Publications by authors named "James A Bennett"

30 Publications

  • Page 1 of 1

Herbal Medicines Attenuate PD-L1 Expression to Induce Anti-Proliferation in Obesity-Related Cancers.

Nutrients 2019 Dec 5;11(12). Epub 2019 Dec 5.

Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan.

Pro-inflammatory hormones and cytokines (leptin, tumor necrosis factor (TNF)-α, and interleukin (IL)-6) rise in obesity. Elevated levels of hormones and cytokines are linked with several comorbidities such as diabetes, heart disease, and cancer. The checkpoint programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) plays an important role in obesity and cancer proliferation. L-thyroxine (T) and steroid hormones up-regulate PD-L1 accumulation and promote inflammation in cancer cells and diabetics. On the other hand, resveratrol and other herbal medicines suppress PD-L1 accumulation and reduce diabetic effects. In addition, they induce anti-cancer proliferation in various types of cancer cells via different mechanisms. In the current review, we discuss new findings and visions into the antagonizing effects of hormones on herbal medicine-induced anti-cancer properties.
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http://dx.doi.org/10.3390/nu11122979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949899PMC
December 2019

Efficacy and tolerability of AFPep, a cyclic peptide with anti-breast cancer properties.

Toxicol Appl Pharmacol 2018 04 6;345:10-18. Epub 2018 Mar 6.

Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, United States. Electronic address:

Purpose: The purpose of this study is to assess the efficacy and safety profile of AFPep, a 9-amino acid cyclic peptide prior to its entry into pre-clinical toxicology analyses en route to clinical trials.

Methods: AFPep was assessed for anti-estrogenic activity in a mouse uterine growth assay and for breast cancer therapeutic efficacy in a human tumor xenograft model in mice. AFPep was assessed for tolerability in a variety of in vivo models, notably including assessment for effects on rat liver and human hepatocellular carcinoma cell lines and xenografts.

Results: AFPep arrests the growth of human MCF-7 breast cancer xenografts, inhibits the estrogen-induced growth of mouse uteri, and does not affect liver growth nor stimulate growth of human hepatocellular carcinoma cell lines when growing in vitro or as xenografts in vivo. AFPep is well tolerated in mice, rats, dogs, and primates.

Conclusions: AFPep is effective for the treatment of ER-positive breast cancer and exhibits a therapeutic index that is substantially wider than that for drugs currently in clinical use. The data emphasize the importance of pursuing pre-clinical toxicology studies with the intent to enter clinical trials.
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http://dx.doi.org/10.1016/j.taap.2018.03.004DOI Listing
April 2018

Tetrac downregulates β-catenin and HMGA2 to promote the effect of resveratrol in colon cancer.

Endocr Relat Cancer 2018 03 18;25(3):279-293. Epub 2017 Dec 18.

Pharmaceutical Research InstituteAlbany College of Pharmacy and Health Sciences, Albany, New York, USA.

The molecular pathogenesis of colorectal cancer encompasses the activation of several oncogenic signaling pathways that include the Wnt/β-catenin pathway and the overexpression of high mobility group protein A2 (HMGA2). Resveratrol - the polyphenolic phytoalexin - binds to integrin αvβ3 to induce apoptosis in cancer cells cyclooxygenase 2 (COX-2) nuclear accumulation and p53-dependent apoptosis. Tetraiodothyroacetic acid (tetrac) is a de-aminated derivative of l-thyroxine (T), which - in contrast to the parental hormone - impairs cancer cell proliferation. In the current study, we found that tetrac promoted resveratrol-induced anti-proliferation in colon cancer cell lines, in primary cultures of colon cancer cells, and The mechanisms implicated in this action involved the downregulation of nuclear β-catenin and HMGA2, which are capable of compromising resveratrol-induced COX-2 nuclear translocation. Silencing of either β-catenin or HMGA2 promoted resveratrol-induced anti-proliferation and COX-2 nuclear accumulation which is essential for integrin αvβ3-mediated-resveratrol-induced apoptosis in cancer cells. Concurrently, tetrac enhanced nuclear abundance of chibby family member 1, the nuclear β-catenin antagonist, which may further compromise the nuclear β-catenin-dependent gene expression and proliferation. Taken together, these results suggest that tetrac targets β-catenin and HMGA2 to promote resveratrol-induced-anti-proliferation in colon cancers, highlighting its potential in anti-cancer combination therapy.
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http://dx.doi.org/10.1530/ERC-17-0450DOI Listing
March 2018

A Project to Promote Adherence to Blood Pressure Medication Among People Who Use Community Pharmacies in Rural Montana, 2014-2016.

Prev Chronic Dis 2017 06 29;14:E52. Epub 2017 Jun 29.

Transforming Chronic Care, Bozeman, Montana.

Introduction: Pharmacists can assist patients in managing their blood pressure levels. We assessed whether adherence to blood pressure medication improved among people who used community pharmacies in rural Montana after pharmacists initiated consultations and distributed educational materials developed for the Million Hearts Initiative's "Team Up. Pressure Down." (TUPD) program.

Methods: From 2014 to 2016, the Cardiovascular Health Program at the Montana Department of Public Health and Human Services conducted a statewide project to evaluate an intervention for adherence to blood pressure medication administered through community pharmacies. After the year 1 pilot, we redesigned the program for year 2 and year 3 and measured the percentage of participating patients who adhered to blood pressure medication. We also conducted a statewide survey to assess pharmacy characteristics, computer-system capabilities, and types of consulting services provided by pharmacists.

Results: Twenty-five community pharmacies completed Montana's TUPD program: 8 pharmacies in the pilot year, 11 pharmacies in year 2, and 6 pharmacies in year 3. For year 2 and year 3 combined, the percentage of participating patients who achieved blood pressure medication adherence improved preintervention to postintervention from 73% to 89%, and adherence improved in 15 of the 17 pharmacies. The pilot pharmacies identified 3 major barriers to project success: patient buy-in, staff burden in implementing the project, and funding. In the statewide assessment, TUPD-funded pharmacies were significantly more likely than non-TUPD-funded pharmacies to provide prescription synchronization and medication management with feedback to the patient's physician.

Conclusion: Community pharmacies in rural areas can effectively use brief consultations and standard educational materials to improve adherence to blood pressure medication.
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http://dx.doi.org/10.5888/pcd14.160409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494815PMC
June 2017

Acetic Acid Ketonization over FeO/SiO for Pyrolysis Bio-Oil Upgrading.

ChemCatChem 2017 05 18;9(9):1648-1654. Epub 2017 Jan 18.

European Bioenergy Research Institute Aston University BirminghamB4 7ET UK.

A family of silica-supported, magnetite nanoparticle catalysts was synthesised and investigated for continuous-flow acetic acid ketonisation as a model pyrolysis bio-oil upgrading reaction. The physico-chemical properties of FeO/SiO catalysts were characterised by using high-resolution transmission electron microscopy, X-ray absorption spectroscopy, X-ray photo-electron spectroscopy, diffuse reflectance infrared Fourier transform spectroscopy, thermogravimetric analysis and porosimetry. The acid site densities were inversely proportional to the FeO particle size, although the acid strength and Lewis character were size-invariant, and correlated with the specific activity for the vapour-phase acetic ketonisation to acetone. A constant activation energy (∼110 kJ mol), turnover frequency (∼13 h) and selectivity to acetone of 60 % were observed for ketonisation across the catalyst series, which implies that FeO is the principal active component of Red Mud waste.
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http://dx.doi.org/10.1002/cctc.201601269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434921PMC
May 2017

Unique case of orbital 'progressive transformation of the germinal centre'-type immunoglobulin-G4 disease with a heralding lesion in the inguinal lymph nodes.

Clin Exp Ophthalmol 2016 Jan-Feb;44(1):65-7. Epub 2015 Jul 27.

Department of Ophthalmology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.

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http://dx.doi.org/10.1111/ceo.12572DOI Listing
September 2016

Heterogeneous catalysis for sustainable biodiesel production via esterification and transesterification.

Chem Soc Rev 2014 Nov;43(22):7887-916

European Bioenergy Research Institute, Aston University, Aston Triangle, Birmingham B4 7ET, UK.

Concern over the economics of accessing fossil fuel reserves, and widespread acceptance of the anthropogenic origin of rising CO2 emissions and associated climate change from combusting such carbon sources, is driving academic and commercial research into new routes to sustainable fuels to meet the demands of a rapidly rising global population. Here we discuss catalytic esterification and transesterification solutions to the clean synthesis of biodiesel, the most readily implemented and low cost, alternative source of transportation fuels to meet future societal demands.
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http://dx.doi.org/10.1039/c4cs00189cDOI Listing
November 2014

Development of an active site peptide analog of α-fetoprotein that prevents breast cancer.

Cancer Prev Res (Phila) 2014 Jun 4;7(6):565-73. Epub 2014 Apr 4.

Authors' Affiliations: Department of Obstetrics and Gynecology, Center for Cardiovascular Sciences, and Center for Immunology and Microbial Diseases, Albany Medical College, Albany, NY.

Epidemiologic studies associate elevated maternal serum levels of α-fetoprotein (AFP) with reduced breast cancer risk for parous women. Laboratory studies demonstrate direct anti-breast cancer activity of AFP. Here, we review the development of a small cyclic peptide that is an active site analog of AFP, referred to as AFPep, which is composed exclusively of amino acids, is orally active, has no discernable toxicity, and is effective for the treatment and prevention of breast cancer in animal models.
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http://dx.doi.org/10.1158/1940-6207.CAPR-13-0405DOI Listing
June 2014

Orai3 is an estrogen receptor α-regulated Ca²⁺ channel that promotes tumorigenesis.

FASEB J 2013 Jan 19;27(1):63-75. Epub 2012 Sep 19.

Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208, USA.

Store-operated Ca(2+) entry (SOCE) encoded by Orai1 proteins is a ubiquitous Ca(2+)-selective conductance involved in cellular proliferation and migration. We recently described up-regulation of Orai3 channels that selectively mediate SOCE in estrogen receptor α-expressing (ERα(+)) breast cancer cells. However, the connection between ERα and Orai3 and the role of Orai3 in tumorigenesis remain unknown. Here, we show that ERα knockdown decreases Orai3 mRNA (by ∼63%) and protein (by ∼44%) with no effect on Orai1. ERα knockdown decreases Orai3-mediated SOCE (by ∼43%) and the corresponding Ca(2+) release-activated Ca(2+) (CRAC) current (by ∼42%) in ERα(+) MCF7 cells. The abrogation of SOCE in MCF7 cells on ERα knockdown can be rescued by ectopic expression of Orai3. ERα activation increased Orai3 expression and SOCE in MCF7 cells. Epidermal growth factor (EGF) and thrombin stimulate Ca(2+) influx into MCF7 cells through Orai3. Orai3 knockdown inhibited SOCE-dependent phosphorylation of extracellular signal-regulated kinase (ERK1/2; by ∼44%) and focal adhesion kinase (FAK; by ∼46%) as well as transcriptional activity of nuclear factor for activated T cells (NFAT; by ∼49%). Significantly, Orai3 knockdown selectively decreased anchorage-independent growth (by ∼58%) and Matrigel invasion (by ∼44%) of ERα(+) MCF7 cells with no effect on ERα(-) MDA-MB231 cells. Moreover, Orai3 knockdown inhibited ERα(+) cell tumorigenesis in immunodeficient mice (∼66% reduction in tumor volume). These data establish Orai3 as an ERα-regulated channel and a potential selective therapeutic target for ERα(+) breast cancers.
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http://dx.doi.org/10.1096/fj.12-213801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528310PMC
January 2013

Microbial synthesis of core/shell gold/palladium nanoparticles for applications in green chemistry.

J R Soc Interface 2012 Jul 7;9(72):1705-12. Epub 2012 Mar 7.

Unit of Functional Bionanomaterials, School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

We report a novel biochemical method based on the sacrificial hydrogen strategy to synthesize bimetallic gold (Au)-palladium (Pd) nanoparticles (NPs) with a core/shell configuration. The ability of Escherichia coli cells supplied with H(2) as electron donor to rapidly precipitate Pd(II) ions from solution is used to promote the reduction of soluble Au(III). Pre-coating cells with Pd(0) (bioPd) dramatically accelerated Au(III) reduction, with the Au(III) reduction rate being dependent upon the initial Pd loading by mass on the cells. Following Au(III) addition, the bioPd-Au(III) mixture rapidly turned purple, indicating the formation of colloidal gold. Mapping of bio-NPs by energy dispersive X-ray microanalysis suggested Au-dense core regions and peripheral Pd but only Au was detected by X-ray diffraction (XRD) analysis. However, surface analysis of cleaned NPs by cyclic voltammetry revealed large Pd surface sites, suggesting, since XRD shows no crystalline Pd component, that layers of Pd atoms surround Au NPs. Characterization of the bimetallic particles using X-ray absorption spectroscopy confirmed the existence of Au-rich core and Pd-rich shell type bimetallic biogenic NPs. These showed comparable catalytic activity to chemical counterparts with respect to the oxidation of benzyl alcohol, in air, and at a low temperature (90°C).
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http://dx.doi.org/10.1098/rsif.2012.0003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367827PMC
July 2012

Expression of the aryl hydrocarbon receptor is not required for the proliferation, migration, invasion, or estrogen-dependent tumorigenesis of MCF-7 breast cancer cells.

Mol Carcinog 2013 Jul 2;52(7):544-54. Epub 2012 Mar 2.

Laboratory of Molecular Toxicology, Wadsworth Center, New York State Department of Health, Albany, New York 12201-0509, USA.

The AhR was initially identified as a ligand-activated transcription factor mediating effects of chlorinated dioxins and polycyclic aromatic hydrocarbons on cytochrome P450 1 (CYP1) expression. Recently, evidence supporting involvement of the AhR in cell-cycle regulation and tumorigenesis has been presented. To further define the roles of the AhR in cancer, we investigated the effects of AhR expression on cell proliferation, migration, invasion, and tumorigenesis of MCF-7 human breast cancer cells. In these studies, the properties of MCF-7 cells were compared with those of two MCF-7-derived sublines: AH(R100) , which express minimal AhR, and AhR(exp) , which overexpress AhR. Quantitative PCR, Western immunoblots, 17β-estradiol (E2 ) metabolism assays, and ethoxyresorufin O-deethylase assays showed the lack of AhR expression and AhR-regulated CYP1 expression in AH(R100) cells, and enhanced AhR and CYP1 expression in AhR(exp) cells. In the presence of 1 nM E2 , rates of cell proliferation of the three cell lines showed an inverse correlation with the levels of AhR mRNA. In comparison with MCF-7 and AhR(exp) cells, AH(R100) cells produced more colonies in soft agar and showed enhanced migration and invasion in chamber assays with E2 as the chemoattractant. Despite the lack of significant AhR expression, AH(R100) cells retained the ability to form tumors in severe combined immunodeficient mice when supplemented with E2 , producing mean tumor volumes comparable to those observed with MCF-7 cells. These studies indicate that, while CYP1 expression and inducibility are highly dependent on AhR expression, the proliferation, invasion, migration, anchorage-independent growth, and estrogen-stimulated tumor formation of MCF-7 cells do not require the AhR.
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http://dx.doi.org/10.1002/mc.21889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433635PMC
July 2013

Design and synthesis of biologically active peptides: a 'tail' of amino acids can modulate activity of synthetic cyclic peptides.

Peptides 2011 Dec 12;32(12):2504-10. Epub 2011 Oct 12.

Center for Cardiovascular Science, Albany Medical College, Albany, NY 12208, USA.

In earlier work, we synthesized a cyclic 9-amino acid peptide (AFPep, cyclo[EKTOVNOGN]) and showed it to be useful for prevention and therapy of breast cancer. In an effort to explore the structure-function relationships of AFPep, we have designed analogs that bear a short 'tail' (one or two amino acids) attached to the cyclic peptide distal to its pharmacophore. Analogs that bore a tail of either one or two amino acids, either of which had a hydrophilic moiety in the side chain (e.g., cyclo[EKTOVNOGN]FS) exhibited greatly diminished biological activity (inhibition of estrogen-stimulated uterine growth) relative to AFPep. Analogs that bore a tail of either one or two amino acids which had hydrophobic (aliphatic or aromatic) side chains (e.g., cyclo[EKTOVNOGN]FI) retained (or had enhanced) growth inhibition activity. Combining in the same biological assay a hydrophilic-tailed analog with either AFPep or a hydrophobic-tailed analog resulted in decreased activity relative to that for AFPep or for the hydrophobic-tailed analog alone, suggesting that hydrophilic-tailed analogs are binding to a biologically active receptor. An analog with a disrupted pharmacophore (cyclo[EKTOVGOGN]) exhibited little or no growth inhibition activity. An analog with a hydrophilic tail and a disrupted pharmacophore (cyclo[EKTOVGOGN]FS) exhibited no growth inhibition activity of its own and did not affect the activity of a hydrophobic-tailed analog, but enhanced the growth inhibition activity of AFPep. These results are discussed in the context of a two-receptor model for binding of AFPep and ring-and-tail analogs. We suggest that tails on cyclic peptides may comprise a useful method to enhance diversity of peptide design and specificity of ligand-receptor interactions.
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http://dx.doi.org/10.1016/j.peptides.2011.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230782PMC
December 2011

Microbial engineering of nanoheterostructures: biological synthesis of a magnetically recoverable palladium nanocatalyst.

ACS Nano 2010 May;4(5):2577-84

School of Earth, Atmospheric & Environmental Sciences and Williamson Research Centre for Molecular Environmental Science, University of Manchester, Manchester M13 9PL, UK.

Precious metals supported on ferrimagnetic particles have a diverse range of uses in catalysis. However, fabrication using synthetic methods results in potentially high environmental and economic costs. Here we show a novel biotechnological route for the synthesis of a heterogeneous catalyst consisting of reactive palladium nanoparticles arrayed on a nanoscale biomagnetite support. The magnetic support was synthesized at ambient temperature by the Fe(III)-reducing bacterium, Geobacter sulfurreducens , and facilitated ease of recovery of the catalyst with superior performance due to reduced agglomeration (versus conventional colloidal Pd nanoparticles). Surface arrays of palladium nanoparticles were deposited on the nanomagnetite using a simple one-step method without the need to modify the biomineral surface, most likely due to an organic coating priming the surface for Pd adsorption, which was produced by the bacterial culture during the formation of the nanoparticles. A combination of EXAFS and XPS showed the Pd nanoparticles on the magnetite to be predominantly metallic in nature. The Pd(0)-biomagnetite was tested for catalytic activity in the Heck reaction coupling iodobenzene to ethyl acrylate or styrene. Rates of reaction were equal to or superior to those obtained with an equimolar amount of a commercial colloidal palladium catalyst, and near complete conversion to ethyl cinnamate or stilbene was achieved within 90 and 180 min, respectively.
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http://dx.doi.org/10.1021/nn9017944DOI Listing
May 2010

A proposed unified mechanism for the reduction of human breast cancer risk by the hormones of pregnancy.

Cancer Prev Res (Phila) 2010 Feb 24;3(2):212-20. Epub 2009 Nov 24.

Center for Immunology and Microbial Diseases, Albany Medical College, NY 12208, USA.

Parity in women is associated with reduced lifetime risk of breast cancer, and hormones of pregnancy [estrogen (E), progesterone (P), human chorionic gonadotropin (hCG)] are implicated. Parity also reduces mammary cancer risk in carcinogen-exposed rats, and administering pregnancy hormones to these animals is similarly effective. Because pregnancy hormones are also able to stimulate cancer growth, we proposed to resolve this dichotomy by determining whether administered pregnancy hormones elicit the cancer-inhibiting agent alpha-fetoprotein (AFP) from the liver, which would implicate AFP as a proximal effector of hormonal anticancer activity. Accordingly, we treated groups of nitrosomethylurea-exposed rats with saline, E(3), E(2) + P, E(3) + P, hCG, or allowed them to experience pregnancy, and then monitored mammary cancer incidence and serum levels of AFP over time. Each hormone treatment reduced mammary cancer incidence and elevated serum AFP levels. To challenge human tissues, human HepG2 liver cells in culture were treated with the same hormonal agents. Each hormone regimen increased the levels of AFP in the culture medium. Medium containing AFP elicited by hCG inhibited the E(2)-stimulated proliferation of cultured human MCF7 breast cancer cells, whereas hCG alone did not inhibit their growth. Furthermore, antibodies to AFP neutralized the growth-inhibiting effect of AFP-containing HepG2 medium. We conclude that in the treatment of carcinogen-exposed rats with the hormones of pregnancy, and by inference in women who have experienced pregnancy, that AFP is a proximal agent that inhibits mammary gland cancer.
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http://dx.doi.org/10.1158/1940-6207.CAPR-09-0050DOI Listing
February 2010

Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells.

Toxicol Appl Pharmacol 2009 Nov 18;240(3):355-66. Epub 2009 Jul 18.

Laboratory of Molecular Toxicology, Wadsworth Center, New York State Department of Health, Albany, NY 12201-0509, USA.

The cumulative exposure to estrogens is an important determinant in the risk of breast cancer, yet the full range of mechanisms involving estrogens in the genesis and progression of breast cancer remains a subject of debate. Interactions of estrogens and environmental toxicants have received attention as putative factors contributing to carcinogenesis. Mechanistic studies have demonstrated interactions between estrogen receptor alpha (ERalpha) and the aryl hydrocarbon receptor (AhR), with consequences on the genes that they regulate. Many studies of ERalpha and AhR-mediated effects and crosstalk between them have focused on the initial molecular events. In this study, we investigated ERalpha- and AhR-mediated effects in long-term estrogen exposed (LTEE) MCF-7 human breast cancer cells, which were obtained by continuous culturing for at least 12 weeks in medium supplemented with 1 nM of 17beta-estradiol (E(2)). With these LTEE cells and with parallel control cells cultured without E(2) supplementation, we performed an extensive study of cytochrome P450 (CYP) induction, carcinogen bioactivation, global gene expression, and tumorigenicity in immunocompromised mice. We found that LTEE cells, in comparison with control cells, had higher levels of AhR mRNA and protein, greater responsiveness for AhR-regulated CYP1A1 and CYP1B1 induction, a 6-fold higher initial level of benzo(a)pyrene-DNA adducts as determined by liquid chromatography tandem mass spectrometry, marked differences in the expression of numerous genes, and a higher rate of E(2)-dependent tumor growth as xenografts. These studies indicate that LTEE causes adaptive responses in MCF-7 cells, which may reflect processes that contribute to the overall carcinogenic effect of E(2).
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http://dx.doi.org/10.1016/j.taap.2009.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180932PMC
November 2009

AFPep, a novel drug for the prevention and treatment of breast cancer, does not disrupt the estrous cycle or fertility in rats.

Oncol Rep 2009 Jul;22(1):49-56

Laboratory for Cancer Control, Center for Cardiovascular Science, Albany Medical College, Albany, NY 12208, USA.

Pregnancy lowers the risk of breast cancer, largely attributable to alpha-fetoprotein (AFP). A small AFP-derived peptide (AFPep) which mimics the active site of AFP has been developed and may be useful for decreasing the risk of breast cancer for women. AFPep has been shown previously to stop the growth of estrogen-dependent human breast cancer xenografts in mice and prevent carcinogen-induced breast cancer in a rat model. Since AFPep disrupts an estrogen-responsive pathway, it is essential to assess its effects on the female reproductive cycle and fertility. Ten cycling female Sprague-Dawley rats (age 81 days) were given 100 microg AFPep in saline s.c. daily for 20 days. A second group of ten rats was given 50 microg tamoxifen s.c. daily and a third group received saline only. Vaginal smears were obtained twice per day and stained to assess estrous cycle phase. After completion of estrous cycle assessment (five cycles, 21 days), rats were maintained on drug and allowed to mate. Effects on birth of offspring and maternal body weights were assessed. AFPep had no significant effect on the incidence or duration of any estrous cycle phase, and no effect on reproductive potential or maternal body mass. Tamoxifen significantly increased the length of diestrus, locking the cycle in this phase for most animals. Only half of the tamoxifen-treated rats mated, and none became pregnant. Tamoxifen significantly slowed the rate of body mass increase. In rats, AFPep has no toxicity and no effect on female reproduction. This molecule may be developed into an attractive modality for prevention of breast cancer in women.
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http://dx.doi.org/10.3892/or_00000405DOI Listing
July 2009

Resveratrol prevents doxorubicin cardiotoxicity through mitochondrial stabilization and the Sirt1 pathway.

Free Radic Biol Med 2009 Jun 19;46(12):1589-97. Epub 2009 Mar 19.

Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208, USA.

Doxorubicin (DOX) is one of the most effective chemotherapeutic drugs; however, its incidence of cardiotoxicity compromises its therapeutic index. DOX-induced heart failure is thought to be caused by reduction/oxidation cycling of DOX to generate oxidative stress and cardiomyocyte cell death. Resveratrol (RV), a stilbene found in red wine, has been reported to play a cardioprotective role in diseases associated with oxidative stress. The objective of this study was to test the ability of RV to protect against DOX-induced cardiomyocyte death. We hypothesized that RV protects cardiomyocytes from DOX-induced oxidative stress and subsequent cell death through changes in mitochondrial function. DOX induced a rapid increase in reactive oxygen species (ROS) production in cardiac cell mitochondria, which was inhibited by pretreatment with RV, most likely owing to an increase in MnSOD activity. This effect of RV caused additional polarization of the mitochondria in the absence and presence of DOX to increase mitochondrial function. RV pretreatment also prevented DOX-induced cardiomyocyte death. The protective ability of RV against DOX was abolished when Sirt1 was inhibited by nicotinamide. Our data suggest that RV protects against DOX-induced oxidative stress through changes in mitochondrial function, specifically the Sirt1 pathway leading to cardiac cell survival.
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http://dx.doi.org/10.1016/j.freeradbiomed.2009.03.011DOI Listing
June 2009

Antiestrogenic and anticancer activities of peptides derived from the active site of alpha-fetoprotein.

J Pept Sci 2009 Apr;15(4):319-25

Laboratory for Cancer Control, Albany Medical College, Albany, NY 12208, USA.

Cyclo[EKTOVNOGN] (AFPep), a cyclic 9-amino acid peptide derived from the active site of alpha-fetoprotein, has been shown to prevent carcinogen-induced mammary cancer in rats and inhibit the growth of ER(+) human breast cancer xenografts in mice. Recently, studies using replica exchange molecular dynamics predicted that the TOVN region of AFPep might form a dynamically stable putative Type I beta-turn, and thus be biologically active without additional amino acids. The studies presented in this paper were performed to determine whether TOVN and other small analogs of AFPep would inhibit estrogen-stimulated cancer growth and exhibit a broad effective-dose range. These peptides contained nine or fewer amino acids, and were designed to bracket or include the putative pharmacophoric region (TOVN) of AFPep. Biological activities of these peptides were evaluated using an immature mouse uterine growth inhibition assay, a T47D breast cancer cell proliferation assay, and an MCF-7 breast cancer xenograft assay. TOVN had very weak antiestrogenic activity in comparison to AFPep's activity, whereas TOVNO had antiestrogenic and anticancer activities similar to AFPep. OVNO, which does not form a putative Type I beta-turn, had virtually no antiestrogenic and anticancer activities. A putative proteolytic cleavage product of AFPep, TOVNOGNEK, significantly inhibited E(2)-stimulated growth in vivo and in vitro over a wider dose range than AFPep or TOVNO. We conclude that TOVNO has anticancer potential, that TOVNOGNEK is as effective as AFPep in suppressing growth of human breast cancer cells, and that it does so over a broader effective-dose range.
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http://dx.doi.org/10.1002/psc.1119DOI Listing
April 2009

Hormones of pregnancy, alpha-feto protein, and reduction of breast cancer risk.

Adv Exp Med Biol 2008 ;617:477-84

Albany Medical College, Albany, NY, USA.

Parity profoundly reduces breast cancer (BC) risk later in life. It has been reasoned that hormones (either estradiol E2 or estriol E3), progesterone (P) or human chorionic gonadotropin (hCG) in the serum of pregnant women might lead to that reduction in risk. These agents have been shown to reduce BC incidence in nonpregnant rats. We investigated the hypothesis that exogenously added E2, E3, P, or hCG are not the proximal effectors of risk reduction, but that they elicit alpha-fetoprotein (alphaFP) from the nonpregnant liver, and that cFP is the proximal agent by which reduction of BC risk is obtained. Methylnitrosourea (MNU)-exposed animals were treated with saline, E3, E2 + P, E3 + P, hCG, or were allowed to experience pregnancy, and AFP levels were measured in the serum and subsequent tumor incidence was recorded. Human HepG2 liver cells in culture were treated with E3, E2 + P, P, or hCG and elicited AFP was measured in the media. The HepG2 culture media containing elicited AFP was assessed for its ability to inhibit proliferation of T47D cells when applied to these human BC cells in culture, and to inhibit the estrogen-induced phosphorylation of the estrogen receptor in T47D cells. For each condition in the prevention studies, hormone treatment reduced the incidence of BC to an extent similar to that reported by the original studies. In each condition, alphaFP levels in serum were elevated over that in control animals. In culture, treatment of human liver cells with E3, E2 + P, or hCG, but not P alone, led to increased levels of AFP in the media. Media containing hCG-elicited AFP inhibited the estrogen-stimulated proliferation of T47D cells in culture, and inhibited phosphorylation of the estrogen receptor, whereas, estrogens and hCG did not inhibit the growth of these tumor cells in culture. In conclusion, since the hormones of pregnancy elicit alphaFP from the liver, and alphaFP but not the hormones of pregnancy has direct antitumor properties, it is concluded that alphaFP is the proximal agent through which reduction in BC incidence is realized from the experience of pregnancy.
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http://dx.doi.org/10.1007/978-0-387-69080-3_47DOI Listing
July 2008

A peptide derived from alpha-fetoprotein inhibits the proliferation induced by estradiol in mammary tumor cells in culture.

Oncol Rep 2008 Jan;19(1):229-35

Laboratorio de Ultrastructuras, INTA-Universidad de Chile, Santiago 7830489, Chile.

This study was aimed to obtain additional information on the activity of a cyclized 9-amino acid peptide (cP) containing the active site of alpha fetoprotein, which inhibits the estrogen-stimulated proliferation of tumor cells in culture and of xenografts in immunodeficient mice. Breast cancer cells cultured in the presence of 2 nM estradiol were exposed to cP for different periods and their proliferation, estradiol binding parameters, clustering tendency and expression of E-cadherin and p21Cip1 were analyzed by biochemical and cell biology methods. The proliferation of MCF7 cells was significantly decreased by the addition of 2 microg/ml cP to the medium. cP did not increase cell death rate nor alter the number of binding sites for estradiol nor the endogenous aromatase activity of MCF7 cells. cP also decreased the proliferation of estrogen-dependent ZR75-1 cells but had no effect on estrogen-independent MDA-MB-231 cells. An increased nuclear p21Cip1 expression detected after cP treatment suggests that cP slows MCF7 cell proliferation via this regulator. We propose that cP could represent a novel breast cancer therapeutic agent whose mechanism of action is different from that of tamoxifen or of inhibitors of aromatase.
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January 2008

Computational design and experimental discovery of an antiestrogenic peptide derived from alpha-fetoprotein.

J Am Chem Soc 2007 May 19;129(19):6263-8. Epub 2007 Apr 19.

Hamilton College, Department of Chemistry, Center for Molecular Design, 198 College Hill Road, Clinton, New York 13323, USA.

Breast cancer is the most common cancer among women, and tamoxifen is the preferred drug for estrogen receptor-positive breast cancer treatment. Many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Consequently, there is an ongoing need for breast cancer drugs that have different molecular targets. Previous work has shown that 8-mer and cyclic 9-mer peptides inhibit breast cancer in mouse and rat models, interacting with an unsolved receptor, while peptides smaller than eight amino acids did not. We show that the use of replica exchange molecular dynamics predicts the structure and dynamics of active peptides, leading to the discovery of smaller peptides with full biological activity. Simulations identified smaller peptide analogues with the same conserved reverse turn demonstrated in the larger peptides. These analogues were synthesized and shown to inhibit estrogen-dependent cell growth in a mouse uterine growth assay, a test showing reliable correlation with human breast cancer inhibition.
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http://dx.doi.org/10.1021/ja070202wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272344PMC
May 2007

Use of resveratrol to improve the effectiveness of cisplatin and doxorubicin: study in human gynecologic cancer cell lines and in rodent heart.

Am J Obstet Gynecol 2006 May 21;194(5):e23-6. Epub 2006 Apr 21.

Department of Obstetrics and Gynecology, Albany Medical College, Albany, NY 12208, USA.

Objective: The purpose of this study was to investigate whether resveratrol adds to the growth inhibitory effects of cisplatin and doxorubicin on ovarian and uterine cancer cells and to evaluate whether resveratrol diminishes the cardiac toxicity of doxorubicin in rodent heart.

Study Design: Human ovarian (OVCAR-3) and uterine (Ishikawa) cancer cells in culture were treated with cisplatin and doxorubicin, respectively, with and without resveratrol; and cell growth and viability were evaluated. Neonatal rat ventricular myocytes received doxorubicin in the presence and absence of resveratrol, and cell viability was evaluated. Mice received doxorubicin +/- resveratrol, and electrocardiograms were evaluated. Data were analyzed with analysis of variance and Scheffe's test.

Results: Resveratrol combined with cisplatin or with doxorubicin demonstrated an additive growth-inhibitory anticancer effect with a left shift of the cisplatin and doxorubicin dose/response curves. Resveratrol increased the viability of neonatal rat ventricular myocytes that were treated with doxorubicin and reduced doxorubicin-induced bradycardia and QTc interval prolongation in mice.

Conclusion: Resveratrol adds to the growth inhibitory/anticancer activity of cisplatin and doxorubicin in vitro and protects against doxorubicin-induced cardiac toxicity both in vitro and in mice.
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http://dx.doi.org/10.1016/j.ajog.2005.11.030DOI Listing
May 2006

AFPep: an anti-breast cancer peptide that is orally active.

Breast Cancer Res Treat 2006 Jul 15;98(2):133-41. Epub 2006 Mar 15.

Center for Immunology and Microbial Diseases, Albany Medical College, Albany, NY 12208, USA.

Background: We have synthesized a cyclic nonapeptide (AFPep) that is effective, after being administered by parenteral routes, for the treatment or the prevention of breast cancer. To test the hypothesis that AFPep remains safe and efficacious after oral administration, three different whole-animal bioassays were utilized, and the mechanism by which AFPep functions was investigated.

Methods: Using a human breast cancer xenograft model in mice for therapeutic activity, a carcinogen-induced breast cancer model in rats for prevention efficacy, and a mouse uterus growth inhibition model of anti-estrogenic activity, AFPep was administered by oral gavage (p.o.) and its effects compared to those following intraperitoneal (i.p.) and subcutaneous (s.c.) administration. Toxicity studies evaluated body weights and organ weights in mice and rats receiving AFPep. Preliminary mechanistic studies were carried out in T47D human breast cancer cells growing in culture and evaluated the effect of AFPep on estrogen-stimulated cell growth, phosphorylation of the estrogen receptor (ER), and on level of ER-related kinases.

Results: Orally administered AFPep stopped the growth of human tumor xenografts in mice, decreased the incidence and multiplicity of breast cancers in carcinogen-exposed rats, and inhibited the estrogen-stimulated growth of mouse uteri. In each of these systems, orally administered AFPep produced an effect similar to that obtained for AFPep administered by either i.p or s.c. routes. In rodents, no evidence of toxicity was seen for the peptide, even at very high doses. In culture, AFPep inhibited the estrogen-stimulated growth, but not the basal growth, of T47D cells, and it inhibited the estrogen-stimulated phosphorylation of Serine 118 in the ER of these cells, which was not explainable by early changes in ER-related kinases.

Conclusions: Chronic oral administration of AFPep appears to be safe and effective for the treatment or prevention of breast cancer in animal models.
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http://dx.doi.org/10.1007/s10549-005-9140-5DOI Listing
July 2006

Prevention of N-methyl-N-nitrosourea-induced breast cancer by alpha-fetoprotein (AFP)-derived peptide, a peptide derived from the active site of AFP.

Clin Cancer Res 2005 Dec;11(23):8512-20

Center for Cardiovascular Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, Albany Medical College, Albany, New York 12208, USA.

Purpose: alpha-Fetoprotein (AFP) is a protein of pregnancy associated with a decrease in lifetime risk of breast cancer in parous women. A synthetic, cyclic nonapeptide has been developed that mimics the antioncogenic active site of AFP. To test the hypothesis that the AFP-derived peptide (AFPep) can prevent breast cancer, the N-methyl-N-nitrosourea-induced breast cancer model was used in rats.

Experimental Design: AFPep was given daily by injection beginning 10 days after N-methyl-N-nitrosourea treatment and continued for 23 days (a time designed to mimic pregnancy) or for other times to assess efficacy as a function of drug duration. Tumor incidence, multiplicity, and latency were noted as end points. At necropsy, pathology analysis of tumors and major organs were obtained.

Results: AFPep prevented cancer in a dose-dependent fashion. Significantly longer mean tumor-free days (P < 0.02), lower tumor incidence (P = 0.004), and lower tumor multiplicity were observed for AFPep-treated groups. No evidence of host toxicity as measured by body weight, cage activity, fur texture, and organ weights (liver, uterus, heart, kidney, and spleen) were found in animals treated with AFPep. Mechanistic studies using transplantable human breast cancer xenografts showed that the peptide interfered with estrogen-dependent breast cancer growth inhibited the phosphorylation of the estrogen receptor and activated phosphorylation of p53.

Conclusions: AFPep is a well-tolerated, mechanistically novel, chemopreventive agent in models of breast cancer and warrants further development for the prevention and treatment of this disease in humans.
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http://dx.doi.org/10.1158/1078-0432.CCR-05-1651DOI Listing
December 2005

Rhodium catalysed hydroformylation of alkenes using highly fluorophilic phosphines.

Dalton Trans 2005 Dec 14(24):3862-7. Epub 2005 Oct 14.

Department of Chemistry, University of Leicester, UK.

Highly fluorophilic phosphines incorporating at least one aromatic ring containing two directly attached perfluoroalkyl groups have been synthesised, their partition coefficients (organic phase : fluorous phase) measured and their electronic properties probed using (1)J(PtP) data for their trans-[PtCl(2)L(2)] complexes. These phosphines have been used as modifying ligands for the rhodium catalysed hydroformylation of 1-octene in perfluorocarbon solvents. Catalyst activity, regioselectivity and the levels of rhodium leaching to the product phase vary with the substitution patterns of the modifying ligands that do not correlate with the electronic properties or partition coefficients of these ligands, but can be interpreted in terms of differences in the resting states of the catalysts.
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http://dx.doi.org/10.1039/b510766kDOI Listing
December 2005

Elevated sod2 activity augments matrix metalloproteinase expression: evidence for the involvement of endogenous hydrogen peroxide in regulating metastasis.

Clin Cancer Res 2003 Jan;9(1):424-32

Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.

Purpose: Elevated manganese superoxide dismutase (Sod2) levels have been reported to be associated with an increased frequency of tumor invasion and metastasis in certain cancers, and the aim of this study is to examine the molecular mechanisms by which this occurs.

Experimental Design: Sod2 and catalase overexpressing HT-1080 fibrosarcoma cell lines were used to evaluate the H(2)O(2)-dependent regulation of matrix metalloproteinase (MMP)-1 promoter activity, mitogen-activated protein (MAP) kinase signaling, DNA-binding activity, and MMP mRNA levels. The invasive and metastatic potential of Sod2 overexpressing cells was characterized using subrenal capsular implantation or tail vein injection of tumor cells into nude mice, respectively.

Results: Our data reveal that Sod2 overexpression increases the DNA-binding activity of transcription factors critical for MMP expression but also enhances MMP-1 promoter activity via the Ras//MAP/extracellular signal-regulated kinase (MEK) signaling cascade. A single nucleotide polymorphism that creates an Ets site at position -1607 bp confers Sod2-dependent MMP-1 promoter activity. Sod2 overexpression also increases the mRNA levels of MMPs-2, -3, -7, -10, -9, -11 and enhances the metastatic potential of fibrosarcoma cells when implanted in immunodeficient mice. The Sod2-dependent increases in AP-1 and SP-1 DNA-binding activity, MMP-1 promoter activity, general MMP expression, and collagen degradation can be reversed by the hydrogen peroxide-detoxifying enzyme, catalase.

Conclusion: MMPs play a critical role in the process of stromal invasion and metastasis, and these findings suggest that the association between increased Sod2 and poor prognosis in certain cancers may be attributed to elevated MMP production.
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January 2003

Evaluating process changes in a pediatric hospital medication system.

Outcomes Manag 2002 Jan-Mar;6(1):10-5; quiz 16

PHT Corporation, Charlestown, Mass., USA.

This article describes a process change designed to increase the safety of prescribing and interpreting complex order sets. All chemotherapy orders written for pediatric oncology patients at a major teaching hospital in the Eastern United States and the affiliated ambulatory clinic from June 1998 through February 2000 (n = 1792) were reviewed to evaluate a new process for communication of chemotherapy orders. The multidisciplinary check (MDC) is a forum where all disciplines simultaneously review and change complex order sets. Evaluation of the MDC included monthly completion rate and classification of changes made to orders at MDC. Over the study period, 96% of eligible orders received a multidisciplinary check, and 44% were changed. The most common change was to clarify discrepancies between the order and the protocol. Changes were made to avoid medication errors in 99 of 451 orders. Changes to avoid medication errors were more likely to involve nonchemotherapy medications. The MDC is an efficient and feasible process to increase safety at the beginning of the medication system.
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January 2003

Resveratrol induced serine phosphorylation of p53 causes apoptosis in a mutant p53 prostate cancer cell line.

J Urol 2002 Aug;168(2):748-55

Medical Research Service, Stratton Veterans Affairs Medical Center, Department of Medicine, Albany Medical College and Wadsworth Center, New York State Department of Health, Albany, New York, USA.

Purpose: Resveratrol (Calbiochem, La Jolla, California) is a naturally occurring stilbene reported to cause apoptosis in various cultured cancer cells. In the current study the effect of resveratrol was determined in the androgen insensitive DU 145 prostate cancer cell line. Induction of apoptosis and activation of apoptosis related signal transduction pathways were measured.

Materials And Methods: DU 145 cells were treated with resveratrol and apoptosis was measured by determining nucleosome content. Activation of mitogen activated protein kinase (MAPK) (extracellular signal-regulated kinase 1/2), p53 content and serine-15 phosphorylation of p53 were measured by immunoblot. Electrophoretic mobility shift assay of p53 binding to DNA, and measurement of p21 and glyceraldehyde-3-phosphate dehydrogenase messenger RNA were also done.

Results: Resveratrol induced apoptosis in DU 145 cells. The stilbene activated MAPK and caused increased abundance of p53 and serine-15 phosphorylated p53. Resveratrol induced serine-15 phosphorylation of p53 was blocked by PD 98059 (Calbiochem), a MAPK kinase inhibitor, implicating MAPK activation in the phosphorylation of p53. PD 98059 also inhibited resveratrol induced apoptosis. These results suggest that apoptosis induction by resveratrol in DU 145 cells requires serine-15 phosphorylation of p53 by MAPK. Inhibition of MAPK dependent serine-15 phosphorylation resulted in reduced p53 binding to a p53 specific oligonucleotide on electrophoretic mobility shift assay. Pifithrin-alpha (Calbiochem), a p53 inhibitor, blocked resveratrol induced serine-15 phosphorylation of p53 and p53 binding to DNA. Resveratrol caused a p53 stimulated increase in p21 messenger RNA. Transfection of additional wild-type p53 into DU 145 cells induced apoptosis, which was further enhanced by resveratrol treatment.

Conclusions: Resveratrol causes apoptosis in DU 145 prostate cancer cells. This action depends on the activation of MAPK, increase in cellular p53 content, serine-15 phosphorylation of p53 and increased p53 binding to DNA.
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August 2002

Assessing diabetes patients' healthcare needs.

Diabetes Educ 2002 Jan-Feb;28(1):40-4, 49-50

Mr. Bennett is with James Bennett Apothecaryin Corinth, Mississippi.

Pharmacists who possess the proper skills and knowledge can intervene with patients in a proactive manner by initiating a dialogue at the point of dispensing medication. After patients complete the DPAQ and the pharmacist assesses the information, a plan of care is developed. Proper documentation (e.g., using the SOAP format) is the first and most important step in caring for patients with diabetes. Such encounters impact on the level of care provided and are professionally and financially rewarding for the pharmacist.
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http://dx.doi.org/10.1177/014572170202800105DOI Listing
May 2002

A peptide derived from alpha-fetoprotein prevents the growth of estrogen-dependent human breast cancers sensitive and resistant to tamoxifen.

Proc Natl Acad Sci U S A 2002 Feb 5;99(4):2211-5. Epub 2002 Feb 5.

Albany Medical College, Albany, NY 12208, USA.

An 8-mer peptide (EMTOVNOG) derived from alpha-fetoprotein was compared with tamoxifen for activity against growth of human breast cancer xenografts implanted in immune-deficient mice. Both peptide and tamoxifen prevented growth of estrogen-receptor-positive MCF-7 and T47D human breast cancer xenografts. A subline of MCF-7, made resistant to tamoxifen by a 6-month exposure to this drug in culture, was found to be resistant to tamoxifen in vivo. Peptide completely prevented the xenograft growth of this tamoxifen-resistant subline of MCF-7. Neither peptide nor tamoxifen was effective in slowing the xenograft growth of the estrogen-receptor-negative MDA-MB-231 human breast cancer. A worrisome side effect of tamoxifen is its hypertrophic effect on the uterus. In this study, tamoxifen was shown to stimulate the growth of the immature mouse uterus in vivo, and the peptide significantly inhibited tamoxifen's uterotrophic effect. The mechanism of action of peptide is different from that of tamoxifen in that the peptide does not interfere with the binding of [(3)H]estradiol to the estrogen receptor. In conclusion, alpha-fetoprotein-derived peptide appears to be a novel agent that interferes with the growth of tamoxifen-sensitive as well as tamoxifen-resistant estrogen-receptor-positive human breast cancers; it inhibits the uterotrophic side effect of tamoxifen and, thus, it may be useful in combination with or in place of tamoxifen for treatment of estrogen-receptor-positive human breast cancers.
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http://dx.doi.org/10.1073/pnas.251667098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC122344PMC
February 2002