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PubMedDate not supplied

Restoration of estrogen responsiveness by blocking the HER-2/neu pathway.

HER-2/neu gene amplification or protein overexpression is evident in 20-30% of primary breast cancers. Its amplification correlates with poor prognosis. There appears to be an association between HER-2/neu overexpression and estrogen independence. The MCF-7 human breast carcinoma cell line is estrogen-dependent and sensitive to the anti-estrogen, tamoxifen (TAM). This line, when transfected with the HER-2/neu gene, becomes estrogen-independent and resistant to TAM. Blockade of the HER-2/neu receptor with 1-5 nM of the humanized HER-2/neu antibody, Herceptin, restored estrogen, as well as TAM, sensitivity. These results suggest that Herceptin or similar drugs may restore estrogen sensitivity and the administration of a HER-2/neu inhibitor with an anti-estrogen to premenopausal patients should be considered.

Antibodies, Monoclonal↗
PubMed2002

A novel mechanism by which N-(4-hydroxyphenyl)retinamide inhibits breast cancer cell growth: the production of nitric oxide.

N-(4-Hydroxyphenyl)retinamide (4-HPR) induces apoptosis in breast cancer cells; however, the molecular basis by which 4-HPR induces apoptosis is not well understood. In breast cancer cells, nitric oxide (NO) is predominantly an apoptotic inducer. Apoptotic agents, such as phorbol ester, tumor necrosis factor-alpha, and peptide hormones, have been shown to increase NO production in breast cancer cells. Therefore, we hypothesized that the production of No is vital for 4-HPR to induce apoptosis in breast cancer cells. We found that 4-HPR induced NO production in a dose-dependent manner in all of the breast cancer cell lines tested. The degree of growth inhibition and apoptotic induction by 4-HPR was directly correlated with the amount of NO produced. To prove that NO is essential for 4-HPR to induce apoptosis, breast cancer cells were coincubated with a competitive NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine (L-NMMA), and 4-HPR, L-NMMA prevented 4-HPR from inducing inhibitory effects, indicating that NO is crucial for 4-HPR to induce its apoptotic effects in breast cancer cells. IFNs and tamoxifen (TAM) have been shown to potentiate 4-HPR effects in breast cancer cells. Both IFN-gamma and TAM enhanced the ability of 4-HPR to induce NO production in breast cancer cells, which was correlated with increased apoptosis. Alone, 4-HPR increased expression of both inducible NOS (NOSII) and endothelial NOS (NOSIII). When combined with 4-HPR, IFN-gamma and TAM enhanced NOSII expression. Thus, we have identified a novel mechanism by which 4-HPR induces apoptosis in breast cancer cells, i.e., by increasing NOS expression to induce NO production.

Antineoplastic Agents↗
PubMed2002

Genotypic and phenotypic resistance patterns in early-stage HIV-1-infected patients failing initial therapy with stavudine, didanosine and nevirapine.

The objectives of this study were to determine the genotypic and phenotypic patterns of resistance in a group of early-stage antiretroviral-naive patients failing initial therapy with didanosine, stavudine and nevirapine. These patterns of resistance were determined at baseline and at time of virological failure in 89 antiretroviral-naive patients with CD4 cells >500 cells/ml and viral load >5000 copies/ml who received initial antiretroviral therapy with didanosine plus stavudine and nevirapine as part of the SCAN study, and who failed after having reached undetectable plasma levels (<200 copies/ml). Of the 89 patients recruited in the SCAN study, 14 (16%) developed a virological failure after reaching a viral load below 200 copies/ml after a median of 20 months of follow-up. At baseline, none of these 14 patients had genotypic resistance. At time of failure, six out of 14 (43%) failing patients had wild-type genotype and no phenotypic resistance. Suboptimal compliance could be documented in four of these six patients. Seven patients (50%) had nevirapine resistance mutations (mainly K103N [4/7], Y181C/I [2/7], G190A/S [2/7] and V108I [1/7]) associated with phenotypic high-level resistance to nevirapine, delavirdine and efavirenz (nevirapine >47.4- to 58.1-fold, delavirdine >74.4- to 168.9-fold and efavirenz >56.0- to 347.2-fold). Four of these seven patients also had thymidine analogue-associated mutations (TAM) (T215Y/F [2/4], M41L [1/4], D67N [2/4] and K70R [1/4]). Finally, one patient (7%) had exclusively TAM mutations (M41L). None of the patients developed mutations associated with didanosine resistance or phenotypic resistance to didanosine or stavudine. Suboptimal compliance or selection of nevirapine resistance often with TAM mutations was frequently associated with virological failure in a cohort of early-stage chronic HIV-1-infected patients treated with a protease inhibitor-sparing regimen.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Adipocyte spatial distributions in bone marrow: implications for skeletal dosimetry models.

UNLABELLED: Few studies have been conducted to quantify the spatial distributions of adipocytes in the marrow cavities of trabecular bone. Nevertheless, such data are needed for the development of 3-dimensional (3D) voxel skeletal models where marrow cellularity is explicitly considered as a model parameter for dose assessment. In this investigation, bone marrow biopsies of the anterior iliac crest were examined to determine the size distribution of adipocyte cell clusters, the percentage of perimeter coverage of trabecular surfaces, and the presence or absence of adipocyte density gradients in the marrow space, all as a function of the biopsy marrow cellularity (5%-95%). METHODS: Biopsy slides from 42 patients were selected as designated by the hematopathologist as either normocellular or with no evidence of disease. Still-frame video image captures were made of 1-3 regions of interest per biopsy specimen, with subsequent image analysis of adipocyte spatial characteristics performed via a user-written MATLAB routine. RESULTS: A predictable shift was found in cluster size with decreasing marrow cellularity from single adipocytes to clusters of >or=3 cells; the percentage of 2-cell clusters remained relatively constant with changing cellularity. Also, a nonlinear increase in trabeculae perimeter coverage was found with increasing fat tissue fraction at marrow cellularities between 50% and 80%. Finally, it was demonstrated that only in the range of 20%-50% marrow cellularity was a slight gradient in adipocyte concentration indicated with adipocytes localized preferentially toward the trabecular surfaces. CONCLUSION: Electron transport simulations were conducted in 4 different 3D voxel models of trabecular bone for sources localized in the active marrow (TAM), bone volume (TBV), bone endosteum (TBE), and bone surfaces (TBS). Voxel model simulations demonstrated that absorbed fractions to active marrow given by the ICRP 30 model (MIRDOSE2) are exceedingly conservative for both TBV and TBS sources, except in the case of high-energy particles (>500 keV) at high values of marrow cellularity (>70%). Values of both phi(TAM<--TBV) and phi(TAM<--TBS) given by the Eckerman and Stabin model (MIRDOSE3) were shown to be reasonably consistent with 3D voxel model simulations at the reference cellularity of 25%, except in the case of low-energy emitters (<100 keV) on the bone surfaces.

Adipocytes↗
PubMed2003

Overadditive anti-proliferative and pro-apoptotic effects of a combination therapy on colorectal carcinoma cells.

The prognosis of advanced colorectal carcinoma (CC) is poor. Established chemotherapy shows only limited efficacy but significant side effects. We investigated how far a combination of tamoxifen (TAM), 9-cis-retinoic acid (CRA) and the fluoroquinolone ciprofloxacin (CIP) synergize to inhibit proliferation and promote apoptosis of CC cells in vitro. The CC cell lines LOVO, CC-531 and SW-403 were incubated with TAM, CRA and CIP (10(minus;4)-10(minus;6) M) as single agents and in combination. Cell proliferation was assessed by bromodeoxyuridin incorporation. Apoptosis was quantified immunohistochemically and by FACS analysis after staining with propidium iodide. Changes in the expression of caspase 3, bax, bcl-2 and p21cip/waf were assessed by quantitative Western blotting. CRA and TAM monotherapy was moderately effective. Their combination enhanced apoptosis from 60% to more than 80% in all cell types. Apoptosis was paralleled by inhibition of proliferation and further potentiated by addition of CIP. The combination effectively up-regulated caspase 3 and bax and down-regulated bcl-2 and p21cip/waf. Combinations of biomodulaters act synergistically to inhibit proliferation and promote apoptosis in CC cells. Due to their known safety profile, this justifies clinical trials for colorectal cancer using combinations of these biological response modifiers.

Alitretinoin↗
PubMed2003

Fulvestrant in postmenopausal women with advanced breast cancer.

PURPOSE: Patients with hormone-sensitive breast cancer who have responded to tamoxifen (TAM) may receive additional benefit from a second endocrine agent after progression or relapse after TAM therapy. Fulvestrant (FVT; Faslodex; i.m. injection, ICI 182,780; AstraZeneca Pharmaceuticals, Wilmington, DE) was developed as a selective antagonist of estrogen. In postmenopausal women, FVT is reported to inhibit the proliferative effects of estrogen on sensitive tissues and has no apparent measurable estrogenic activity. In this report, we describe the data and analyses supporting marketing approval for FVT by the United States Food and Drug Administration (FDA). EXPERIMENTAL DESIGN: The FDA review of 16 clinical trials and 6 pharmacokinetic trials, as well as preclinical pharmacology and chemistry data, are described. The bases for marketing approval are summarized. RESULTS: Toxicology studies in the mouse, rat, and dog showed minimal toxicity except for antiestrogenic effects. Because of FVT aqueous insolubility, an i.m. formulation, given at monthly intervals, was selected for clinical studies. Pharmacokinetic studies demonstrated sustained concentrations with monthly injection. In in vitro studies FVT was extensively metabolized, primarily by hepatic cytochrome P450 3A4. Phase I studies showed minimal toxicity, and the maximal dose (250 mg) was limited by FVT solubility. In two Phase III trials, 851 patients were randomized to either 250 mg FVT i.m. monthly or to anastrozole (ANZ) 1 mg p.o. daily. Ninety-six percent of patients had received TAM previously for early (adjuvant treatment) or advanced breast cancer. Response rates (RR) were 17% for both FVT and ANZ study arms in the North American trial, and were 20% versus 15% for FVT versus ANZ, respectively, in the European trial. There were no observed differences between study arms with respect to time to progression or survival. The most common FVT adverse events reported as potentially treatment-related were injection site reactions and hot flashes. CONCLUSIONS: FVT was approved on April 25, 2002 by the FDA for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression after antiestrogen therapy. The recommended dose is 250 mg i.m. monthly as a single 5 ml injection or as two concurrent 2.5 ml injections into the buttocks. Approval was based on results of two randomized trials comparing response rates and time to progression of FVT- and ANZ-treated patients. Complete prescribing information is available on the FDA website.

Anastrozole↗
PubMed2003

[The reverse effect on drug-resistance against tyrosine kinase inhibitor STI571 in mdr1 and bcr-abl positive leukemic cells].

To explore the possibility of leukemia cell line of both bcr-abl and mdr-1 positive were cross-resistant to tyrosine kinase inhibitor STI571 and its reversal way, the inhibitory effect of STI571 on K562-n/VCR cells was detected with MTT method and reverse effects of CsA, TAM, IFN-alpha and CsA cominated with IFN-alpha were observed. The results showed that K562-n/VCR cell line expressing bcr-abl and mdr1 positive was resistant to STI571, and could be reversed by 5.18, 1.82 and 1.67-fold respectively, when treated with CsA, TAM, and IFN-alpha. It could be reversed by 34.87-fold with combination of half-dose CsA and IFN-alpha. In conclusion, amplification of mdr1 gene may contribute to drug-resistance of bcr-abl positive leukemic cells against STI571. The reversal agents, CsA, TAM and IFN-alpha show obviously reverse effects on drug-resistance. The combination of half-dose of both CsA and IFN-alpha display stronger effect than the full dose of either.

Antineoplastic Agents↗
PubMed2003

[Preliminary study on pathway of follicle-stimulating hormone on human epithelial ovarian cancer cell proliferation].

OBJECTIVE: There is only a limited direct indication that gonadotropins play a role in the genesis and development of epithelial ovarian cancer (EOC). Follicle-stimulating hormone (FSH) can enhance the growth of epithelial ovarian cancer cell in vitro. The research is to investigate the pathway of FSH action in epithelial ovarian cancer cell. METHODS: Epithelial ovarian cancer cell line OVCAR3 was transfected with FSH receptor cDNA expressing vector. The transfected cells that are sensitive highly to FSH stimulation were got, and named OVCAR3-FSHR. Adding FSH to the cells, or treating the cells with protein kinase C (PKC) activator tetradenocanoyl phorbol acetate (TPA), PKC inhibitor tamoxifen (TAM) in meantime, methyl thiazolyl tetrazolium (MTT) method was used to study the proliferation of cells. RT-polymerase chain reaction was used to identity the mRNA expression of various PKC subtypes. Westernblot was for detection of protein expression of PKCalpha and phosphorylated PKCalpha. RESULTS: FSH can promote proliferation of OVCAR3-FSHR (1.9 folds). There is some increase in PKCalpha by the FSH stimulation. The phosphorylated PKCalpha expression were enhanced significantly too. Both the amount and activity of PKCalpha were increased in response to FSH. TPA and TAM suppress FSH-stimulated cell growth (60% and 47%). Meanwhile expression level of PKCalpha was decreased with the co-treatment of TPA or TAM and FSH comparing with treatment with FSH only. CONCLUSIONS: FSH promoted epithelial ovarian cancer cell proliferation through PKC pathway. It plays a role in the development of epithelial ovarian cancer.

Blotting, Western↗
PubMedDate not supplied

High-dose tamoxifen modulates drug resistance to doxorubicin, dacarbazine and ifosfamide in metastatic uterine leiomyosarcoma.

A 46-year-old female patient suffered from uterine malignant leiomyosarcoma. Ten months after abdominal subtotal hysterectomy, multiple lung, bone and spine metastases developed. She received 3 cycles of infusional ADI chemotherapy (adriamycin 60 mg/m2, 96-hour i.v. infusion, dacarbazine 500 mg/m2, 96-hour i.v. infusion and ifosfamide 5,000 mg/m2, 72-hour i.v. infusion, repeated every 3 weeks), but the metastatic tumors progressed. An empirical ADI-TAM chemotherapy which incorporated high-dose tamoxifen (TAM) (150 mg/m2/day, in 4 divided doses) into the original ADI regimen was applied from the fourth cycle. High-dose tamoxifen consisted of 240 mg/day for 4 days during chemotherapy and 40 mg/day between cycles. Good partial response with nearly total tumor reduction was achieved after 3 cycles of ADI-TAM therapy. The excellent tumor response by simple addition of high-dose tamoxifen into a previously inactive ADI regimen advocates further investigation for the development of chemotherapy in metastatic uterine leiomyosarcoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

The balance between MMP-2/-9 and TIMP-1/-2 is shifted towards MMP in renal cell carcinomas and can be further disturbed by hydrogen peroxide.

In malignant tumors the balance of matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP) is disturbed. Radical oxygen species (ROS) and hydrogen peroxide potentially influence this balance. Therefore, we analyzed the balance of MMP and TIMP in renal cell carcinoma (RCC) specimens and cell lines. In RCC specimens MMP-2, MMP-9, TIMP-1, and TIMP-2 were immunohistochemically detected. Tumor-associated macrophages (TAM) as a potential source of ROS were characterized with an anti-CD68 antibody. Three RCC cell lines were treated with sublethal concentrations of hydrogen peroxide to simulate the effects of radical oxygen species. MMP-2 and MMP-9 protein expression was measured by zymography. mRNA expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 was assessed by quantitative reverse transcriptase polymerase chain reaction. Tumor cell-derived reactive oxygen species were measured by FACS analysis and dihydrorhodamine 123 oxidation. In RCCs the MMP and TIMP expression profile was variable. The balance between MMP and TIMP was shifted towards MMP in comparison to matched normal controls. TAM were localized in a close vicinity to MMP expresssing tumor cells. As in RCC specimens, the expression of MMP and TIMP in the analyzed RCC cell lines varied. Hydrogen peroxide induced MMP-2 and -9 mRNA and protein expression, whereas TIMP-1 and TIMP-2 mRNA levels remained unaffected in cell lines. Thus, the ratio between MMP and TIMP was shifted towards MMP. Tumor cells did not increase the production of reactive oxygen species stimulation with phorbol ester or hydrogen peroxide. In RCC the balance between MMP and TIMP is disturbed. Oxidative stress potentially increases this imbalance. TAM might be one source of hydrogen peroxide thus supporting the invasive properties of RCCs.

Adenocarcinoma, Clear Cell↗
PubMedDate not supplied

[Cardioprotective effect of energostim in toxic allergic myocarditis].

Energostim is a combined drug comprising a mixture of nicotinamide adenine dinucleotide (0.5 mg), cytochrome C (10 mg), and inosine (80 mg), representing antihypoxant and antioxidant of direct action in one ampule. After pretreatment and subsequent 3-day energostim therapy of animals with 3-day toxico-allergic myocarditis (3d-TAM), the ECG was free of any rhythm disorders and showed evidence of improved conduction, restoration of the normal form of T-wave and the position of ST segment, while the content of myofibrillar fraction of creatine phosphokinase and toxic products of disturbed metabolism (degree of endotoxemia) decreased to the upper normal level. Under the action of energostim, neither pressure nor the maximum rate of pressure buildup in the left ventricle are reduced (as they do upon 3d-TAM); neither systolic and diastolic functions are disturbed, nor their coordination (r = 0.79 between dP/dtmin and dP/dtmax, p < 0.01). The restoration of contractile activity and maximum rate of relaxation of myocardial microfibrils during 3d-TAM is accompanied by an increase in the content of adenyl nucleotides, in the ATP/ADP, ADP/AMP, NAD/NADH, and NADP/NADPH ratios, and in the cytosol phosphorylation potential. The energostim-induced improvement in the energy supply system are accompanied by restoration of the ability of sarcoplasmic reticulum to efflux Ca2+. Thus, it is demonstrated that the effect of energostim is related to its ability to actively participate in intracell metabolic processes in myocardium, abolish necrotic changes and endotoxicosis, and restore homeostasis in the systems responsible for the contraction--relaxation process (thus preventing from the development of dysfunction of the left ventricle and the heart failure).

Animals↗
PubMed2005

[Study on the modulation of estrogen receptor isoforms alpha in endometrial carcinoma cells using antisense oligodeoxyribonucleotides].

OBJECTIVE: To verify the roles of estrogen receptor alpha in the tumogenesis of endometrial cancer in relationship with estrogen and tamoxifen, and to explore an efficient way to modulate the expression of estrogen receptor (ER) isoform alpha to built up a model of endometrial cancer cells expressing predominant one isoform of ERs for ultimately probing therapeutical and preventive antiestrogen for endometrial cancer. METHODS: A series of oligodeoxyribonucleotides against regions of the human ERalpha was synthesized and tested in human endometrial cancer cell line (HEC-1B cells) that expressed functional ERalpha. The expressions of ER isoforms were detected by Western blot using specific antibody. The change of HEC-1B cell proliferation in response to 17beta-estradiol(E2) and tamoxifen(TAM) under the impact of antisense oligodeoxyribonucleotides (AS-ODN) was studied. RESULTS: (1) Transfection with AS-ODN directed against the human ERalpha significantly inhibited ERalpha protein expression. (2) The proliferation of endometrial cancer cell line HEC-1B could be increased by both E(2) and TAM. The cells lost the ability to proliferate in response to E(2) after being transfected with ERalpha-AS-ODN at hours 24, 48 and 72. After being transfected with ERalpha-AS-ODN, HEC-1B cells lost the ability to proliferate in response to TAM at hour 48. CONCLUSION: (1) AS-ODNs directed against the human ERalpha can inhibit the expression of ER alpha effectively. The method can be used to built up a model of endometrial cancer cells expressing predominant one isoform of ERs. (2) ERalpha may be the primary receptor in the proliferation of HEC-1B cells in response to 17beta-estradiol and tamoxifen.

Cell Proliferation↗
PubMed2005

Interleukin-15 and transforming growth factor alpha are associated with depletion of tumor-associated macrophages in colon cancer.

We examined the effects of IL-15 and TGF-alpha on the inhibition of macrophage infiltration into colon cancer tissue, and secretion of amphoterin from colon cancer cells. Production of IL-15 and/or TGF-alpha was associated with depletion of tumor-associated macrophages (TAMs) in both Dukes' B and C tumors (P = 0.0324 and 0.0051, respectively). Production of IL-15 and/or TGF-alpha was also associated with amphoterin mRNA expression in colon cancer tissues with TAM depletion in both Dukes' B and C tumors (P = 0.0167 and P = 0.0062, respectively). WiDr human colon cancer cells treated with IL-15 and/or TGF-alpha induced reduction of nucleus-localized amphoterin and an increase in cytosolic and membranous amphoterin. Moreover, IL-15 and/or TGF-alpha treatment increased amphoterin secretion by WiDr cells. Most notably, IL-15 and TGF-alpha treatment induced the increase of cytosol/membrane localization and secretion of amphoterin and the most pronounced effect among the treatments carried out. These results suggested that IL-15/TGF-alpha promotes depletion of TAMs and secretion of amphoterin in colon cancer.

Antigens, CD↗
PubMed2005

Changes in hepatic parenchymal ultrasound images in tamoxifen medication patients.

We experienced changes in ultrasonographic features of hepatic parenchyma in 156 patients treated with Tamoxifen (TAM) as an adjuvant hormonal therapy for breast cancer. After the treatment with TAM subsequent to the surgery for breast cancer, 36% of patients showed changes in ultrasonographic features of the liver more than Grade 2, despite no obvious hepatic involvement at the start of the medication. Forty-five percent of affected patients showed Grade 2 or 3 changes in hepatic parenchymal images within the first 6 months of TAM medication, while the average interval of change was 11.3 months. Abdominal ultrasound inspection should be undertaken within 6 months of surgery to aid the early detection of liver metastasis and fatty liver changes, which may play an important role in determining postoperative follow-up care for breast cancer patients.

Antineoplastic Agents, Hormonal↗
PubMed2005

[Assessment of goserelin treatment in adjuvant therapy for premenopausal patients with breast cancer in Japan-zoladex breast cancer study group trial-B].

OBJECTIVE: Goserelin (GOS) therapy in an adjuvant setting for estrogen receptor(ER)-positive premenopausal patients with breast cancer was assessed in a randomised comparative study. METHODS: ER positive premenopausal patients with n + or n 0 and T > or = 3 cm received tamoxifen (TAM) 20 mg/day, GOS 3.6 mg/4 weeks or GOS + TAM for 2 years, and the clinical efficacy and safety of these regimens were assessed. RESULTS: In the data analysis of total 207 patients, hazard ratios of disease free survival (DFS) and overall survival (OS) in the GOS group compared to the TAM group were 0.87 and 2.10,respectively. The incidence of adverse drug reactions was similar (42-55%) in all three groups. Since the number of patients in this study did not reach the target number, the efficacy could not be assessed from a statistical aspect. Therefore,meta-analysis with similar foreign studies(ZIPP) was implemented. The results of meta-analysis showed that the hazard ratios of DFS and OS in the GOS group compared to the non-GOS group were 0.83 and 0.85, respectively. CONCLUSION: Although the analysis of 207 patients did not show any statistically significant difference between each of the treatment groups, the results of meta-analysis showed a significant prolongation of DFS in the GOS group. Also high tolerability of GOS was suggested. From these results, GOS was considered highly useful in adjuvant therapy for ER-positive premenopausal patients with breast cancer.

Adult↗
PubMedDate not supplied

Antitumor effect of lonidamine alone or combined with tamoxifen or medroxyprogesterone acetate in breast cancer cells.

The effect of Lonidamine (LND) alone or combined with the antiestrogen Tamoxifen (TAM) or Medroxyprogesterone acetate (MPA) on cell proliferation and steroid hormone receptor content of a human estrogen sensitive breast cancer cell line was investigated. LND has a direct growth inhibitory action, even if used at relatively low concentrations (10(-7) M), and shows the maximum effect at 10(-4) M. The combination of LND with the antiestrogen does not produce a potentiation of the TAM-induced reduction of cell number, while the association of the drug with MPA seems more effective with respect to MPA alone, at least at certain concentrations. The negative interference observed between LND and TAM may be due to the LND-induced decrease of estrogen receptor levels.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

[Adjuvant endocrine treatment of postmenopausal patients with breast cancer with high risk of recurrence. 5. Results from the DBCG (Danish Breast Cancer Cooperative Group) 77C randomized trial].

The role of antiestrogen treatment of postmenopausal breast cancer patients with high risk of recurrent disease is evaluated in a nationwide, prospective trial conducted by the Danish Breast Cancer Cooperative Group (DBCG). After total mastectomy and postoperative radiotherapy (RT), 840 patients were randomized to treatment with tamoxifen (RT + TAM) for one year, and 824 were randomized to no further therapy (RT). The recurrenceree survival (RFS) after ten years of lifeable analysis is 31% in the RT + TAM treated group, and 28% in the RT group (p = 0.01). Survival is 38% and 34% in the two treatment groups, respectively (p = 0.04). The data were further analyzed with respect to prognostic factors such as age, number of positive nodes, tumour size, and degree of anaplasia. Survival is prolonged in nearly all subgroups of patients treated with RT + TAM. However, the prolongation is only significant in patients with four or more positive nodes, with tumours of less than 5 centimeters or with tumours of anaplasia grade II. Estrogen (ER) and progesterone receptor (PgR) concentrations were measured in tumours from 309 and 219 patients, respectively. Only patients with ER and PgR values above 100 fmol/mg cytosol protein seemed to have a prolongation of survival. In conclusion, a modest survival benefit is achieved with one year of adjuvant tamoxifen treatment. Nevertheless, this is the first example of a systemic treatment approach being able to change the fatal course of breast cancer in postmenopausal patients. By means of endocrine therapy, and in the context of a new randomized trial, the DBCG will try to improve the survival in these patients even further.

Aged↗
PubMed1991

Energy transduction in the myocardial contractile protein system under normal conditions and in toxi-allergic myocarditis.

Energy transduction in purified myocardial myofibrils from normal rabbits and those having toxi-allergic myocarditis (TAM) was compared. In TAM a sharp decrease in the rate and value of ATP hydrolysis enthalpy released during free contraction of myofibrils takes place, and is accompanied by a rise in the amount of energy dissipated as heat. It is concluded that, at the early stages of shrinkage force generation during myofibril contraction in TAM, a breakdown of actin activation of Mg(2+)-ATPase activity for myosin occurs, the character of the bonds is changed, and the efficiency of myosin cross-bridge interaction with the protomeres of the actin thin filaments is decreased. The contractile process becomes wasteful.

Adenosine Triphosphate↗