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PubMed2000

The interferon-beta and tamoxifen combination induces apoptosis using thioredoxin reductase.

Interferons (IFNs) suppress cell growth by inducing cellular genes. The anti-estrogen tamoxifen (Tam), binds to estrogen receptor and inhibits transcription of estrogen stimulated genes. In cells resistant to IFN-induced growth suppression, IFN/Tam combination causes cell death. We previously reported that the combination of IFN-beta and Tam was a more potent growth suppressor of human tumor xenografts than either agent alone. The IFN/Tam combination acts in a manner similar to the IFN/retinoic acid combination. Using a genetic technique, we have recently identified several genes associated with retinoid-IFN-induced mortality (GRIM). One such gene, GRIM-12, was identical to human thioredoxin reductase (TR). In the present study we have examined whether the IFN/Tam combination also requires GRIM-12 for inducing cell death. We report here that GRIM-12 is necessary for mediating the cell death effects of IFN/Tam, and its expression is induced by IFN/Tam at a post-transcriptional stage. Repression of GRIM-12 levels either by antisense expression or by dominant negative inhibitors caused resistance to IFN/Tam induced death and promoted cell growth. Overexpression of GRIM-12 increased IFN/Tam induced apoptosis. Thus, these studies have identified a critical role for GRIM-12 (TR) in apoptosis.

Animals↗
PubMed2001

Direct effects of GnRH agonists in human hormone-sensitive endometrial cells.

The antiproliferative effect of two GnRH agonists (leuprorelin acetate and triptorelin), alone or combined with tamoxifen (TAM) or medroxyprogesterone acetate (MPA), on human estrogen-sensitive endometrial cancer cells (Ishikawa) was investigated. Although ineffective when tested alone in all the culture conditions used, both analogues counteracted or even suppressed the estrogen-stimulated growth of Ishikawa cells. The antiestrogenic effect of TAM or MPA was not modified by their association with high doses of the GnRH analogues, but low concentrations of triptorelin combined with MPA 10(-7) M determined a reduction in cell numbers which was greater than that obtained with the progestin or the analogue alone. In addition, analogue treatment prevented the estrogen-induced decrease in the level of estrogen receptors. Our data provide evidence that GnRH agonists can directly inhibit estrogen-stimulated endometrial cancer cell growth and suggest that they may interfere with steroid-receptor machinery.

Antineoplastic Agents, Hormonal↗
PubMed2002

Growth-stimulatory and transcriptional activation properties of raloxifene in human endometrial Ishikawa cells.

Raloxifene (Ral) has estrogenic activity in bone and cardiovascular tissues, but is antiestrogenic in breast and has limited uterotrophic activity in mice. Here we report that Ral stimulates the growth of human endometrial Ishikawa tumors implanted in the mammary fat pad of nude ovariectomized mice. In cultured Ishikawa cells, Ral has agonist effects on transcription mediated by the progesterone receptor, an endogenous estrogen target gene, and on expression of reporter genes containing estrogen response elements (EREs). Both Ral and tamoxifen (Tam), but not estradiol, stimulated transcription mediated by the activator protein 1 at micromolar concentrations. However, this effect correlated with induction of cellular death at high concentrations of Ral or Tam and was not observed at lower concentrations. Our results suggest that Ral has stimulatory effects in Ishikawa cells on both cellular growth and gene transcription, and that EREs can mediate some of these effects.

Animals↗
PubMed1998

Expression of monocyte chemotactic protein-1 in human invasive ductal breast cancer.

Monocyte chemotactic protein-1 (MCP-1) is a chemokine involved in the macrophage infiltration of tumor tissue. Tumor associated macrophages (TAMs) are a population of mononuclear-phagocytic cells, which can express complex functions related to tumor biology. The present study was designed to analyse the expression of MCP-1 in parenchymal and stromal elements on frozen sections of 27 breast invasive ductal carcinomas not otherwise specified (NOS) by immunohistochemistry. The expression of MCP-1 in tumor parenchyma and the degree of tumor differentiation were assessed. MCP-1 was detected in the parenchyma in 15 of 27 ductal carcinomas. Positive immunoreactivity manifested as diffuse, homogeneous, moderate or strong, cytoplasmic staining, confined to tumor epithelium. Generally, MCP-1-negative tumors tended to be well differentiated, while chemokine-positive tumors exhibited a low level of differentiation. MCP-1 immunoreactivity was also present in TAMs (CD68 positive cells) in 23 of 27 tumors, and in endothelial cells in 11 of 27 tumors. These results indicate that parenchymal and, more variably, stromal elements of human invasive ductal carcinomas NOS can express MCP-1 in vivo. Additionally, these findings suggest that MCP-1 expression in tumor parenchyma is correlated with the histological grade of ductal invasive breast carcinoma.

Breast Neoplasms↗
PubMed1984

Fasciectomy and Dupuytren's disease: a comparison between the open-palm technique and wound closure.

An analysis of 153 patients treated surgically for Dupuytren's disease is presented. One hundred fifteen patients were treated with the closed-palm technique, while 38 patients were treated with the open-palm technique. The groups were comparable in terms of preoperative metacarpophalangeal and proximal interphalangeal joint involvement, as well as the total number of rays involved. The patients were analyzed in terms of average pre- and post-operative total active motion (TAM) in the digital joints. The patients in the closed-palm group had a 10% improvement in TAM surgery, while those in the open-palm group had a 17% improvement (p less than 0.05). The complication rate in the closed-palm group was 19% and in the open-palm group, 8%. There were no hematomas in the open-palm group and no infections in either group. In a later follow-up of 103 patients who could be contacted, 33 of the 78 closed-palm group showed residual contracture (42%), while five of the 25 open-palm group were similarly affected (20%).

Dupuytren Contracture↗
PubMed1988

Delayed repair of flexor profundus tendon in the palm (zone 3) with superficialis transfer.

Transfer of a flexor superficialis tendon was done in an attempt to restore flexor profundus function, as a secondary procedure, in the palm (zone 3) in 16 hands. These were cases in which direct repair was not possible. Eight patients achieved a total active motion (TAM) above 200 degrees and two more were above 180. Of those eight with TAM above 200 degrees four required a secondary tenolysis to improve to that level. Transfers in six patients were regarded as failures. Failures were associated with a poor tendon bed and noncompliant patients. This is a procedure that has limited indication in a cooperative patient with a good tendon bed who reports late with both flexor tendons cut in zone 3.

Follow-Up Studies↗
PubMed1988

Staged flexor tendon reconstruction in the fingers and hand.

A two-stage tendon-grafting technique was used to reconstruct 130 fingers in 101 patients between 1973 and 1984. Eighty-nine patients with 117 fingers that had undergone operation were evaluated 6 months or longer after stage II surgery. Sixty-five percent of the patients were in the Boyes salvage group before operation. Overall, 54% had good or excellent results by the total active motion (TAM) as a percentage of total passive motion (TPM) method, although only 19% had final TAM of greater than 180 degrees. Complications included infection in 15%, rupture in 4%, amputation in 4%, and reflex sympathetic dystrophy in 1% of the patients. Sixteen percent of the patients required tenolysis after stage II surgery. Factors associated with a poor result included zone I or II injury and patients who were less than 10 years of age. Factors associated with a better result included zone IV or V injury and all postoperative therapy under the direct supervision of the treating surgeon.

Adolescent↗
PubMed1996

Activation of the human estrogen receptor by estrogenic and antiestrogenic compounds in Saccharomyces cerevisiae: a positive selection system.

The yeast URA3 gene was used as a reporter to investigate the activities of estrogenic and antiestrogenic compounds in yeast Saccharomyces cerevisiae. The control sequences of the wild type (wt) URA3 promoter were replaced with zero, two, or six copies of estrogen-response elements (ERE). Insertion of two and six copies of ERE rendered the expression of the URA3 gene to be dependent on the presence of the human estrogen receptor (ER) and the hormone 17beta-estradiol (E2). Two versions of the ER genes were constructed: a full-length wild-type ER (ERa-f) and a truncated ER with domains C, D, and E (ERcde). Both forms of the ER were able to activate the ERE-URA3 reporter in a hormone-dependent manner. The growth of yeast transformants were hormone-dependent when the reporter constructs were inserted into chromosomes using yeast integrating vectors (YIp) but not with the 2mu-based episomal (high-copy number, YEp) or centromeric (low-copy number, YCp) vectors. The integrated transformants were employed to investigate the effects of estrogenic and antiestrogenic compounds. The estrogenic compounds, E2, diethylstilbestrol (DES), and estrone (EST), activated expression of the reporter genes at 1 nM concentration, which is the same concentration exhibiting activity in mammalian cells. None of the antiestrogens, at concentrations up to 1 microM, including tamoxifen (TAM), raloxifene (RAL), and ICI 164,384 (ICI) antagonized 1 nM of E2 against either form of the ER. In fact, TAM, RAL, and ICI displayed slight agonistic activity at high concentrations of 300 nM or greater to the ERcde. This system can be used to investigate or clone the missing factor(s) that is responsible for the antagonistic activity of the ER in yeast, and is also suitable for screening for the effectors of the ER.

Cloning, Molecular↗
PubMed1997

Solid-phase extraction and high-performance liquid chromatographic determination of tamoxifen and its major metabolites in breast tumour tissues.

A sensitive (200 ng/g) and selective reversed-phase high-performance liquid chromatography separation has been developed to determine the levels of tamoxifen, 4-hydroxytamoxifen (4-OH) and desmethyltamoxifen (DMT) in tumour tissue taken from patients undergoing tamoxifen therapy. A muBondapak C18 10 microm column (30 cm x 3.8 mm I.D.) was used, with a mobile phase of methanol-1% triethylamine at pH 9 (89:11, v/v). Sample preparation was carried out using a C2 (500 mg sorbent, 3 ml reservoirs) solid-phase extraction method, and extraction efficiencies were followed in individual extracts using a [3H]TAM radiolabelled spike (10000 dpm), with a range of 60-90%. Accuracy and precision (standard deviation) as determined from tumour spiked with radioinert tamoxifen and its metabolites ranged from 83.4-92.3% (+/-23-33%) at 20 microg/g; 85.2-87.7% (+/-18-23%) at 2 microg/g; 88-101% (+/-15-50%) at 0.2 microg/g and 63-94% (+/-13-24%) at 0.02 microg/g. Results from seventy-two patients show mean values (+/-S.D.) of 174+/-203 ng/g for 4-OH; 783+/-1326 ng/g for DMT and 410+/-458 ng/g for TAM, variations reflecting heterogeneity in levels between patients. This methodology can be routinely applied to the determination of tamoxifen and its metabolites in tumour tissues from patients undergoing tamoxifen therapy.

Antineoplastic Agents, Hormonal↗
PubMed1992

Staged flexor tendon reconstruction in children.

The medical records of 12 children, aged 1 to 15 (mean 8.4 years) who had a total of 14 staged flexor tendon reconstructions for zone 2 flexor tendon injuries between the years of 1974 and 1989 were reviewed. One patient with one treated finger was lost to follow-up one month after Stage II surgery. The rest were followed either to failure or for a minimum of six months after Stage II surgery (range 6 to 108 months; mean 45 months). Results were graded by the percentage of total passive motion after Stage I converted to active motion after Stage II, and the final total active motion (TAM). Overall, there were seven poor, one fair, two good, and three excellent results. Mean final TAM was 140 degrees (range 90-210 degrees). Results were better in those children whose rehabilitation was supervised by a trained hand therapist (three excellent, one good, and one poor result). Complications included four infections after Stage I, and one infection and one rupture after Stage II. After treatment, these complications resulted in four poor results. Staged flexor tendon reconstruction in children in this series had a higher risk of complications and failure than the same procedure in adults reported in a previous series from this institution. Results in children may be improved by close attention to postoperative care and by patient selection based on ability to cooperate with the postoperative program.

Adolescent↗
PubMed1999

The role of macrophages in antitumor defense of patients with ovarian cancer.

Macrophages have diverse effects on tumor biology, including neovascularization, growth rate, and stroma formation. Tumor-associated macrophages (TAMs) represent a major subpopulation of the mononuclear leukocytes present in malignant ascites of ovarian cancer patients. TAMs appear to participate in the immunologic antitumor defense mechanism through cytotoxic activities, such as direct cellular cytotoxicity and the release of cytokines, and may represent key targets for a variety of therapeutic interventions.

Cytotoxicity, Immunologic↗
PubMedDate not supplied

Early controlled motion with dynamic splinting versus static splinting for zones III and IV extensor tendon lacerations: a preliminary report.

Recent developments in the understanding of tendon healing and the effects of early motion have led to early controlled motion programs (ECM) for lacerated extensor tendons. The purpose of this study was to determine whether there were differences in length of treatment and final results when patients who had been treated with ECM with dynamic splinting were compared with patients who had been treated with traditional static extension splinting (SES) for zone III and zone IV extensor tendon lacerations. A retrospective study of patient charts from June 1984 through January 1990 was conducted. A total of 36 charts were reviewed. Twenty-seven patients met the study criteria: treatment with ECM with dynamic splinting (n = 10) and treatment with traditional SES using a finger-hand splint (n = 17). Data were analyzed for total number of therapy visits (V), total number of weeks of therapy before discharge (W), total active motion achieved (TAM), total passive motion achieved (TPM), and incidence of complications. Significance was established at the p = 0.05 level for all statistical analyses. There were no significant differences between the groups for V (t = 1.76, p = 0.09), W (t = 0.58, p = 0.57), TPM (t = 0.12, p = 0.90), TAM (t = 0.44, p = 0.66), or the incidence of extensor lag (chi 2 = 2.264). The Cohen stat power analysis value was 0.40, revealing that the number of patients was too small for significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1999

Prognostic significance of mutations in the p53 gene, particularly in the zinc-binding domains, in lymph node- and steroid receptor positive breast cancer patients. Austrian Breast Cancer Study Group.

The aim of our study was to evaluate if p53 mutations, especially those in the L2/L3 domains of the p53 gene, add prognostic information for node-positive and steroid receptor positive breast cancer patients. Two hundred and five tumour samples from a randomised clinical trial of 596 lymph node- and steroid receptor positive breast cancer patients were included. All patients had been randomly allocated to receive 20 mg of adjuvant tamoxifen (TAM) daily for 2 years or TAM plus one cycle of low-dose, short-term chemotherapy. For detection of p53 mutations we used in vitro amplification by polymerase chain reaction and consecutively performed temperature gradient gel electrophoresis (PCR-TGGE) and direct sequencing. We found p53 mutations in 42/205 (20%) cases: 16/42 (38%) p53 mutations occurred within the L2/L3 domains of the p53 gene, and 26/42 (62%) outside the L2/L3 domains. p53 mutation served as a statistically significant parameter in predicting disease-free survival in univariate (P = 0.02) and multivariate (P = 0.009) analysis. For overall survival, no significant differences were observed. Patients with tumours that had p53 mutations within the L2/L3 domains of the gene showed no significant difference to those with mutations outside the L2/L3 domains for disease-free survival. For overall survival, mutations in the L2/L3 domains showed a marginally significant difference (P = 0.05) in multivariate analysis, but not in univariate analysis (P = 0.13). We conclude that mutation in the L2/L3 domains of the p53 gene is not an independent prognostic indicator of disease outcome for patients suffering from breast cancer with lymph node metastases and positive steroid receptors.

Adult↗
PubMed2001

EM-652 (SCH57068), a pure SERM having complete antiestrogenic activity in the mammary gland and endometrium.

In order to minimize the risks of endometrial cancer and the development of resistance to antiestrogen therapy, we have synthesized the orally active antiestrogen EM-652 which is the most potent of the known antiestrogens and exerts pure antiestrogenic activity in the mammary gland and endometrium. EM-652 inhibits the AF-1 and AF-2 functions of both ERalpha and beta while the inhibitory action of OH-TAM is limited to AF-2. EM-652, thus, inhibits Ras-induced transcriptional activity and blocks SRC-1-stimulated activity of the two receptors. The absence of blockade of AF-1 by OH-TAM could explain why resistance develops to Tamoxifen treatment. Not only the development, but also the growth of established DMBA-induced mammary carcinoma is inhibited by treatment with EM-800, the prodrug of EM-652. EM-652 is the most potent antiestrogen to inhibit the growth of human breast cancer ZR-75-1, MCF-7 and T-47D cells in vitro. When incubated with human Ishikawa endometrial carcinoma cells, EM-800 has no stimulatory effect on the estrogen-sensitive parameter alkaline phosphatase activity. When administered to ovariectomized animals, EM-800 prevents bone loss, and lowers serum cholesterol and triglyceride levels. EM-800 has shown benefits in women with breast cancer who had failed Tamoxifen. The above-summarized preclinical and clinical data clearly suggest the interest of studying this compounds in the neoadjuvant and adjuvant settings and, most importantly, for the prevention of breast and uterine cancer.

Animals↗
PubMed2003

Extensor tendon repair: mobilise or splint?

OBJECTIVES: The aim of this study was to assess the static and dynamic hand therapy regimes used at Mount Vernon Hospital, following extensor tendon injury during 1995-2000 and compare them to the early active regimes published. METHODS: Sixty-five patients were included and their hand function recorded by calculating total active motion (TAM), percentage combined motion and extensor lag at 4-6 weeks and at 10 weeks postinjury. RESULTS: The results in two groups were good, with mean TAMs of 202 and 258 at 4-6 weeks and at 10 weeks, respectively, for the static regime and 214 and 245, respectively, for the dynamic regime, during the same time periods. CONCLUSION: The results from each group compare favourably with the published series of patients undergoing early active motion, where mobilisation is commenced almost immediately. The authors' preference is the static regime as it is simple, effective and particularly useful in poorly compliant patients.

Adult↗
PubMed2000

Superinduction of cyclooxygenase-2 by NO(*) and agonist challenge involves transcriptional regulation mediated by AP-1 activation.

Superinduction of cyclooxygenase-2, in murine RAW 264.7 macrophages as well as human pulmonary type II A549 epithelial cells, is achieved by the simultaneous addition of agonists such as lipopolysaccharide or interleukin-1beta and the NO(*) donor S-nitrosoglutathione. NO(*)-evoked superinduction of cyclooxygenase-2 in the presence of agonists was dose-dependent and required transcriptional as well as translational regulation. We sought to further analyze NO(*)-elicited superinduction at the level of the transcription factor NF-kappaB that is obligatory for cyclooxygenase-2 expression. NO(*)-mediated NF-kappaB activation was restricted to low concentrations of S-nitrosoglutathione (50-200 microM), while a higher dose of S-nitrosoglutathione (1 mM) was ineffective. Not observing a correlation between NF-kappaB activation and cyclooxygenase-2 expression under NO(*)-delivery stimulated our interest in analyzing AP-1. NO(*) efficiently activated AP-1 at all concentrations tested. The involvement of AP-1 in promoting cyclooxygenase-2 superinduction was established in cells transfected with the dominant-negative c-Jun mutant, TAM-67. Enhanced expression of cyclooxygenase-2 by lipopolysaccharide/S-nitrosoglutathione-treatment was attenuated in TAM-67 transfectants, while the response to lipopolysaccharide alone remained unaffected. We conclude that AP-1 activation exclusively conveys the NO(*) signal that is required for superinduction of cyclooxygenase-2. Superinduction of cyclooxygenase-2 is restricted to a situation where both, NF-kappaB and AP-1 are activated. Under inflammatory conditions this might be achieved by the costimulatory signals provided by agonist challenge and NO(*).

Animals↗
PubMed2006

Substituent effects on Gd(III)-based MRI contrast agents: optimizing the stability and selectivity of the complex and the number of coordinated water molecules.

Hydroxypyridinone (HOPO)-based Gd(III) complexes have previously been shown to exhibit high relaxivity, especially at the high magnetic fields that are clinically relevant for present and future clinical use. This is due to more than one coordinated water molecule exchanging rapidly with bulk solvent. These complexes, however, present poor water solubility. Heteropodal complexes which include a terephthalamide (TAM) moiety maintain the high relaxivity characteristics of the HOPO family and have been functionalized with solubilizing substituents of various charges. The charge of the substituent significantly affects the stability of the Gd(III) complex, with the most stable complex presenting a neutral charge. The solubilizing substituent also moderately affects the affinity of the complex for physiological anions, with the highest affinity observed for the positively charged complex. In any case, only two anions, phosphate and oxalate, measureably bind the Gd(III) complex with weak affinities that are comparable to other q = 1 complexes and much weaker than DO3A, q = 2 based complexes. Furthermore, unlike poly(amino-carboxylate)-based complexes, HOPO-based Gd(III) complexes do not show any noticeable interaction with carbonates. The nature of the substituent can also favorably stabilize the coordination of a third water molecule on the Gd(III) center and lead to a nine-coordinate ground state. Such complexes that attain q = 3 incorporate a substituent beta to the terminal amide of the TAM podand that is a hydrogen-bond acceptor, suggesting that the third water molecule is coordinated to the metal center through a hydrogen-bond network. These substituents include alcohols, primary amines, and acids. Moreover, the coordination of a third water molecule has been achieved without destabilizing the complex.

Contrast Media↗
PubMed2005

In vivo evaluation of gadolinium hydroxypyridonate chelates: initial experience as contrast media in magnetic resonance imaging.

The effect of ligand structure on the magnetic resonance (MR) imaging and biodistribution of six gadolinium (Gd) chelates based on a hydroxypyridonate-terephthalimide (HOPO-TAM) ligand design was investigated. Modifications to the molecular structure of the Gd-HOPO-TAM chelates (hydrophilicity and aromatic group substitution) significantly influence the efficacy of imaging and biodistribution. MR imaging was performed on female mice after intravenous (iv) injection of 100 micromol of Gd/kg of body weight of the different complexes. The biodistribution results indicate that the liver uptake of the complexes is enhanced by a short poly(ethyleneoxy) (PEO) chain, while blood pool localization is facilitated by a very long PEO chain. There is a direct correlation between the blood pool localization of the complexes and the signal intensity of blood vessels in the MRI. The imaging results are consistent with in vitro NMR measurements that indicate long PEO chains increase image enhancement capabilities in the presence of serum albumin.

Animals↗