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PubMedDate not supplied

The proliferation in uterine compartments of intact rats of two different strains exposed to high doses of tamoxifen or toremifene.

Uterine Cell proliferation was studied in intact Sprague-Dawley (SD) and Fischer 344 (F344) rats exposed to the antiestrogens tamoxifen (TAM; 5, 10, 20, or 40 mg/kg) and toremifene (TOR: 21.2 or 42.4 mg/kg). The antiestrogens were administered to animals via gavage daily for 2 or 12 wk. Uterine proliferation was assessed using markers for the proliferating cell nuclear antigen (PCNA) and by the bromodeoxyuridine (BrdU) method. Diethylstilbestrol (DES) was used as an estrogenic reference compound. The antiestrogens either reduced or prevented changes of myometrial and stromal proliferation indices (PI). TAM and TOR caused a time-dependent reduction of endometrial glands without an associated decrease in cell proliferation. In the luminal columnar epithelium, the antiestrogens depressed PCNA PI but enhanced BrdU PI, indicating a low continuous DNA synthesis in otherwise quiescent cells. The antiestrogens induced focal hyperplastic multilayered epithelia with PCNA-positive basal cells along segments of the luminal uterine epithelium. We suggest that this hyperplastic epithelium represents remnants from the glandular epithelium. DES was less efficient in inducing these changes but induced squamous metaplasias in the F344 rats. Uterine effects of the 2 antiestrogens were comparable with the exception of I TAM-exposed (40 mg/kg) SD rat that showed squamous metaplasia. F344 rats were more sensitive to the estrogenic action of DES than were the SD rats.

Animals↗
PubMed2005

Induction and inhibition of oocyte maturation by EDCs in zebrafish.

BACKGROUND: Oocyte maturation in lower vertebrates is triggered by maturation-inducing hormone (MIH), which acts on unidentified receptors on the oocyte surface and induces the activation of maturation-promoting factor (MPF) in the oocyte cytoplasm. We previously described the induction of oocyte maturation in fish by an endocrine-disrupting chemical (EDC), diethylstilbestrol (DES), a nonsteroidal estrogen. METHODS: In this study, stimulatory and inhibitory effects of EDCs and natural steroids on oocyte maturation were examined in zebrafish. For effective agents, some details about the mechanism in induction or inhibition of maturation were examined. Possible groups of DES interacting with the MIH receptor are discussed based on relative potency of steroids to induce maturation. RESULTS: Among agents tested, tamoxifen (TAM) and its metabolite 4-hydroxytamoxifen (4-OHT) showed stimulatory activity similar to DES. The time courses of the change in germinal vesicle breakdown and an intracellular molecular event (the synthesis of cyclin B) induced by TAM were indistinguishable from those induced by MIH. In contrast, pentachlorophenol (PCP) had a potent inhibitory effect on MIH-induced oocyte maturation. PCP inhibited not only MIH-induced maturation but also DES- and TAM-induced maturation. Methoxychlor also inhibited maturation when oocytes were pre-treated with this agent. CONCLUSION: These results suggest that EDCs act as agonists or antagonists in the induction of oocyte maturation in fish.

Animals↗
PubMed1998

Phase II study of carmustine, dacarbazine, cisplatin, and tamoxifen in advanced melanoma: a Southwest Oncology Group study.

PURPOSE: The combination of carmustine (BCNU), dacarbazine (DTIC), cisplatin (DDP), and tamoxifen (Tam) has been reported in small series to provide a response rate of 50%, but with significant myelosuppression and risk of thromboembolic complications. We performed this phase II study to assess the antitumor activity and important toxicities of this combination in the cooperative group setting. PATIENTS AND METHODS: Seventy-nine eligible patients were treated with BCNU 150 mg/m2/d, every 6 weeks, DTIC 220 mg/m2/d on days 1 to 3 every 3 weeks, DDP 25 mg/m2/d on days 1 to 3 every 3 weeks, and Tam 20 mg orally daily throughout treatment. Treatment cycles were repeated every 6 weeks in responding or stable patients for a maximum duration of 1 year. RESULTS: Twelve objective responses were achieved (response rate 15%, 95% confidence interval 8%-25%). Five responses were complete (CR) and seven were partial (PR). The median response duration was 8+ (range, 4-19+) months, (16+ [4-19+] for CR and 8+ [4-11] for PR), and the median survival of the entire group was 9 months. The toxicities were predominantly neutropenia and thrombocytopenia. Four patients developed thromboembolic events. Two patients died while on protocol therapy, one with complications of neutropenia, and the other with disease progression. CONCLUSION: The activity of this regimen is in the range reported for single agents or DTIC plus DDP, and the addition of BCNU and Tam appears to increase toxicity. We do not recommend this combination for routine treatment of advanced melanoma or as the control arm in randomized studies of combination therapy.

Adolescent↗
PubMed2005

Randomized trial comparing axillary clearance versus no axillary clearance in older patients with breast cancer: first results of International Breast Cancer Study Group Trial 10-93.

PURPOSE: Axillary clearance in early breast cancer aims to improve locoregional control and provide staging information but is associated with undesirable morbidity. We therefore investigated whether avoiding axillary surgery in older women would result in improved quality of life (QL) with similar disease-free survival (DFS) and overall survival (OS). PATIENTS AND METHODS: Between 1993 and 2002, women > or = 60 years old with clinically node-negative operable breast cancer in whom adjuvant tamoxifen was considered indicated regardless of pathologic nodal status were randomly assigned to primary surgery plus axillary clearance (Sx + Ax) followed by tamoxifen (Tam) versus Sx without Ax followed by Tam for 5 consecutive years. The primary end point was QL reported by the patient and by physician assessment. RESULTS: A total of 473 patients (234 to Sx + Ax, 239 to Sx) were randomly assigned. The median age was 74 years; 80% had estrogen receptor-positive disease. In both the patients' subjective assessment of their QL and the physicians' perception of the patients' QL, the largest adverse QL effects of Ax were observed from baseline to the first postoperative assessment, but the differences tended to disappear in 6 to 12 months. At a median follow-up of 6.6 years, results for Sx + Ax and Sx yielded similar DFS (6-year DFS, 67% v 66%; hazard ratio [HR] Sx + Ax/Sx, 1.06; 95% CI, 0.79 to 1.42; P = .69) and OS (6-year OS, 75% v 73%; HR Sx + Ax/Sx, 1.05; 95% CI, 0.76 to 1.46; P = .77). CONCLUSION: Avoiding axillary clearance for women > or = 60 years old who have clinically node-negative disease and receive Tam for endocrine-responsive disease yields similar efficacy with better early QL.

Aged↗
PubMed1989

Effects of tamoxifen, tamoxifen metabolites, and nafoxidine on adenosine 3',5'-monophosphate phosphodiesterase: correlations with growth inhibitory activities but not estrogen receptor affinities.

Triphenylethylenes [Tamoxifen (TAM), TAM metabolites, and nafoxidine] were found to inhibit Ca2+-calmodulin (CaM)-dependent cAMP phosphodiesterase (PDE) activity of the quail oviduct, whereas 17 beta-estradiol was inactive. The Ca2+-CaM-independent PDE activity was not affected by triphenylethylenes, suggesting that they do not interact directly with the active site of the enzyme. Kinetic analysis indicated that these drugs competitively inhibited the activation of PDE by CaM with the following potencies: N-desmethyltamoxifen, Ki = 3 microM; metabolite Z, trans-4-hydroxytamoxifen, and TAM Ki = 5 microM; nafoxidine, Ki = 8.5 microM; and metabolite Y and cis-4-hydroxytamoxifen, Ki = 50 microM. Injected alone into immature quails, none of these drugs significantly affected oviduct weight. When administrated together with estradiol benzoate, these drugs reduced the trophic effect of estradiol in a dose-dependent relationship, with ID50 values ranging from 0.07 mg/kg for N-desmethyltamoxifen to 2.02 mg/kg for cis-4-hydroxytamoxifen. The order of growth inhibitory potency was not correlated with estrogen receptor affinities, but was the same as that reported for PDE inhibition. This correlation suggests that interaction of antiestrogen with Ca2+-CaM dependent PDE may be one of the mechanisms responsible for the estrogen antagonist activity of these drugs.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1991

Tamoxifen inhibition of prolactin action in the mouse mammary gland.

Binding of lactogenic hormones to particulate and solubilized microsomal membranes isolated from mammary glands of lactating mice is inhibited by direct addition of 10(-10) M or greater concentrations of triphenylethylene antiestrogens [i.e. tamoxifen (TAM), 4-hydroxy-tamoxifen, and Nafoxidine] to the binding assays. Estradiol and other antiestrogens such as BPEA (-2-(4-tert-butyl-phenoxy) ethyl diethylamine hydrochloride, LY117018, and LY 156758 do not have this effect. The triphenylethylene antiestrogens bind to the membrane-associated antiestrogen binding sites (AEBS). Effectiveness of binding to the AEBS parallels the effectiveness of inhibition of the lactogen binding. The effect is selective in that binding of epidermal growth factor and insulin to these same membranes is unaffected by the antiestrogens. Binding of PRL to membranes prepared from the livers of the lactating mice is also unaffected. Both the PRL receptor and AEBS are primarily localized to the microsomal membrane fraction of cells. Maximal inhibition of PRL binding by TAM is observed in the light microsomes that contain plasma membranes. In addition to inhibition of PRL binding, TAM also prevents the PRL-induced accumulation of caseins by cultured mouse mammary explants. Thus it appears that the triphenylethylene antiestrogens, acting through the AEBS, act as antilactogens in the normal mammary gland.

Animals↗
PubMed2004

17beta-estradiol activation of the c-Jun N-terminal kinase pathway leads to down-regulation of class II major histocompatibility complex expression.

Class II major histocompatibility complex (MHC) proteins are important for specific recognition of foreign antigens by the immune system. Previously we showed that 17beta-estradiol (E2) down-regulates class II MHC expression by attenuation of histone acetylation and cAMP response element binding protein (CREB)-binding protein recruitment to the class II MHC promoter. Estrogen signals through nuclear receptors to mediate genomic effects; however, estrogen is also known to mediate rapid nongenomic effects. Our observation that ER antagonists fail to prevent E2 inhibition of class II MHC expression suggests that E2 is signaling in a nonclassical manner. We find that E2, as well as the antiestrogens tamoxifen (TAM) and ICI 182,780 (ICI), inhibit class II MHC expression through activation of the c-Jun N-terminal kinase (JNK) pathway. Pharmacological JNK inhibitors reverse the inhibitory effects of E2, TAM, and ICI on class II MHC expression. E2, TAM, and ICI activate the JNK pathway and subsequently activate c-Jun and activating transcription factor-2 transcription factors. Our results demonstrate that blocking E2 activation of the JNK signaling pathway prevents estrogen-mediated attenuation of histone acetylation and CREB-binding protein recruitment to the class II MHC promoter. Collectively, these findings demonstrate that the JNK signaling pathway is necessary for E2-mediated inhibition of class II MHC expression.

Acetylation↗
PubMed2005

The G protein-coupled receptor GPR30 mediates the proliferative effects induced by 17beta-estradiol and hydroxytamoxifen in endometrial cancer cells.

The growth of both normal and transformed epithelial cells of the female reproductive system is stimulated by estrogens, mainly through the activation of estrogen receptor alpha (ERalpha), which is a ligand-regulated transcription factor. The selective ER modulator tamoxifen (TAM) has been widely used as an ER antagonist in breast tumor; however, long-term treatment is associated with an increased risk of endometrial cancer. To provide new insights into the potential mechanisms involved in the agonistic activity exerted by TAM in the uterus, we evaluated the potential of 4-hydroxytamoxifen (OHT), the active metabolite of TAM, to transactivate wild-type ERalpha and its splice variant expressed in Ishikawa and HEC1A endometrial tumor cells, respectively. OHT was able to antagonize only the activation of ERalpha by 17beta-estradiol (E2) in Ishikawa cells, whereas it up-regulated c-fos expression in a rapid manner similar to E2 and independently of ERalpha in both cell lines. This stimulation occurred through the G protein-coupled receptor named GPR30 and required Src-related and epidermal growth factor receptor tyrosine kinase activities, along with the activation of both ERK1/2 and phosphatidylinositol 3-kinase/AKT pathways. Most importantly, OHT, like E2, stimulated the proliferation of Ishikawa as well as HEC1A cells. Transfecting a GPR30 antisense expression vector in both endometrial cancer cell lines, OHT was no longer able to induce growth effects, whereas the proliferative response to E2 was completely abrogated only in HEC1A cells. Furthermore, in the presence of the inhibitors of MAPK and phosphatidylinositol 3-kinase pathways, PD 98059 and wortmannin, respectively, E2 and OHT did not elicit growth stimulation. Our data demonstrate a new mode of action of E2 and OHT in endometrial cancer cells, contributing to a better understanding of the molecular mechanisms involved in their uterine agonistic activity.

Androstadienes↗
PubMed1998

Extinction of insulin-like growth factor-I mitogenic signaling by antiestrogen-stimulated Fas-associated protein tyrosine phosphatase-1 in human breast cancer cells.

Steroidal (ICI 182, 780) and nonsteroidal hydroxytamoxifen (OH-Tam) antiestrogens inhibit growth factor-mitogenic activity in MCF 7 estrogen receptor-positive human breast cancer cells. Cell inhibition is correlated with an increase in membrane protein tyrosine phosphatase (PTP) activity, and the addition of orthovanadate prevents OH-Tam inhibition. After RT-PCR cloning of PTPs expressed in MCF 7 cells with primers to their catalytic domains, we have shown, by differential screening, that the expression of two enzymes, leukocyte common antigen-related PTP (LAR) and Fas-associated PTP-1 (FAP-1), was modulated by antiestrogens. By comparative RT-PCR, in situ hybridization, and Northern blot, LAR and FAP-1 mRNAs accumulation was found to be dose- and time-dependently increased by antiestrogens. To further demonstrate that PTPs were key mediators of antiestrogen-inhibitory action on the growth factor pathway, a panel of stable FAP-1 transfectants expressing low to high levels of antisense mRNAs was established. In these clones, the level of antisense RNA expression was correlated with a reduction in basal levels and a complete inhibition of antiestrogen-stimulated values of PTP activity. When FAP-1 expression was abolished, OH-Tam was no longer able to block insulin-like growth factor I mitogenic activity even though it remained strongly antiestrogenic. However, ICI 182,780 was still inhibitory, indicating that its effect was not exclusively mediated by PTP. Our data first demonstrate that a specifically regulated phosphatase (FAP-1) is implicated in the triggering of negative proliferation signals in breast cancer cells.

Breast Neoplasms↗
PubMed1980

Abnormal microtubule deployment during defective macronuclear division in a Paramecium mutant.

The tam 8 mutant of Paramecium tetraurelia is a representative of a class of mutants characterized by abnormal nuclear divisions during binary fission and the failure of trichocysts to attach to the plasma membrane. Compared with wild-type organisms the following abnormalities occur in tam 8 individuals. (I) The spherical interphase macronucleus is not positioned near the oral apparatus; it is randomly located in the cytoplasm of interfission organisms. (2) The macronucleus does not migrate towards the anterior dorsal cortex as its division starts, nor is it dorsally and subcortically positioned as it elongates. (3) Elongating macronuclei exhibit variable and irregular shapes. (4) This elongation is delayed and reduced. (5) Longitudinally oriented microtubules assemble in the nucleoplasm of dividing macronuclei but their spatial deployment is abnormal. (6) Unequal segregation of micronuclei between daughter organisms occurs during binary fission. The abnormal arrangement of nucleoplasmic microtubules provides support for the proposal that a microtubule sliding mechanism is involved during the elongation of dividing macronuclei. The extent to which macronuclear division may be controlled by the cell cortex is considered in relation to tthe pleiotropic effects of the tam 8 mutation.

Animals↗
PubMed2006

Improvement of cumulus-free oocyte maturation in vitro and its application to microinsemination with primary spermatocytes in mice.

In micromanipulation experiments using immature oocytes, final ooplasmic maturation is often compromised because the oocytes are usually first freed from their nurturing cumulus cells. This study was undertaken to determine whether cumulus-free in vitro maturation (IVM) in mice could be improved by modifying IVM medium having defined components. Cumulus-free germinal vesicle (GV) stage oocytes were subjected to IVM in either alphaMEM medium, TYH medium, or a 1:1 mixture of the two (termed TaM). TYH medium produced a better maturation rate (181/196; 92.3%) than alphaMEM (184/257; 71.6%). However, alphaMEM supported better embryo development to the morula/blastocyst stage than TYH following in vitro fertilization (93.3% vs. 76.5%) or parthenogenetic activation (82.4% vs. 60.4%). Mitochondrial distribution in MII oocytes was diffuse following IVM in alphaMEM, but was aggregated with TYH. The maturation promoting factor (MPF) activity in MII oocytes was significantly higher in TYH than in alphaMEM (P<0.05). Oocytes cultured in TaM had intermediate characteristics and essentially resembled in vivo matured oocytes, with the mitochondrial distribution pattern being most typical of that condition. The highest rate of development from GV oocytes to full-term fetuses following in vitro fertilization and embryo transfer to foster mothers (23.8%) was obtained using TaM. When this IVM system was applied to MI oocytes injected with spermatocytes, offspring were first obtained without cytoplasmic replacement at MII. Thus, optimization of the culture medium can considerably improve the quality of cumulus-free oocyte IVM in mice.

Animals↗
PubMed2004

Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells.

De novo and acquired resistance to the anti-tumour drug gefitinib (ZD1839; Iressa), a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has been reported. We have determined whether signalling through the IGF-I receptor (IGF-1R) pathway plays a role in the gefitinib-acquired resistance phenotype. Continuous exposure of EGFR-positive MCF-7-derived tamoxifen resistant breast cancer cells (TAM-R) to 1 microM gefitinib resulted in a sustained growth inhibition (90%) for 4 months before the surviving cells resumed proliferation. A stable gefitinib-resistant subline (TAM/TKI-R) was established after a further 2 months and this showed no detectable basal phosphorylated EGFR activity. Compared with the parental TAM-R cells, the TAM/ TKI-R cells demonstrated (a) elevated levels of activated IGF-1R, AKT and protein kinase C (PKC)delta, (b) an increased sensitivity to growth inhibition by the IGF-1R TKI AG1024 and (c) an increased migratory capacity that was reduced by AG1024 treatment. Similarly, the EGFR-positive androgen-independent human prostate cancer cell line DU145 was also continuously challenged with 1 microM gefitinib and, although substantial growth inhibition (60%) was seen initially, a gefitinib-resistant variant (DU145/TKI-R) developed after 3 months. Like their breast cancer counterparts, the DU145/TKI-R cells showed increases in the levels of components of the IGF-1R signalling pathway and an elevated sensitivity to growth inhibition by AG1024 compared with the parent DU145 cell line. Additionally, DU145/TKI-R cell migration was also decreased by this inhibitor. We have therefore concluded that in breast and prostate cancer cells acquired resistance to gefitinib is associated with increased signalling via the IGF-1R pathway, which also plays a role in the invasive capacity of the gefitinib-resistant phenotype.

Antineoplastic Agents↗
PubMed2002

The effect of long-term treatment with steroid hormones or tamoxifen on oestrogen receptors (alpha and beta) in the endometrium of ovariectomized cynomolgus macaques.

The effects of oestrogen are mediated by two specific intracellular receptors, oestrogen receptors (ER) alpha and beta, which function as ligand-activated transcriptional regulators. Ovariectomized macaques (Macaca fascicularis) were used to study the regulation of ERalpha and ERbeta in the endometrium by immunohistochemistry and in situ hybridization after long-term hormone treatment. Animals were treated continuously for 35 Months with either conjugated equine oestrogen (CEE), medroxyprogesterone acetate (MPA), combined CEE/MPA, or tamoxifen (TAM). Treatment with CEE/MPA down-regulated ERalpha in the superficial glands. In the superficial stroma the ERalpha level was lower in the CEE/MPA group than in the CEE and MPA groups. ERbeta immunostaining was faint with minor variation in response to treatment, but increased in the superficial stroma after MPA treatment. The ratio of ERbeta/ERalpha increased in superficial stroma and gland after CEE/MPA treatment, and also in stroma after MPA and TAM. Cystic endometrial hyperplasia was observed in TAM-treated animals, in combination with a high level of ERalpha protein expression. The present data show that long-term hormone treatment affects the ERalpha and ERbeta protein levels in the endometrium. The balance between ERalpha and ERbeta seems to be important for the proliferative response to oestrogen.

Animals↗
PubMedDate not supplied

Questionnaire development to predict mammography intention among women in southeastern Louisiana.

This article summarizes the development and psychometric analysis of the Thoughts About Mammography (TAM) questionnaire to predict mammography intention using the Theory of Planned Behavior (TPB). Key themes, obtained from elicitation interviews (N = 45), were categorized, ranked and extracted for item construction. Initial pilot testing supported test-retest reliability (alpha = .85 to .97), internal consistency (alpha = .67 to .91), and content validity (0.86-1.00). After pilot testing, the TAM was administered to 302 rural women in southeastern (SE) Louisiana. The instrument was internally consistent (alpha = 0.77 to 0.92), construct valid (alpha = .18 to .64), and predicted 24% of the variance of mammography intention. The TAM adequately demonstrated reliability and validity to measure mammography intention in rural southeastern Louisiana women.

Adult↗
PubMed2005

Phosphorus extractability of soils amended with stockpiled and composted cattle manure.

Managing fertilizer applications to maintain soil P below environmentally unacceptable levels should consider the contribution of manure and synthetic fertilizer sources to soluble and extractable forms of P. Our objective was to evaluate soil and manure characteristics and application rates on P extractability in recently amended soils. Five soils of the U.S. southern High Plains were amended with beef cattle manures, composted beef manure, and inorganic fertilizers [Ca(H(2)PO(4))(2) or KH(2)PO(4)] at five rates and incubated under controlled conditions. Mehlich 3-, Olsen (NaHCO(3))-, Texas A&M extractant (TAM)-, and water-extractable P were determined for the soils after selected incubation periods. Except for TAM and some water extractions, P extractability as a function of total P applied was linear (P < 0.001) for a wide range of application rates. Mehlich-3, NaHCO(3), and water P extraction efficiencies of KH(2)PO(4)-amended soils averaged 22, 34, and 115% greater (P < or = 0.036), respectively, than efficiencies of soils amended with manures except for the Texline (calcareous) loam and Pullman clay loam soils. Phosphorus extraction efficiencies decreased with time for KH(2)PO(4)-amended soils (P < 0.05) but remained stable or increased for manure-amended soils during the 8-wk incubation period. Across all soils and manure sources, changes in water-extractable P per unit increase in Mehlich 3-, NaHCO(3)-, and TAM-extractable P averaged 100, 85, and 125% greater, respectively, for inorganic as compared with manure-amended soils. These source-dependent relationships limit the use of agronomic soil extractants to make correct inferences about water-extractable P and dissolved P in runoff.

Animals↗
PubMed2000

Comparative pharmacokinetics of the carbapenems: clinical implications.

During the last few decades, several carbapenems have been developed. The major characteristic of the newer drugs, such as MK-826, is a prolonged half-life. Alternatively, some carbapenems have been developed that can be given orally, such as CS-834 and L-084. Although imipenem and panipenem have to be administered with a co-drug to prevent degradation by the enzyme dehydropeptidase-1 and reduce nephrotoxicity, the newer drugs such as meropenem, biapenem and lenapenem are relatively stable towards that enzyme. Structural modifications have, besides changes in pharmacology, also led to varying antimicrobial properties. For instance, meropenem is relatively more active against Gram-negative organisms than most other carbapenems, but is slightly less active against Gram-positive organisms. Except for half-life and bioavailability, the pharmacokinetic properties of the carbapenems are relatively similar. Distribution is mainly in extracellular body-water, as observed both from the volumes of distribution and from blister studies. Some carbapenems have a better penetration in cerebrospinal fluid than others. In patients with renal dysfunction, doses have to be adjusted, and special care must be taken with imipenem/cilastatin and panipenem/betamipron to prevent accumulation of the co-drugs, as the pharmacokinetic properties of the co-drugs differ from those of the drugs themselves. However, toxicity of the co-drugs has not been shown. The carbapenems differ in proconvulsive activity. Imipenem shows relatively the highest proconvulsive activity, especially at higher concentrations. Pharmacodynamic studies have shown that the major surrogate parameter for antimicrobial efficacy is the percentage of time of the dosage interval above the minimum inhibitory concentration (MIC). The minimum percentage percentage of time above the MIC (TaM) needed for optimal effect is known in animals (30 to 50%), but not in humans. It is probably less than 100%, but may be higher than 50%. Dosage regimens currently in use result in a TaM of about 50% at 4 mg/L, which is the current 'susceptible' breakpoint determined by the National Committee for Clinical Laboratory Standards (NCCLS) for most micro-organisms. Dosage regimens in patients with reduced renal clearance should be based on the TaM. The increased half-life of the newer carbapenems will probably lead to less frequent administration, although continuous infusion may still be the optimal mode of administration for these drugs. The availability of oral carbapenems will have a profound effect on the use of carbapenems in the community.

Carbapenems↗
PubMed1991

Estrogen receptor in primary breast cancer estimated in paraffin-embedded tissue. A study of its usefulness compared to dextran-coated charcoal assay.

Estrogen receptor (ER) was estimated immunohistochemically in formalin-fixed and paraffin-embedded tissue from the primary breast cancer in 349 postmenopausal patients with a high risk of recurrence and compared with the results of dextran-coated charcoal assay. There was a highly significant correlation between the ER classification obtained by the two methods (p less than 10(-6)). Patients ER positive according to immunohistochemical estimate had a significantly longer disease-free survival (p less than 0.001) and survival (p less than 0.001) than ER negative patients. The DCC assay showed an advantage of ER positive patients of the same magnitude. The patients, who were followed for a median of 86 months, were a subset of 1,700 patients participating in the Danish Breast Cancer Cooperative Group's randomized trial of adjuvant tamoxifen (TAM) treatment. In the presently analyzed subset of patients there were no statistically significant difference in disease-free survival (p = 0.52) or survival (p = 0.54) between patients who received adjuvant TAM and the controls. The same was true for receptor-defined subgroups regardless if the ER receptor was estimated in paraffin-embedded tissue or by the dextran-coated charcoal method. The analyzed subset might have been too small for demonstrating a positive effect of adjuvant TAM treatment.

Breast Neoplasms↗
PubMed1996

Proper sequence of endocrine therapies in advanced breast cancer.

Tamoxifen (TAM) is widely used as therapy in early breast cancer and first-line endocrine therapy in metastatic disease. Despite this therapy, many patients relapse and an important question is: What is the preferred sequence of endocrine therapies in metastatic breast cancer (MBC). While treatment with oophorectomy, aminoglutethimide or progestins have been a logical choice after failure to Tamoxifen recent research has extended the options for endocrine therapy of MBC. New selective aromatase inhibitors (AI) are now in clinical use. The first commercially available of these inhibitors is LENTARON. The active ingredient of LENTARON is a steroidal compound 4-OH-androstenedione: Formestane. It is presented as a depot formulation and applied as an i.m. injection of 250 mg every second week. Previous findings from phase II trials have indicated similar activity as other endocrine treatment modalities. Clinical investigations in properly conducted phase III trials have revealed that the efficacy of LENTARON matches the results which can be obtained with TAM and Megace in trials of first and second-line endocrine therapy. Fifty-four and 51% of MBC patients, respectively, did benefit from therapy with LENTARON in these phase III trials by achieving objective responses or stable disease. Moreover, similar overall survival was seen. The systemic tolerability of LENTARON is comparable to that of TAM, and LENTARON seems less systemically toxic than Megace. Local side effects occured in approximately 7% of the patients giving rise mainly to pain or inflammation at the injection site. In elderly patients, LENTARON therapy assures compliance and no interference with other oral medications has been observed. In conclusion, since the endocrine treatment modalities are comparable in terms of efficacy the optimal sequence of these treatments is based upon differences in tolerability. Patients previously treated with Tamoxifen and with a high probability of a further endocrine response could preferably be treated with a selective AI like LENTARON as second-line endocrine therapy followed by a progestin upon progression in responders.

Androstenedione↗