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PubMed2003

Plant damage and yield response to the Russian wheat aphid (Homoptera: Aphididae) on susceptible and resistant winter wheats in Colorado.

Plant damage and yield response to the Russian wheat aphid, Diuraphis noxia (Mordvilko), were evaluated on a susceptible (TAM 107) and a resistant (RWA E1) winter wheat, Triticum aestivum L., in three Colorado locations in the 1993 and 1994 crop years. Russian wheat aphid was more abundant on TAM 107 than on RWA E1. Russian wheat aphid days per tiller were greater at the higher infestation levels. Yield losses as a result of Russian wheat aphid infestation occurred most of the time with TAM 107 but rarely with RWA E1. Seed densities were reduced at higher infestation levels in TAM 107 at two locations. Russian wheat aphids per tiller had a negative relationship to yield in TAM 107 but not in RWA E1. In TAM 107 yield decreased as aphid densities increased, but yield remained constant regardless of initial aphid abundance on RWA E1 in all environments. Seed densities were reduced at higher infestation levels in TAM 107 at two locations. The resistance conferred by the Dn4 gene seems to be an effective management approach across a range of field conditions.

Animals↗
PubMed2006

Evolution of HIV resistance mutations in patients maintained on a stable treatment regimen after virologic failure.

OBJECTIVE: We compared the rate of emergence of thymidine analogue mutations (TAMs) and major protease inhibitor mutations in adherent patients who remained on stable treatment with a thymidine analogue and/or protease inhibitor after the onset of virologic failure. DESIGN: Follow-up genotypic resistance testing was done using archived plasma obtained from patients having 0 or 1 TAM and/or 0 or 1 major protease inhibitor resistance mutation at the onset of virologic failure. RESULTS: The median duration of observed failure was 691 days. There were 41 thymidine analogue regimens and 34 protease inhibitor regimens; concomitant ritonavir was used 4 times. New major protease inhibitor mutations emerged more rapidly than did new TAMs (P = 0.0019); new TAMs emerged more rapidly in thymidine analogue regimens that did not include lamivudine (P = 0.0073). The emergence of TAMs and major protease inhibitor mutations did not differ if lamivudine was not part of the thymidine analogue regimen. The evolution of CD4 cell counts and plasma viral loads (pVLs) during virologic failure was similar regardless of whether or not a new TAM or major protease inhibitor mutations emerged or, for thymidine analogue-containing regimens, whether lamivudine was or was not used. CONCLUSIONS: Major protease inhibitor mutations arose more frequently and rapidly than did TAMs in patients with sustained virologic failure who received lamivudine.

Anti-HIV Agents↗
PubMed1983

Concentrations of methicillin in blood, normal milk and mastitic milk of cows after intramuscular injection of methicillin and tamethicillin.

Tamethicillin (TAM) is a basic ester pro-drug of methicillin (MET) which is converted in the body by non-specific esterases to MET. Equal doses of MET and TAM were administered intramuscularly in a crossover trial involving four dairy cows. Acute mastitis was induced in each cow by infusing two quarters of the udder with Escherichia coli endotoxin 3 h before antibiotic administration. Peak serum MET concentrations after MET injection were significantly (P less than 0.001) higher than peak serum drug concentrations after TAM injection. The t1/2 of MET in serum after MET and TAM treatments were 18 min and 2 h, respectively. Normal milk MET concentrations during the first 8 h after TAM administration were significantly (P less than 0.05) higher than after MET treatment. Mastitic milk MET concentrations during the period 2-6 after MET injection were significantly (P less than 0.01) higher than after TAM administration. However, MET concentrations which were equal to or higher than the minimal inhibitory concentrations for penicillin G-resistant staphylococci were maintained in the mastitic milk for 8 h after treatment with MET and TAM.

Animals↗
PubMed1995

Photofrin accumulation in malignant and host cell populations of a murine fibrosarcoma.

Photofrin (25 mg/kg) was administered to the FsaR fibrosarcoma-bearing mice (either syngeneic or severe combined immunodeficient [SCID]) and the tumors were excised 24 h later. The photosensitizer content in the cells dissociated from tumor tissue was analyzed using flow cytometry. Staining the cell suspensions with the monoclonal antibodies against specific membrane markers served to identify the malignant cells and various types of host immune cells infiltrating the tumor. Photofrin content was also examined in the cells from normal tissues of the tumor-bearing mice (spleen, heart muscle, peritoneal macrophages). The results show a marked heterogeneity in the Photofrin cellular content of FsaR tumor, particularly within the population of tumor-associated macrophages (TAM). The Photofrin levels in some TAM were lower or similar to those in the malignant cells. In contrast, a subpopulation of TAM accumulated very high levels of the photosensitizer, which exceeded by far the levels found in the other tumor cell populations. This TAM fraction was characterized by particularly high expression of interleukin-2 receptors and increased cell size and granularity when compared to the other TAM, which suggests that these macrophages are in the activated state. Their average Photofrin content was almost 13 times higher than in the malignant cells. The lowest photosensitizer levels in the tumor were found in tumor-infiltrating leukocytes other than TAM. In FsaR tumors growing in SCID mice, the pattern of Photofrin distribution in TAM and other cellular populations was similar to that found in tumors growing in syngeneic mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Endoxifen, a secondary metabolite of tamoxifen, and 4-OH-tamoxifen induce similar changes in global gene expression patterns in MCF-7 breast cancer cells.

We recently demonstrated that endoxifen (4-hydroxy-N-desmethyl-tamoxifen), a pharmacogenetically regulated metabolite of tamoxifen, is equipotent to 4-hydroxy-tamoxifen (4-OH-Tam) with respect to estrogen receptor binding and inhibition of 17beta-estradiol (E2)-induced cell proliferation. Endoxifen was also found to be more abundant in human plasma than 4-OH-Tam, and its formation has been shown to be primarily catalyzed by cytochrome P450 2D6 (CYP2D6). Here, we report studies evaluating the effects of endoxifen, 4-OH-Tam, and E2 on gene expression in MCF-7 cells using Affymetrix U133A GeneChip Arrays (Santa Clara, CA). We detected 4062 genes that were E2-regulated (1924 induced; 2138 suppressed), and the ratio of E2-induced versus E2-suppressed genes was consistent regardless of the cutoff value. In the presence of E2, 2444 and 2390 genes were affected by 4-OH-Tam and endoxifen, respectively, when no minimal -fold change cutoff was implemented. The majority of genes regulated by the tamoxifen metabolites were also E2-responsive (74.4 and 73.3%, respectively). Endoxifen and 4-OH-Tam had overlapping effects on 1365 E2-sensitive genes, whose -fold effects between these metabolites were highly correlated (R2 = 0.99). A significant correlation was also found between the -fold effects of 249 E2-insensitive genes coregulated by both metabolites (R2 = 0.99). Hierarchical clustering analysis demonstrated similar gene regulation patterns between these metabolites, which were distinct from E2 or vehicle treatment patterns. Using real time-polymerase chain reaction, we validated the gene expression patterns of five genes that were differentially regulated by endoxifen and 4-OH-Tam. We conclude that endoxifen and 4-OH-Tam have similar effects on global gene expression patterns in MCF-7 cells and that the majority of the affected genes are estrogen-regulated genes.

Breast Neoplasms↗
PubMed2005

The L74V mutation in human immunodeficiency virus type 1 reverse transcriptase counteracts enhanced excision of zidovudine monophosphate associated with thymidine analog resistance mutations.

Thymidine analog mutations (TAMs) in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) confer resistance to zidovudine (AZT) by increasing the rate of ATP-dependent phosphorolysis of the terminal nucleotide monophosphate (primer unblocking). By contrast, the L74V mutation, which confers resistance to didanosine, sensitizes HIV-1 to AZT and partially restores AZT susceptibility when present together with one or more TAMs. To compare rates of primer unblocking in RTs carrying different clusters of TAMs and to explore the biochemical mechanism by which L74V affects AZT susceptibility, ATP-mediated rescue of AZT-blocked DNA synthesis was assayed using a series of purified recombinant RTs. Rates of primer unblocking were higher in the 67N/70R/219Q RT than in the 41L/210W/215Y enzyme and were similar to rates observed with an RT carrying six TAMs (41L/67N/70R/210W/215Y/219Q). The presence of 74V in an otherwise wild-type RT reduced the rate of primer unblocking to a degree similar to that observed with the M184V mutation for lamivudine resistance, which also sensitizes HIV-1 to AZT. Introduction of 74V into RTs carrying TAMs partially counteracted the effect of TAMs on the rate of primer unblocking. The effect of 74V was less marked than that of the 184V mutation in the 67N/70R/219Q and 41L/210W/215Y RTs but similar in the RT carrying six TAMs. These results demonstrate that L74V enhances AZT susceptibility by reducing the extent of its removal by ATP-dependent phosphorolysis and provides further evidence for a common mechanism by which mutations conferring resistance to didanosine and lamivudine sensitize HIV-1 to AZT.

Adenosine Triphosphate↗
PubMed2006

The K65R mutation in human immunodeficiency virus type 1 reverse transcriptase exhibits bidirectional phenotypic antagonism with thymidine analog mutations.

The K65R mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is selected in vitro by many D-nucleoside analog RT inhibitors (NRTI) but has been rarely detected in treated patients. In recent clinical trials, the K65R mutation has emerged frequently in patients experiencing virologic failure on antiretroviral combinations that do not include 3'-azidothymidine (AZT). The reason for this change is uncertain. To gain insight, we examined trends in the frequency of K65R in a large genotype database, the association of K65R with thymidine analog mutations (TAMs) and other NRTI mutations, and the viral susceptibility profile of HIV-1 with K65R alone and in combination with TAMs. Among >60,000 clinical samples submitted for genotype analysis that contained one or more NRTI resistance mutations, the frequency of K65R increased from 0.4% in 1998 to 3.6% in 2003. Among samples with K65R, a strong negative association was evident with the TAMs M41L, D67N, L210W, T215Y/F, and K219Q/E (P<0.005) but not with other NRTI mutations, including the Q151M complex. This suggested that K65R and TAMs are antagonistic. To test this possibility, we generated recombinant HIV-1 encoding K65R in two different TAM backgrounds: M41L/L210W/T215Y and D67N/K70R/T215F/K219Q. K65R reduced AZT resistance from >50-fold to <2.5-fold in both backgrounds. In addition, TAMs antagonized the phenotypic effect of K65R, reducing resistance to tenofovir, abacavir, 2',3'-dideoxycytidine, dideoxyinosine, and stavudine. In conclusion, K65R and TAMs exhibit bidirectional phenotypic antagonism. This antagonism likely explains the negative association of these mutations in genotype databases, the rare emergence of K65R with antiretroviral therapies that contain AZT, and its more frequent emergence with combinations that exclude AZT.

Adenine↗
PubMedDate not supplied

Age-dependent alterations in the tumoricidal functions of tumor-associated macrophages.

Age-dependent tumor cytolytic functions of tumor-associated macrophages (TAM) obtained from mice bearing different stages of Dalton's lymphoma (DL), a spontaneous T cell lymphoma, were studied. Mice were separated into three groups on the basis of their reproductive status as indicator of age: young (prereproductive); adult (reproductive) and old (postreproductive). DL was injected (1 x 10(5) cells/mouse) intraperitoneally in mice; days 4, 10 and 16 from the day of injection were referred to as early, mid and late tumor stages, respectively. Normal peritoneal macrophages and macrophages isolated from the ascitic fluid of DL-bearing mice (TAM); 1 x 10(5) cells activated with lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma) and assayed for age-dependent alterations in macrophage tumoricidal functions such as: tumor cell binding, cytotoxicity, production of reactive nitrogen intermediates (RNI), expression of inducible nitric oxide synthase (iNOS) and oncostatin-M (OSM) were observed. TAM from old mice were observed to be inhibited with respect to tumor cell binding, cytotoxicity and expression of iNOS and OSM, as compared to macrophages of young and adult mice. TAM obtained from early tumor stages showed augmented tumor cytotoxicity as well as enhanced expression of iNOS and OSM in all the age groups. This effect was most pronounced in the TAM obtained from adult mice and least in the TAM obtained from old mice. The reasons for the observed difference are discussed. These observations should be helpful in understanding the effect of progressive tumor growth and age on the functions of TAM and their responsiveness towards therapeutic manipulations.

Aging↗
PubMed1987

Antagonism of sexual behavior in female rats by ventromedial hypothalamic implants of antiestrogen.

The present experiments sought to identify brain regions in which implants of an antiestrogen would antagonize the ability of a systemic estradiol treatment to activate sexual behavior in female rats. In experiment 1, ovariectomized female rats were implanted subcutaneously with 5-mm Silastic capsules containing a 5% concentration of estradiol and injected with 500 micrograms progesterone 2 days later, 4-5 h before testing for sexual behavior. Bilateral intracranial implants of 1% crystalline concentrations of the high-affinity antiestrogens monohydroxytamoxifen (TAM) or keoxifene placed into the ventromedial nucleus of the hypothalamus (VM) 24 h prior to estradiol treatment significantly reduced lordosis responsivity compared with control females receiving empty cannulae. Implants of 1% TAM into the medial preoptic area or medial amygdala 24 h prior to estradiol that no significant effect on lordosis. Similarly, implants of 1% TAM into the VM 12 h after estradiol had no effect on lordosis. In experiment 2, lordosis was activated by subcutaneous implants of Silastic capsules containing 1% estradiol plus 500 micrograms progesterone. In this experiment, implants of 1% TAM into the VM 24 h prior to estradiol significantly reduced lordosis only if both cannulae tips were in, or adjacent to, the VM. Females receiving intracranial 1% TAM, but whose cannulae (even unilaterally) were outside the VM, had levels of lordosis equivalent to those of control females. Increasing the concentration of intracranial TAM to 10% virtually eliminated lordosis in females with bilateral implants in the VM, whereas females receiving intracranial 10% TAM in the region of, but outside, the VM showed no evidence of a lordosis deficit.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

The K65R reverse transcriptase mutation in HIV-1 reverses the excision phenotype of zidovudine resistance mutations.

The HIV-1 nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir (TFV), abacavir, didanosine and stavudine can select for K65R, whereas zidovudine (AZT) and stavudine can select for thymidine analogue mutations (TAMs) in HIV-1 reverse transcriptase (RT). HIV-1 with TAMs shows reduced susceptibility to all NRTIs, most notably AZT, whereas HIV-1 with K65R shows reduced susceptibility to all NRTIs except AZT. K65R and TAMs rarely occur together in patients. However, when present together, K65R can restore susceptibility to AZT. This study characterizes the underlying mechanisms of resistance of these RT mutants to TFV and AZT. K65R mediated decreased binding/incorporation of TFV and AZT (increased Ki/Km of 7.1- and 4.3-fold, respectively), but also decreased excision of TFV and AZT (0.7- and 0.3-fold, respectively) when compared with wild-type RT. By contrast, TAMs mediated increased TFV and AZT excision (11- and 5.4-fold, respectively), and showed no changes in binding/incorporation. When these mutations were combined, K65R reversed TAM-mediated AZT resistance by strongly reducing AZT excision. Molecular modelling studies suggest that K65R creates additional hydrogen bonds that reduce the conformational mobility of RT, resulting in reduced polymerization and excision. Thus, consistent with clinical HIV-1 genotyping data, there appears to be no net NRTI resistance benefit for TAMs and K65R to develop together in patients taking AZT and TFV disoproxil fumarate, where the TAM pathway alone provides the greatest resistance for both drugs.

Cell Line↗
PubMed2003

Effects of SERM (selective estrogen receptor modulator) treatment on growth and proliferation in the rat uterus.

BACKGROUND: Selective estrogen receptor modulators (SERMs) have been developed in order to create means to control estrogenic effects on different tissues. A major drawback in treatment of estrogen receptor (ER) positive breast cancer with the antagonist tamoxifen (TAM) is its agonistic effect in the endometrium. Raloxifene (RAL) is the next generation of SERMs where the agonistic effect on the endometrium has been reduced. METHODS: The aim of the present study was to determine the effect of SERM treatment on the uterus, as assessed by proliferation markers and several factors involved in uterine growth. Ovariectomized (ovx) rats were treated with estradiol (E2), tamoxifen (TAM), RAL, ICI182780 (ICI) or vehicle (OVX-controls). We studied the effects on mRNA levels of the growth hormone (GH) receptor, insulin-like growth factor-I (IGF-I), ERalpha and ERbeta. In addition, by immunohistochemistry the proliferation markers PCNA and Ki-67, as well as ERalpha and ERbeta, were detected. RESULTS: The uterine weight of the rats treated with E2 or TAM was increased as compared to OVX-controls. The uterine GH-receptor mRNA level was highest in the E2 treated animals. In ICI treated rats no GH-receptor mRNA could be detected. The IGF-I mRNA level increased 16-fold in uteri of the TAM treated group and 9-fold in the E2 treated rats as compared to OVX-controls. The ERalpha mRNA level was increased in the E2 treated rats, while the ERbeta mRNA level was increased after TAM treatment. The proliferation, as assessed by PCNA, was lowest in ICI treated animals. CONCLUSIONS: The uterine wet weight, the LE height and the GH-receptor mRNA levels showed similar patterns, indicating that GH is involved in the regulation of uterine weight. Tamoxifen, which has been related to increased incidence of endometrial carcinoma in women, dramatically increased IGF-I mRNA levels in rat uterus. Since proliferation was not higher in TAM and E2 treated rats than in OVX controls, this assay of simple, early proliferation does not give the full explanation of why TAM should enhance the risk of developing endometrial cancer.

Animals↗
PubMed2005

Farnesyl-transferase inhibitor R115,777 enhances tamoxifen inhibition of MCF-7 cell growth through estrogen receptor dependent and independent pathways.

INTRODUCTION: We have previously shown that FTI-277, a farnesyl transferase inhibitor (FTI), enhances the efficacy of tamoxifen (Tam) in inhibiting the proliferation of the estrogen dependent MCF-7 cell line. As the cellular response to Tam is the result of an inhibition of both estrogen receptor-dependent and -independent pathways, we have used the estrogen receptor selective anti-estrogen ICI182,780 and N-pyrrolidine(-phenylmethyl-phenoxy)-ethanamine-HCl (PBPE), a selective ligand of anti-estrogen binding site (AEBS), to dissect out the mechanism(s) associated with the observed additivity resulting from combination treatment with FTI-277 and Tam. Moreover, for these studies, FTI-277 has been replaced by R115,777, a FTI currently in phase III clinical trials. METHODS: The quantitative sulphorhodamine B (SRB) colorimetric assay was used to determine the growth inhibitory effect of agents on MCF-7 cells. Dose response interactions between R115,777-Tam, R115,777-ICI182,780 and R115,777-PBPE were evaluated, at the IC50 point, using the isobologram method. Apoptotic cell death (DNA fragmentation, nucleus condensation and cytokeratin 18 cleavage) and inhibition of the mevalonate pathway (western blot) were also determined. RESULTS: Combinations of the specific FTI R115,777 with either ICI182,780 or PBPE exhibit a synergistic effect on MCF-7 cell growth inhibition, while its combination with Tam is additive, as previously reported for FTI-277. Apoptosis is detected after treatment with combinations of R115,777 with either Tam or PBPE but not with ICI182,780, suggesting that each combination inhibits cell proliferation by different mechanisms. Even though the ER pathway has not yet been deciphered, it is shown here that the AEBS pathway is able to interfere with the mevalonate pathway at the level of protein farnesylation. CONCLUSION: Overall, this work reveals that combinations of R115,777 with either selective ER ligands or a selective AEBS ligand are able to induce large increases in their anti-proliferative activities on MCF-7 cells. Moreover, these results suggest that it may be of definite interest to evaluate combinations of R115,777 with different anti-estrogens in the treatment of ER positive breast tumours. Based on these experimental data, such combinations may prove beneficial in different clinical scenarios or when used in specific sequences; studying the combination of R115,777 with ICI182,780 for early treatment and reserving combinations with either Tam or a selective AEBS ligand, such as BMS-217380-01, for more resistant disease.

Antineoplastic Agents, Hormonal↗
PubMed1986

A randomized trial in postmenopausal patients with advanced breast cancer comparing endocrine and cytotoxic therapy given sequentially or in combination. The Australian and New Zealand Breast Cancer Trials Group, Clinical Oncological Society of Australia.

A prospective randomized clinical trial was performed in 339 postmenopausal patients with advanced breast cancer. Two single modality treatment sequences, doxorubicin plus cyclophosphamide (AC) followed on failure by tamoxifen (TAM), and TAM followed by AC, were compared with combined modality chemo-endocrine therapy (TAM plus AC). The response rate to initial TAM (22.1%) was inferior to that for AC (45.1%), and for TAM plus AC (51.3%). However, patients randomized to the sequence TAM followed by AC showed a 42.5% overall tumor response to sequential protocol therapy, similar to the 46.9% for those randomized to AC followed by TAM. Furthermore, survival in all three arms was almost identical. Adverse prognostic factors for survival were liver metastases, short disease-free interval, poor performance status, and prior adjuvant chemotherapy. In no subgroup was significantly better survival associated with initial cytotoxic therapy. Endocrine therapy followed on failure by cytotoxics is appropriate for postmenopausal patients with advanced breast cancer.

Aged↗
PubMed1995

Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer.

PURPOSE: To perform a randomized three-arm comparison of tamoxifen (TAM; 20 mg/d) and two separate doses of toremifene (TOR; 60 mg/d [TOR60] and 200 mg/d [TOR200]) in postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer. MATERIALS AND METHODS: Six hundred forty-eight patients with hormone receptor-positive or -unknown metastatic breast cancer were randomly assigned to receive TAM (n = 215), TOR60 (n = 221), or TOR200 (n = 212). RESULTS: The combined response rates (by intent to treat) were as follows;: TAM, 44%; TOR60, 50%; and TOR200, 48%. Complete and partial response rates were as follows: TAM, 19%; TOR60, 21%, and TOR200, 23% (not statistically different). Median times to progression and overall survival were not significantly different. Adverse events (lethal, serious but nonlethal, and important but non-life-threatening) were similar in all three arms, except that patients in the TOR200 arm had a statistically significantly increased rate of nausea (37% v 26% and 26% for TOR200, TAM, and TOR60, respectively; P = .027). Quality-of-life assessments were not different among the three arms. CONCLUSION: The activity, toxicity, and side effects of TOR in postmenopausal women with hormone receptor-positive or -unknown metastatic breast cancer are similar if not equivalent to those of TAM. We detected no clear evidence of a dose-response effect for TOR. TOR60 is an effective and safe agent for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer and can be considered an alternative to TAM as first-line treatment for such patients.

Adult↗
PubMed2003

Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells.

The development of acquired resistance to antihormonal agents in breast cancer is a major therapeutic problem. We have developed a tamoxifen-resistant (TAM-R) MCF-7 breast cancer cell line to investigate the mechanisms behind this condition. Both epidermal growth factor receptor (EGFR) and c-erbB2 mRNA and protein expression were increased in TAM-R compared with wild-type MCF-7 cells, whereas comparable levels of c-erbB3 mRNA and protein were expressed in both cell lines. Under basal conditions, phosphorylated EGFR/c-erbB2, EGFR/c-erbB3 but not c-erbB2/c-erbB3 receptor heterodimers were detected in TAM-R cells in association with increased levels of phosphorylated extracellular-signal regulated kinase 1/2 (ERK1/2). Both cell lines were capable of generating a range of EGFR-specific ligands and increased expression of transforming growth factor alpha was observed in TAM-R cells. Treatment of TAM-R cells with ZD1839 (Iressa) or trastuzumab (Herceptin) blocked c-erbB receptor heterodimer formation and phosphorylation, reduced ERK1/2 activity, and strongly inhibited cell growth. The MAPK kinase inhibitor PD098059 specifically reduced phosphorylated ERK1/2 levels and inhibited TAM-R growth. All three agents abolished ERK1/2 activity in wild-type cells but caused only small reductions in cell proliferation. These results demonstrate that TAM-R MCF-7 cell growth is mediated by the autocrine release and action of an EGFR-specific ligand inducing preferential EGFR/c-erbB2 dimerization and downstream activation of the ERK pathway.

Antibodies, Monoclonal↗
PubMed1986

Comparison of the physicochemical properties of uterine nuclear estrogen receptors bound to estradiol or 4-hydroxytamoxifen.

We have compared the physicochemical properties of rat uterine nuclear estrogen receptors (ER) labeled with (E2) or the high affinity antiestrogen 4-hydroxytamoxifen [OH Tam; 1-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-hydroxyphenyl) 2-phenyl-but-1-(Z)ene]. Nuclear ER labeled in vivo with either ligand had sedimentation rates of 4.5-5S and mol wt (calculated from sedimentation coefficients and Stokes radii) of about 80,000. The 3S and 4S forms labeled by in vitro exchange with [3H]E2 or [3H]OH Tam, respectively, had mol wt of 31,000 and 50,000. Based on apparent Kd values, numbers of binding sites per uterus, and dissociation kinetics, the ligand-binding sites of the nuclear E2- and OH Tam-ER complexes could not be distinguished. An appreciable proportion (25-75%) of 4.5-5S estrogen- or antiestrogen-ER complexes were retained on DNA-cellulose columns and were eluted with 0.21 M KCl, while the 3S and 4S forms had lost the DNA-binding site. Nuclear ER bound to E2 or OH Tam were differentially sensitive to proteolysis with trypsin or alpha-chymotrypsin. Both in vivo and in vitro labeled [3H]OH Tam-ER complexes sedimented as discrete species (S20,w = 3.8-3.9; mol wt, approximately 40,000) after trypsin treatment (50 micrograms/ml; 1 h at 23 C); under the same conditions, peaks of [3H]E2 were obliterated. After digestion with alpha-chymotrypsin (10 micrograms/ml; 1 h at 23 C), nuclear ER labeled in vivo with [3H]E2 or [3H]OH Tam sedimented at 2.9S (mol wt, 29,000) or 4.0S (mol wt, 47,000), respectively; at 50 micrograms/ml, [3H]E2-ER complexes were barely discernible, while binding of [3H]OH Tam was only partially decreased. Nuclear ER labeled with the nonsteroidal estrogen [3H]diethylstilbestrol resembled [3H]E2-ER complexes in sensitivity to proteolysis. These results suggest that nuclear estrogen- and antiestrogen-ER complexes may differ in conformation such that they are differentially susceptible to degradation. This may influence their interactions with chromatin or specific DNA sequences as well as their release from nuclear binding sites.

Animals↗
PubMed2006

Phase 2 trial of radiation plus high-dose tamoxifen for glioblastoma multiforme: RTOG protocol BR-0021.

Preclinical studies support the concept that inhibition of protein kinase C (PKC) by tamoxifen (TAM) should provide both antineoplastic effects and radiosensitization. High-dose TAM (80 mg/m2 p.o. daily in divided doses) was given with and after conventional radiotherapy (XRT) to inhibit PKC-mediated signaling, which is known to be enhanced in glioblastoma (GBM). Seventy-seven patients were accrued between December 2000 and December 2001; two were ineligible and not included in the efficacy results. Pretreatment characteristics of the patients included the following: 52% were less than 60 years of age, 39% had a Zubrod score of 0, 70% had minor or no neurological symptoms, and 65% were Radiation Therapy Oncology Group-recursive partition analysis (RPA) class III and IV. Eighty-six percent of patients achieved acceptable dosing of TAM. Notable toxicity included late radiation grade 3 in two patients and thromboembolic events in 16 patients (two grade 2, 10 grade 3, three grade 4, and one grade 5), for an incidence of 20.8% (which is lower than expected, based on the literature for deep vein thrombophlebitis in GBM patients not receiving TAM). Median survival time (MST) was 9.7 months as compared (by three different statistical methodologies) to the historical GBM control database of 1457 RPA class III, IV, and V drug/XRT-treated patients. After controlling for RPA class IV, the MST was 11.3 months, which compares to the historical RPA control of 11.3 months (P = 0.37). The results obtained do not exhibit a substantial advance over those of previous studies with various XRT/drug doublets, including BCNU. However, as TAM does not have significant overlapping toxicities with most other drugs, its testing in a combined modality approach with other medications may be justified in future clinical trials. Historically, the incidence of thromboembolic events in GBM patients is approximately 30%. The lower-than-expected incidence seen here has also been observed in other high-dose TAM GBM studies. We speculate that TAM inhibited the PKC-mediated phosphorylation of coagulation factors.

Adult↗
PubMed2005

The anti-oestrogen ICI 182,780, but not tamoxifen, inhibits the growth of MCF-7 breast cancer cells refractory to long-term oestrogen deprivation through down-regulation of oestrogen receptor and IGF signalling.

Long-term culture of MCF-7 wild-type (wt) cells in steroid-depleted medium (LTED) results in hypersensitivity to oestradiol (E2) coinciding with elevated levels of ERalpha and enhanced growth factor signalling. In this study, we aimed to compare the effects of the pure anti-oestrogen ICI 182,780 (ICI) with the competitive anti-oestrogen tamoxifen (TAM) on oestrogen and IGF signalling in these cells. Wt MCF-7 and LTED cells were treated with a log 7 concentration range of E2, TAM or ICI. Effects on cell growth, ERalpha transactivation, expression of ERalpha, ERbeta and components of the IGF pathway were measured with and without insulin. In the presence of insulin, growth of LTED cells was refractory to TAM but inhibited by ICI and E2. In the absence of insulin, LTED cells showed persistent hypersensitivity to E2, and remained inhibited by ICI but were largely unaffected by TAM. ICI but not TAM inhibited ER-mediated gene transcription and treatment with ICI resulted in a dose-dependent reduction in ERalpha levels whilst having no effect on ERbeta expression. IGF-I receptor and insulin receptor substrate 2 levels were increased in LTED versus the Wt MCF-7 cells, and ICI but not TAM reduced their expression in a dose-dependent fashion. Thus IGF signalling as well as ERalpha expression and function are enhanced during LTED. While the resultant cells are resistant to TAM, ICI down-regulates ERalpha, reducing IGF signalling and cell growth. These results support the use of ICI in women with ER-positive breast cancer who have relapsed on an aromatase inhibitor.

Antineoplastic Agents, Hormonal↗