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PubMed1991

Alterations in hepatic peroxidation mechanisms in thioacetamide-induced tumors in rats. Effect of a rhodium(III) complex.

A model of liver hyperplastic noduligenesis was induced in rats in vivo by long-term administration of thioacetamide (TAM; 100 mg/kg day i.p.). Three doses of 50 mg/kg of an antitumoral rhodium(III) complex were administered at 14, 9 and 5 days before the end of TAM treatment. Blood and liver were obtained from either TAM, Rh(III) complex or TAM plus Rh(III) complex-treated rats in order to determine the interaction of both (tumoral and antitumoral) substances with the biochemical pathways related to glutathione redox cycle, enzyme activities involved in the oxidative stress coupled to the NADPH/NADP pair and enzymes related to the mono-oxygenase P450 system. The results showed that TAM induced an imbalance between the activities of glutathione-coupled enzymes. Glutathione reductase activity increased along with the intoxication, while glutathione peroxidase activity decreased. Alterations in the activity of soluble glutathione peroxidase were parallel to those of catalase. These results, together with decreased activities of enzymes related to cytochrome P450 mono-oxygenase system, NADPH cytochrome P450 reductase and NADH cytochrome b5 reductase, suggest that liver cells are not protected against the peroxidative stress produced by chronic administration of TAM. The Rh(III) complex did not produce significant changes in the parameters assayed when administered alone. When this complex was administered to TAM-treated rats, significant restoration of the following activities was observed: those of NADPH-generating enzymes (glucose-6-phosphate dehydrogenase and malic enzyme), that of glutathione reductase (NADPH-consuming enzyme), NADPH-cytochrome P450 reductase and total catalase. These results, together with others in previous studies, suggest that the altered liver function induced by chronic administration of TAM can be partially restored by this rhodium complex. The mechanisms by which this complex counteracts the TAM-induced changes have not yet been established.

Animals↗
PubMed2002

Effects of tamoxifen on human squamous cell carcinoma lines of the head and neck.

Tamoxifen (TAM) is a well-tolerated compound in the treatment of breast cancer and is primarily considered to act by competition with estrogen receptors (ER). Here we investigated the in vitro efficacy and potentially underlying mechanisms of TAM in established cell lines of squamous cell carcinomas of the head and neck (SCCHN). Using proliferation and apoptosis assays the antitumor activity of TAM in five SCCHN and the breast carcinoma line MCF-7 (positive control) was determined. MCF-7 was more sensitive to low-dose TAM (below 1 microM), whereas SCCHN showed significant growth inhibition at higher TAM concentrations (5-10 microM). Growth curve analysis and apoptosis assays were indicative for a cytostatic effect of low-dose TAM and high-dose TAM led to cell loss by apoptosis in sensitive SCCHN. In order to further characterize the observed antitumor effects we determined the amount of steroid hormone receptors with the dextran-coated charcoal method and immunocytochemistry. In addition, production of transforming growth factor (TGF-)-alpha, -beta1 and -beta2 was measured by ELISA, and protein kinase C (PKC) activity was assessed with a radioligand assay. Except MCF-7, none of the SCCHN lines was positive for ER. TAM caused decreased TGF-alpha and increased TGF-beta levels in MCF-7, but not in SCCHN supernatants. Furthermore, the antiestrogen reduced PKC activity in MCF-7, but not in SCCHN. In the present in vitro system, the observed antitumor activity of high-dose TAM in SCCHN cannot be explained by estrogen antagonism, alterations of TGF-alpha/beta levels or decreased PKC activity.

Antineoplastic Agents, Hormonal↗
PubMed1994

Interrelationship between estradiol and tamoxifen responses for clinical breast carcinoma cells cultured on contact-sensitive plates.

An in vitro assay system for predicting the estradiol (E2) sensitivity of clinical cancer cells was applied to 54 patients with breast carcinoma to compare the responses to E2 and tamoxifen (TAM) with the estrogen receptor (ER) status. We found that 18 of the 35 cases in the ER-positive group and 6 of the 19 cases in the ER-negative group were stimulated by E2. It is suggested that ER status alone can not predict the response of cultured cells to E2 in clinical breast cancer. Cell growth of 11/35 (31%) of the ER-positive cases and that of 8/19 (42%) of the ER-negative cases was inhibited by E2. Since the cases inhibited by E2 could not be distinguished by ER status alone, an assay system based on a quantitative proliferative response was considered necessary. There were 20 (83%) cases of inhibition by TAM among the 24 stimulated by E2. Only 18/35 (51%) of the ER-positive group exhibited growth inhibition by TAM. In our (CSP) assay, 20 (83%) of the 24 cases stimulated by E2 were inhibited by TAM, 10 (91%) of the 11 E2-insensitive cases were insensitive to TAM and 13 (68%) of the 19 cases inhibited by E2 were stimulated by TAM. In short, TAM response and E2 response tended to be inversely related (43/54 = 80%, P < 0.01). Furthermore, the E2-response rate showed a good correlation with the TAM-response rate (R2 = 0.825). These results indicate the feasibility of predicting individual tumor responses to either E2 or TAM by using CSPs.

3T3 Cells↗
PubMed1998

Effects of tamoxifen on endometrial carcinogenesis in mice.

Two experiments were conducted to determine the effect of tamoxifen (TAM) in mouse endometrium in comparison with that of 17beta-estradiol (E2). In a medium-term assay, TAM as well as E2 treatment semi-dose-dependently increased the levels of fos/jun mRNA and their oncoproteins (Fos/Jun). The long-term effect of TAM on mouse endometrial carcinogenesis was also examined in the following model. A total of 150 female ICR mice, 12-13 weeks of age, were used. Of these, 125 mice received an injection of N-methyl-N-nitosourea (MNU) solution (1 mg/100 g body weight) into their left uterine tube and saline into the right. One week later, they were divided into four groups: groups 1 (35 mice) and 2 (30 mice) were given 25 ppm and ppm E2-containing diet, respectively, while group 3 (30 mice) was fed 5 ppm TAM-containing diet. Group 5 (30 mice) was fed basal diet alone. The remaining 25 mice (group 4) received 5 ppm TAM-containing diet alone. At the termination of the experiment (30 weeks), endometrial carcinomas were confirmed to be present in the groups exposed to MNU. TAM increased the incidence of preneoplastic lesions of the endometrium, while E2 enhanced the occurrence of the carcinoma. No carcinomas were found in the group given TAM alone. In the ovaries, corpora lutea were lacking in most of the mice exposed to TAM, suggesting that the animals were not cycling. Such findings indicated that TAM has an enhancing effect on endometrial carcinogenesis in mice, probably via a mechanism involving overexpression of Fos/Jun proteins.

Adenocarcinoma↗
PubMed2006

DNA damage and altered gene expression of enzymes for metabolism and DNA repair by tamoxifen and toremifene in the female rat liver.

Effects of hepatocarcinogenic TAM and non-hepatocarcinogenic TOR on the formation of hepatic DNA adducts and on the gene expression of hepatic drug-metabolizing enzymes and DNA repair enzymes/proteins were comparatively examined in female Sprague-Dawley rats treated with TAM (20 or 40 mg/kg/day, i.g.) or TOR (40 mg/kg/day, i.g.) for 1, 2 or 8 weeks. Hepatic TAM-DNA adducts were formed even after 1 week of treatment with TAM at either dose, and the adduct levels increased in a dose- and treatment period-dependent manner, whereas no DNA adducts were detected in any of the TOR-treated rats. Conversely, TAM and TOR showed almost the same capacity for increasing the gene expression of drug-metabolizing enzymes responsible for metabolic activation and detoxification, at least up to the 2-week treatment mark. Accordingly, differences in DNA adduct formation between TAM- and TOR-treated rats would not be primarily dependent on the capacity for inducing hepatic drug-metabolizing enzymes. In addition, a drastic increase in the gene expression of cytochrome P4503A2 (CYP3A2), an activation enzyme of TAM, by the 8-week treatment with TAM might have contributed to the increased formation of DNA adducts. Gene expressions of DNA repair enzymes/proteins responsible for a nucleotide excision repair system were not significantly changed in any of the rats treated with either drug. The present findings suggest that the difference between TAM and TOR in hepatocarcinogenic potency is dependent on the capacity to form DNA adducts rather than modulating the expression of drug-metabolizing enzymes and DNA repair enzymes/proteins.

Animals↗
PubMed1992

Mixed phenotype of blasts in acute megakaryocytic leukaemia and transient abnormal myelopoiesis in Down's syndrome.

Blasts from eight cases with acute megakaryoblastic leukaemia (AMKL) and seven with transient abnormal myelopoiesis in Down's syndrome (TAM) were investigated to clarify their phenotypic characteristics. CD41 and CD7 were the most frequently expressed in both disorders. CD41 was positive in six TAM and five AMKL cases, and CD7 was positive in five TAM and five AMKL cases, respectively. CD33 was detected in four TAM and five AMKL cases. Other myeloid-lineage associated antigens such as CD13 and CD11b could not be found in TAM but were expressed in five AMKL cases. Interestingly, CD56, a neural adhesion molecule, was expressed in three of four TAM and one of five AMKL cases. Cytoplasmic CD3 antigen was also noted in three of five examined cases. A short-term culture study was conducted on blasts from two TAM cases and five AMKL cases. In two cases in which CD41 was not expressed before culture, the expression of CD41 was enhanced after culture with or without 12-O-tetradecanoyl-phorbol-13-acetate (TPA). The expression of CD7 remarkably was depressed, while that of CD13 was enhanced after culture with TPA. These findings suggest that blasts of TAM and AMKL originate from very immature cells and represent a mixed phenotype. In the present study, distinction of phenotypical differences between blast in TAM and AMKL was not possible.

Antigens, CD↗
PubMed2005

Comparison between maximal early diastolic velocity in long-axis direction obtained by M-mode echocardiography and by tissue Doppler in the assessment of right ventricular diastolic function.

Recently the maximal early diastolic velocity in long-axis direction of the right ventricle (RV) obtained by tissue Doppler imaging (MDV TDI) has been introduced in the assessment of RV diastolic function (RVDF). There are reasons to think that also the maximal early diastolic velocity in long-axis direction of the RV obtained using M-mode echocardiography (MDV TAM) could be used to assess RVDF. Therefore, 29 patients were examined with echocardiography and MDV TAM and MDV TDI were measured and compared. A good correlation (r = 0.76, P < 0.001) was found between MDV TAM and MDV TDI indicating that MDV TAM might be used in the assessment of RVDF. However, the velocities obtained by MDV TDI (126.7 +/- 38.9 mm s(-1)) were significantly (P < 0.001) higher than the velocities obtained by MDV TAM (78.3 +/- 27.8 mm s(-1)) and the agreement between MDV TAM and MDV TDI was rather poor probably mainly due to differences in the measuring technique. This means that reference values cannot be used interchangeably between MDV TAM and MDV TDI. If MDV TAM is going to be used in the assessment of RVDF new reference values have to be produced if today's technique and recommendations to measure MDV TAM and MDV TDI are used. However, as most new echocardiographs are equipped with PW-TDI technology it seems preferable to use this technique and compare obtained values with already established reference values.

Diastole↗
PubMed1998

Effect of tamoxifen on bone fractures in older nursing home residents.

OBJECTIVES: To evaluate the association between tamoxifen (TAM) treatment and rate of bone fractures in older, nursing home residents. PARTICIPANTS: A total of 93,031 women, aged 65 years and older, whose data were part of the 1993 New York State MDS and for whom there was documentation of treatment with at least one medication. SETTING: New York State long-term care facilities. DESIGN: Cross-sectional study via secondary analysis of 1385 matched sets of residents. Each set included one resident who was receiving TAM treatment and up to four residents who were not. MEASUREMENTS: Measurements included age, ethnicity, TAM treatment, hormone replacement therapy, vision impairment, any bone fractures, and, specifically, hip fractures. RESULTS: During the 1.5-year period for which bone fractures are documented in the 1993 MDS, the fracture rates were: 7.62% in women not treated with TAM, 3.20% in women receiving 10 mg TAM daily, and 6.73% in women receiving 20 mg TAM daily. The odds ratio (OR) for bone fractures among women receiving 20 mg TAM daily compared with nontreated women was 0.916 (95% confidence interval (CI): 0.720-1.164; P = .472), and was 0.312 (95% CI: 0.112-0.865; P = .025) for those receiving 10 mg daily. The rates of hip fracture were 4.98%, 2.40%, and 4.57% for controls and women receiving 10 mg and 20 mg TAM daily, respectively. Whereas the hip fracture rate for women receiving 20 mg daily was statistically similar to that of the controls (OR = .963; 95% CI: 0.718-1.291; P = .800), the difference between the controls and those receiving 10 mg daily approached significance (OR: 0.313; 95% CI: 0.096-1.018; P = .054). CONCLUSION: Although standard treatment of 20 mg TAM daily offers no apparent protection against bone fracture in older nursing home residents, a daily 10 mg dose seems to be protective.

Aged↗
PubMed1987

Antiestrogens as treatment of female and male infertilities.

Antiestrogens are widely used to treat eugonadal anovulation, luteal phase deficiency (LPD) and oligospermia. This paper reviews the rationales, endocrine effects, profertility effects and side effects of these treatments. Furthermore, we present our own experience of the use of antiestrogens in this field. We have compared the results of clomiphene citrate (CC) to those of tamoxifen (TAM) in a randomized study including 66 infertile women presenting eugonadal anovulation (n = 26) or LPD (n = 40). Both drugs obtained the same pregnancy rate of 80% at 9 months in the anovulatory patients. Conversely, CC was superior to TAM in the LPD cases (pregnancy rates at 6 months of respectively 40 and 11%). The abortion rates were of 11% on CC versus 36% on TAM. Both drugs significantly increased the luteal phase length and plasma progesterone level to the same extent. The results of endometrial biopsies suggest that the difference in their effects on female fertility could result from a detrimental effect of TAM on endometrium. The rates of the side effects proved to be almost identical on both drugs. Thus the use of TAM is not justified as a first-step treatment in ovulation disturbances. TAM should be reserved for patients who experience severe visual side effects on CC. We have also tested TAM in 100 subfertile males. In the 92 oligospermic males, TAM significantly increased the mean sperm count only in the normogonadotropic patients, but as much whether oligospermia was idiopathic or not. Sperm improvement was not significantly related to any hormone criterion except basal serum FSH. The cumulative pregnancy rate was of 41.2% at 1 year. Whether TAM actually improves male fertility, and is superior to CC in this indication, remains to be confirmed in controlled studies.

Anovulation↗
PubMedDate not supplied

Activation of tumor-associated macrophages by thymosin alpha 1.

It was shown earlier that the progressive growth of a transplantable T-cell lymphoma of spontaneous origin, designated as Dalton's lymphoma (DL), in a murine host is associated with an inhibition of macrophages (TAM) along with an involution of thymus. However, it remained unclear if a decline in the level of thymic peptides in DL-bearing host, due to thymic regression, has any implications in the inhibited responses of TAM. Therefore, the present investigation was under taken to study whether the TAM of DL-bearing host can be activated to tumoricidal state by peptides of thymic origin. It was observed that intraperitoneal administration of thymosin alpha 1 to DL-bearing mice resulted in activation of TAM. Such TAM were found to produce enhanced amount of interleukin-1 (IL-1), tumor necrosis factor (TNF), reactive oxygen intermediates (ROI), nitric oxide (NO) and showed an increased abilities of pinocytosis, phagocytosis, antigen presentation and tumor cytotoxicity. The TAM were found to be directly responsive to thymosin alpha1 as in vitro treatment with thymosin alpha 1 could activate TAM to tumoricidal state. Treatment of TAM with thymosin alpha 1 also enhanced their LPS responsiveness for an augmented state of activation. The findings of this study demonstrate for the first time that the TAM of a T cell lymphoma can be activated to tumoricidal state by thymosin alpha 1.

Animals↗
PubMed2005

In vitro activity of SPD754, a new deoxycytidine nucleoside reverse transcriptase inhibitor (NRTI), against 215 HIV-1 isolates resistant to other NRTIs.

SPD754 (also known as AVX-754) is a deoxycytidine analogue nucleoside reverse transcriptase inhibitor (NRTI) with antiretroviral activity against HIV-1 and HIV-2 in vitro and against recombinant viruses containing thymidine analogue mutations (TAMs). In order to better establish the activity of SPD754 against HIV-1 containing TAMs, twelve panels of up to twenty clinical isolates with defined TAM combinations were selected from the ViroLogic database. Phenotypic viral susceptibility to SPD754 and five other NRTIs was tested using the PhenoSense HIV assay and expressed as median fold-change compared with a reference strain. In total, 215 isolates were selected, representing four TAM patterns in both pathways by which TAMs accumulate clinically. The presence of five TAMs in the 41, 215 pathway, at codons 41, 67, 210, 215, and 219 of reverse transcriptase (RT), produced a median 1.8-fold reduction in SPD754 susceptibility, compared with fold reductions to zidovudine, lamivudine, abacavir, didanosine and tenofovir of 438, 4.8, 4.5, 1.4 and 3.6, respectively. Five TAMs in the 67, 70, 219 pathway (at codons 41, 67, 70, 215 and 219) reduced SPD754 susceptibility by a median 1.3-fold, compared with fold reductions for the aforementioned NRTIs of 108, 3.2, 3.0, 1.3 and 2.5, respectively. M184V addition reduced SPD754 susceptibility by 1.8-fold in the presence or absence of TAMs. SPD754 retains a substantial proportion of its antiviral activity against HIV-1 containing multiple TAMs, with or without the M184V mutation. These data suggest that SPD754 is a promising new NRTI for the treatment of NRTI-experienced HIV-infected patients.

Deoxycytidine↗
PubMed1986

Randomized trial of tamoxifen alone or combined with aminoglutethimide and hydrocortisone in women with metastatic breast cancer.

A randomized clinical trial was performed to compare the efficacy of tamoxifen (TAM) alone with that of TAM plus aminoglutethimide (AG) and hydrocortisone (HC). Patients failing TAM could receive AG and HC. Objective responses to therapy were seen in 21 of 49 TAM patients (43%) and 25 of 51 TAM, AG and HC patients (49%). Time to disease progression and survival distributions were not significantly different between the treatment arms. Toxicity was greater for patients treated with TAM, AG, and HC and the trial was discontinued early for this reason. Twenty-four patients received AG and HC after TAM therapy and three (12%) achieved a response. We conclude that the combination of TAM, AG, and HC is not recommended over TAM alone because toxicity appears to outweigh any potential therapeutic advantage.

Adult↗
PubMed1988

Randomized clinical trial of tamoxifen alone or combined with fluoxymesterone in postmenopausal women with metastatic breast cancer.

A randomized clinical trial was performed to determine if combination hormonal therapy with tamoxifen (TAM) and fluoxymesterone (FLU) was more efficacious than TAM alone for the treatment of 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 TAM patients (42%) and 63 of 119 TAM plus FLU patients (53%) (one-sided P = .05). Time to disease progression distributions were better for TAM plus FLU (median, 350 days v 199 days), but the log rank test only approached statistical significance (one-sided P = .07). Duration of response and survival distributions were similar between the two treatment arms. Toxicities, in terms of androgenic side effects, were greater on the TAM plus FLU regimen. Fifty-two patients are evaluable for response with FLU following TAM and 21 (40%) have achieved a response. We conclude that the advantages in terms of response rate and time to progression observed with TAM plus FLU probably represent a biological effect, but are not of sufficient magnitude to justify the routine clinical use of this combination given the lack of survival advantage and side effects encountered.

Adult↗
PubMed1985

Rat uterine growth and induction of progesterone receptor without estrogen receptor translocation.

The rat uterus responds to estradiol (E2) and E2 benzoate stimulation with an increase in progesterone receptor production and with growth. These responses were also elicited to varying degrees by a series of estrogenic (ICI 77,949 and ICI 47,699) and antiestrogenic triphenylethylene derivatives [tamoxifen (TAM), 4-hydroxy-TAM (4-OH-TAM), and 4-CH3-TAM]. These compounds have a range of affinities for the estrogen receptor (ER) and are able to compete with [3H]E2 binding in the uterus in vivo. Within 1-2 h of a sc injection of high affinity ligands (E2, E2B, and 4-OH-TAM), there was decrease in cytosol ER. This decrease was also observed with TAM, which is metabolized to 4-OH-TAM in vivo. In contrast, there was no decrease in cytosolic ER in animals treated with low affinity compounds (ICI 77,949, ICI 47,699, and 4-CH3-TAM) at any time before the onset of an estrogenic response. Furthermore, the nuclear ER increased after administration of a high affinity ligand (E2), as measured by exchange assay, but no increase in nuclear ER was observed after administration of low affinity ligands (ICI 77,949 and 4-CH3-TAM), although estrogenic responses were produced. From these data we have suggested a functional model to explain ER-mediated events in the rat uterus that supports the recent proposal that unoccupied ER is located in the nuclear compartment. In this model, the majority of unoccupied ER may reside in the nucleus in vivo; however, when the cells are disrupted in vitro, the unoccupied receptor or dissociation of low affinity ligand-ER complex causes unoccupied receptor to fall out of the nucleus and be incorporated into the cytosolic fraction. The high affinity ligand-ER complexes are retained in the nucleus. This would suggest that the apparent translocation of the ER from the cytoplasm to the nucleus may be an artifact. The data may reflect differential extraction of unoccupied receptors from the nucleus rather than transfer of receptor complexes to the nucleus.

Animals↗
PubMed1984

Anti-oestrogenic effects of tamoxifen on mammary gland and hypophysis in female rats.

Adult ovariectomized rats were treated for 14 days with oestradiol benzoate (E2B) 15 micrograms/kg/d and oestradiol benzoate 15 micrograms/kg/d + progesterone (PRO) 15 mg/kg/d for induction of mammary gland parenchymal stimulation. Histological examination and whole mount preparation demonstrated that ductal growth in the mammary gland after E2B treatment was completely antagonized by tamoxifen (TAM) 0.5 mg/kg/d. Parallel DNA concentrations in the mammary gland were decreased to control levels by TAM 0.5, 5 and 15 mg/kg/d. E2B-induced hyperprolactinaemia in the forenoon (basal secretion was equally reduced by TAM 0.5, 5 and 15 mg/kg/d). In the afternoon, when prolactin (Prl) secretion is at its maximum, TAM 0.5 mg/kg/d turned out to be ineffective to abolish Prl surge, but TAM 5 and 15 mg/kg/d reduced serum Prl concentrations in a dose-related manner. Immunoperoxidase staining of Prl cells in the pars distalis of the hypophysis indicated that adaptive hypertrophy and signs of hypersecretion after E2B were abolished by TAM 5 mg/kg/d. Luteotrophic cells clearly showed cellular atrophy, regression and secretory inactivity. Maximal tubulo-alveolar mammary parenchymal stimulation in rats treated with E2B-PRO was slightly inhibited by TAM 0.5 mg/kg/d. Histology showed a small disseminated parenchymal islet. DNA concentrations only were partially decreased by the anti-oestrogen though serum Prl concentrations were found to be completely decreased to control levels. Secretory activity of Prl cells was reduced by TAM 0.5 mg/kg/d. In E2B-PRO treated rats lisuride had poor inhibitory activity on Prl levels and none on DNA concentrations in the mammary gland. Combined treatment with TAM and lisuride significantly decreased DNA concentration in the mammary gland compared to animals which received E2B-PRO. Also Prl levels were at a minimum. Histology performed on the mammary gland showed only slight tubulo- but no tubulo-alveolar activation. Luteotrophic cells in the pituitary gland stained by the immunoperoxidase technique appeared regressive, shrunken and atrophied.

Animals↗
PubMed2005

Molecular changes associated with the agonist activity of hydroxy-tamoxifen and the hyper-response to estradiol in hydroxy-tamoxifen-resistant breast cancer cell lines.

The aim of this study was to explore the pharmacological response to 4-hydroxy-tamoxifen (OH-Tam) and to estradiol (E2) in three cell lines: MVLN, a human breast carcinoma cell line derived from MCF-7, and two MVLN-derived OH-Tam-resistant (OTR) cell lines, called CL6.8 and CL6.32. The OH-Tam response in the OTR cells was associated with the development of both an agonist activity of the drug on cell proliferation and the resistance of the cells to OH-Tam-induced apoptosis. The OTR cells also developed an increased sensitivity to the E2 growth-stimulating activity. To delineate the genes that determine such responses, we combined a mini-array-based gene-selection approach and an extensive real-time quantitative PCR exploration in the MVLN and OTR cell lines exposed to three pharmacological conditions: a 4-day treatment with E2, OH-Tam or both E2 and OH-Tam. Compiled data revealed a hyper-response to E2 and a modification of the OH-Tam pharmacological response (loss of antagonist action and agonist activity) at the gene-expression level. The proteins encoded by the genes selected in this study have been reported to be involved in the regulation of cell proliferation, cell transformation, DNA repair and apoptosis, or belong to the ErbB/epidermal growth factor receptor-driven pathway. Our data also provide evidence of changes in transcriptional co-regulator expression, elevated mitogen-activated protein kinase activity and increase in the phosphorylation status of estrogen receptor alpha on serine residue 118 in the OTR cell lines, suggesting the possible involvement of such mechanisms in the agonist activity of OH-Tam and/or the hyper-response of cells to E2. Taken together, our study should enhance our knowledge of the multifactorial events associated with the development of Tam resistance in two independent cell lines issued from the same selection process and should help in the identification of potential molecular targets for diagnosis or therapy.

Antineoplastic Agents, Hormonal↗
PubMed1997

Hormone dependence of mammary tumors induced in rats by intraperitoneal NMU injection.

The purpose of this work was to determine the hormone dependence of mammary tumors induced in Sprague-Dawley rats by three intraperitoneal injections of N-nitroso-N-methylurea at 50, 80, and 110 days of age. Two experimental designs were carried out: (a) Ten days before the first NMU injection, 130 rats were divided into 13 batches and randomly assigned to the following treatments: control, ovariectomy (OVX), tamoxifen (TAM), bromocriptine (BROM), haloperidol (HAL), estradiol (E2), progesterone (Pg), OVX + BROM, TAM + BROM, OVX + HAL, TAM + HAL, OVX + TAM, and E2 + BROM. After 150 days of treatment the following growth parameters were determined: latency period (LP), mean tumor number per rat (n/t), and tumor incidence (TI). LP was significantly increased (p < 0.05) only by Pg and TAM + BROM. The n/t was significantly decreased (p < 0.05) by all treatments except HAL. TI was significantly reduced by OVX, TAM, BROM, and their combinations, (b) Rats bearing ip-NMU-induced mammary tumors were divided into 7 batches and assigned to the following treatments: control, OVX, TAM, BROM, HAL, OVX + BROM, and TAM + BROM. Tumor growth was assessed up to 60 days of treatment; only OVX, TAM and their combination with BROM were able to produce tumor regression. These results support the essential role of E2 and prolactin in the promotion stage of carcinogenesis. However, for established tumors, growth becomes more independent from hormone influence, in particular from prolactin deprivation. We conclude that this model seems suitable for studying the mechanisms underlying the evasion of hormonal control of tumor growth.

Animals↗
PubMed2005

Effect of glibenclamide on N-nitroso-N-methylurea-induced mammary tumors in diabetic and nondiabetic rats.

The objective of this study was to evaluate the antitumor effect of glibenclamide (Gli) alone or in combination with tamoxifen (Tam) on experimental mammary tumors induced by N-nitroso-N-methylurea (NMU) in nondiabetic and diabetic rats. For experimental diabetes induction, Sprague-Dawley rats were injected with streptozotocin (STZ) on the second day of life. For experimental mammary tumor induction, nondiabetic and diabetic rats were injected IP with NMU at 50, 80, and 110 days of life. Nondiabetic and diabetic rats bearing mammary tumors were treated with 0.06 mg/day of Gli orally, Tam 1 mg/kg/day SC, or with the combined treatment (Gli + Tam). After 20 days of treatment, different responses were observed. In nondiabetic rats, 64% of tumors were responsive to Gli treatment (they regressed or remained stable), whereas 57% of tumors under treatment with Tam exhibited a response. Results of the combined Gli + Tam treatment indicated that all tumors were responsive: 58% regressed and 42% remained stable. Diabetic rats receiving Gli treatment did not show response to this treatment, while 65% of the tumors of Tam-treated diabetic rats showed regression. Histopathologic observation indicated an important intratumor secretion in all tumors of Gli-, Tam-, or Gli + Tam-treated rats. No secondary toxic effect was observed after treatment at any assayed doses. In conclusion, the present data demonstrate the in vivo antitumor action of Gli treatment on the experimental mammary tumors employed, indicating that Gli exerted a direct effect on tumor cells in nondiabetic rats. The combined Gli + Tam treatment potentiated the antitumor effect of each drug alone. Future research will examine the molecular aspects of these findings.

Animals↗