned the response rate to 52%, suggesting an important role for TAM. Using the human melanoma cell line T-289, we examined the nature of the interaction between TAM and each member of this combination in clonogenic assays in soft agar. The combination of TAM with DDP was highly synergistic as demonstrated by median effect analysis, whereas TAM was antagonistic with carmustine and an activated form of dacarbazine. The mean combination index at 50% kill was 0.26 +/- 0.02 (mean +/- SD) for TAM and DDP. This marked synergism was observed at concentrations of TAM that are clinically achievable. TAM had no effect on the uptake of the DDP analogue [3H]dichloro(ethylenediamine)platinum(II). There was no effect on the formation or repair of DDP intrastrand DNA adducts. Similarly, there was no effect demonstrated on the intracellular concentrations of glutathione or metallothioneins. We conclude that the interaction between TAM and DDP is truly synergistic in this cell line and is accomplished through none of the four mechanisms commonly associated with DDP resistance.

Carboplatin↗
PubMed1988

Development of tamoxifen-stimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration.

Long-term tamoxifen (TAM) therapy was examined in athymic mice bearing MCF-7 tumors of different sizes. Six months of TAM treatment caused no increase in tumor size (compared to placebo treatment) for animals treated initially following implantation of tumor pieces (approximately 1 mm3) or for animals with 0.2-cm2 tumors (grown with 1 month of estrogen treatment). Tumors could be regrown with estradiol treatment in animals treated with either therapy and these tumors contained both estrogen and progesterone receptors. However, more tumors could be restimulated with estradiol following pretreatment with TAM than with placebo. A third group of animals had larger tumors (grown with 7 weeks of estrogen treatment to a approximately 0.6-cm2 area) before TAM or placebo treatment. These tumors partially regressed after 4 months of TAM or placebo therapy but began to regrow in both groups until the end of the experiment at 8 months. Tumors that grew in both groups were estrogen receptor positive and when retransplanted into athymic animals could grow with estradiol. However, the tumor that grew during TAM therapy, when retransplanted, could grow successfully only with further TAM treatment. Tumors growing with TAM contained double the estrogen receptor content of the estradiol-stimulated MCF-7 tumors that were not exposed to TAM [390 +/- 37 (SE) fmol/mg protein versus 174 +/- 14 fmol/mg protein]. These results may represent a form of TAM resistance, i.e., TAM dependence that may occur before hormone independence is exhibited.

Animals↗
PubMed1993

Tamoxifen modulation of cisplatin sensitivity in human malignant melanoma cells.

Tamoxifen (TAM) markedly increases the response rate of malignant melanoma to treatment with cisplatin (DDP), carmustine, and dacarbazine, and we have previously reported that there is a highly synergistic interaction between TAM and DDP with respect to the cytotoxic effect against the human melanoma cell line T-289 (E. F. Mc Clay et al., Cancer Res., 52: 6790-6796, 1992). The mechanism underlying synergy was investigated by examining the effect of selection for either DDP or TAM resistance on the magnitude of the synergy quantitated by median effect analysis. The combination index at 50% cell kill was 0.26 +/- 0.02 (SD) for parental T-289 cells (indicating marked synergy), 0.54 +/- 0.14 for cells selected for low-level DDP resistance (indicating moderate synergy), and 1.39 +/- 0.20 for cells selected for low-level TAM resistance (indicating antagonism). Thus, factors that regulate DDP sensitivity have a moderate effect on reducing the DDP/TAM synergy, but determinants of TAM sensitivity have a major effect. The known biochemical effects of TAM include antagonism of estrogen at the estrogen receptor (ER) and inhibition of calmodulin and protein kinase C activity. T-289 cells contained undetectable amounts of ER by the dextran-coated charcoal assay and expressed only trace amounts of ER mRNA, and another more avid ER antagonist, droloxifene, failed to interact synergistically with DDP. N-(6-Aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), a potent calmodulin antagonist, failed to demonstrate synergy with DDP, and activation of protein kinase C, instead of interacting antagonistically with DDP, yielded synergy. TAM did not alter the cell cycle phase perturbation produced by exposure to DDP alone. We conclude that the synergy between TAM and DDP is not mediated by the effects of TAM on the ER, calmodulin, protein kinase C, or cell cycle regulation. However, the factors that determine cellular sensitivity to TAM also determine whether TAM interacts synergistically with DDP.

Antineoplastic Agents↗
PubMed2026

Lipid metabolic reprogramming of tumor-associated macrophages drives resistance to immune checkpoint blockade in lung cancer: a narrative review of mechanisms and therapeutic strategies.

BACKGROUND AND OBJECTIVE: Immune checkpoint inhibitors (ICIs), represented by programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), have shown remarkable efficacy in non-small cell lung cancer (NSCLC); however, many patients still develop resistance to immunotherapy. Although small cell lung cancer (SCLC) is also an important histological type of lung cancer, NSCLC accounts for the majority of lung cancer cases. Current research on ICI development, first-line treatment efficacy, and the mechanisms of lipid metabolism in tumor-associated macrophages (TAMs) is predominantly focused on NSCLC. In patients with advanced NSCLC, objective response rates (ORRs) with PD-1/PD-L1 inhibitor monotherapy remain limited. Only in patients with high PD-L1 expression [tumor proportion score (TPS) &#x2265;50%] and without sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements does the ORR increase to approximately 40-45%. TAMs are a key component of the immunosuppressive tumor microenvironment (TME). Lipid metabolic reprogramming profoundly influences the functional and transcriptional features of TAMs. This review aims to integrate relevant evidence, elucidate how TAM lipid metabolism promotes immunosuppression and resistance to ICIs, and outline potential therapeutic strategies. METHODS: We searched PubMed/MEDLINE, Web of Science, and Scopus for publications up to June 2026 using terms combining lung cancer, TAMs, lipid metabolism, and immune checkpoint blockade/resistance. Mechanistic, translational, and clinically relevant studies were selected by author consensus. KEY CONTENT AND FINDINGS: Lipid uptake, de novo lipogenesis, fatty acid oxidation (FAO), cholesterol remodeling, and eicosanoid metabolism are not independent processes in TAMs. Lipid metabolic reprogramming in TAMs ultimately suppresses type I interferon (IFN-I) signaling, upregulates PD-L1 expression, and impairs the function of CD8+ T cells with stem-like features, thereby establishing an immunosuppressive TME and leading to resistance to ICIs. In lung cancer, hypoxia, high lactate levels, and tobacco exposure further shape the lipid phenotype of TAMs, such as lipid raft enrichment and lipid-laden macrophage subsets like SPP1+ macrophages. Different driver genomic backgrounds differentially impact tumor cell-intrinsic metabolism and the lipid metabolic programs of myeloid cells. In preclinical models, interventions targeting these metabolic axes, including TAM-directed delivery systems, have demonstrated potential therapeutic benefit when combined with anti-PD-1/PD-L1 therapy. CONCLUSIONS: Targeting TAM lipid metabolism to convert immunologically cold tumors into more inflamed, ICI-responsive tumors is a promising strategy to overcome resistance in NSCLC. Identification of predictive biomarkers of therapeutic response and development of cell-selective drug delivery systems come to be major challenges.

Non-small cell lung cancer (NSCLC)↗
PubMed1988

Induction of progesterone receptor with tamoxifen in human breast cancer with special reference to its behavior over time.

The behavior of progesterone receptor (PR) values over time in human breast cancer during tamoxifen treatment was studied. Of 97 patients with operable breast cancer, 24 were preoperatively treated with tamoxifen (20 mg twice daily) for 3 days (TAM 3-day), 22 were treated for 7 days (TAM 7-day), 21 for 14 days (TAM 14-day), and 30 received no treatment (control group). Surgically removed breast tumors were assayed for the progesterone receptor by the dextran-coated charcoal method. The PR values (fmol/mg DNA) (mean +/- standard error [SE]) of PR-positive tumors in the control, TAM-3, TAM-7, and TAM-14 day groups were 571 +/- 176, 1699 +/- 408 (P less than 0.01), 1675 +/- 463 (P less than 0.05), and 686 +/- 191, respectively. There was a 4.6-fold increase in the mean PR value in postmenopausal patients and a two-fold increase in premenopausal patients after TAM treatment for 3 and 7 days. We concluded that PR induction provoked by TAM reached a peak on day 3, continuing at this level until day 7. A longer treatment (14 days) with TAM appears to abolish the PR inducing activity, probably because of, first, estrogenic and, later, the antiestrogenic effects of TAM.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Combination hormonal therapy with tamoxifen plus fluoxymesterone versus tamoxifen alone in postmenopausal women with metastatic breast cancer. An updated analysis.

A randomized trial was performed to determine if therapy with tamoxifen (TAM) plus fluoxymesterone (FLU) was more efficacious than TAM alone for postmenopausal women with metastatic breast cancer. Patients failing TAM could subsequently receive FLU. The dose of both drugs was 10 mg orally twice daily. Objective responses were seen in 50 of 119 (42%) TAM patients and 64 of 119 (54%) TAM plus FLU patients (two-sided P = 0.07). Time to disease progression was better for TAM plus FLU (medians: 11.6 versus 6.5 months; Cox model, P = 0.03). Duration of response and survival were similar in the two treatment arms. Among 97 patients with estrogen receptor (ER) of 10 or greater and 65 years of age or older, there were highly significant advantages for treatment with TAM plus FLU in both response rate and time to progression. Of particular note is that in this patient group TAM plus FLU showed a survival advantage (Cox model, P = 0.05). Although these data require confirmation in a prospective randomized trial, they suggest that there is a substantive therapeutic advantage for TAM plus FLU over TAM alone in elderly women with ER of 10 fmol or greater.

Adult↗
PubMed1991

A double-blind trial of tamoxifen plus prednisolone versus tamoxifen plus placebo in postmenopausal women with metastatic breast cancer. A collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic.

This trial was conducted to determine if the reported superiority of tamoxifen (TAM) plus prednisolone (PRDLN) over TAM alone in postmenopausal women with metastatic breast cancer could be corroborated. A total of 326 patients were randomized on a double-blind trial to TAM (10 mg twice daily) plus placebo or TAM plus PRDLN (5 mg twice daily). Six patients (2%) were disqualified. Considering 256 patients with measurable or evaluable disease, objective responses were seen in 48 (38%) of 126 TAM patients and 61 (47%) of 130 TAM plus PRDLN patients (chi-square, P = 0.15). Considering all 320 evaluated patients, median time to disease progression was 11 months for TAM and 10 months for TAM plus PRDLN (log rank, P = 0.81), and median survival time was 35 and 32 months, respectively (P = 0.40). Covariate analyses showed no significant association between treatment and outcome. Weight gain and edema were significantly greater with TAM plus PRDLN. The addition of PRDLN to TAM is not advocated for the management of postmenopausal women with metastatic breast cancer.

Adult↗
PubMed2002

Mechanism of action of a dominant negative c-jun mutant in inhibiting activator protein-1 activation.

The dominant negative c-jun TAM-67 has been shown to inhibit tumor promotion induced by 12-O-tetradecanoylphorbol-13-acetate and okadaic acid (OA). To better understand this phenomenon, we investigated the mechanism of action of TAM-67 in response to OA. To identify the mechanism of action, we used a 6xHis-tagged TAM-67 as well as chimeric constructs of TAM-67 that either cannot bind DNA or cannot heterodimerize with wild-type transcription factors. The results of these studies indicated that TAM-67 acts by blocking or squelching. The results of elecrophoretic mobility-shift assays showed that TAM-67 must act by squelching in response to OA, as TAM-67 cannot be found in DNA-binding complexes. We then identified some of the proteins with which TAM-67 interacts. They include all members of the jun and fos families as well as the cAMP response element binding protein, activating transcription factor-1, activating transcription factor-2, and RelA (p65). Thus, we have shown that TAM-67 squelches the induction of activating transcription factor-1 transactivation in response to OA and that TAM-67 is capable of interacting with proteins that control transactivation by binding to the 12-O-tetradecanoylphorbol-13-acetate response element, cAMP response element and nuclear factor-kappaB sites.

Animals↗