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 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review will discuss the role of aromatase inhibitors (AIs) in the adjuvant setting, and will summarize major strategies behind individual adjuvant trials using aromatase inhibitors. Studies with the third generation AIs including anastrozole, letrozole and exemestane, have shown better outcome and improved therapeutic ratio over second line hormonal approaches (i.e. progestins or aminoglutethimide) and, more recently, over tamoxifen also. These promising results have led recently to testing of AIs in the adjuvant setting for postmenopausal patients. Most trials now in progress are evaluating the role of new AIs versus tamoxifen (T) given x 5 years, which in most institutions is currently the standard hormonal adjuvant therapy for breast cancer. Three adjuvant approaches are being tested. First is the use of AI+T x 5 years in combination versus each agent alone, as reflected in the recently completed ATAC trial. Second is a sequential approach T first x 2-3 years followed by AIs x 2-3 years, or the other way round; and third, T x 5 years followed by AIs for additional 5 years (i.e. total duration of adjuvant hormones of 10 years). Many patients in the above trials will survive their first cancer. Hence, the non-oncological outcomes known to be affected by hormones are of rising importance. Therefore, the assessment of lipids as surrogates for cardiovascular morbidity, and of bone mineral status, as a marker for osteoporosis/bone fractures, is an important component of these trials. Also discussed in this review are proposals for future studies of AIs with focus on hormone resistance, such as early alteration of multiple hormonal agents or their intermittent use, the impact of the new generation of SERMs or 'pure' antiestrogens on activity of AIs, and the rising importance of AIs interacting with biologicals, cytokines or hormone modulators.
J Steroid Biochem Mol Biol 2001 Dec
PMID:Adjuvant trials of aromatase inhibitors: determining the future landscape of adjuvant endocrine therapy. 1185 Feb 17

We determined the differential response of a novel SERM, SP500263, on estrogen receptor (ER) alpha and the more recently cloned ER-beta. Because of the high homology of amino acid residues in the ligand-binding domain of ER-alpha and ER-beta, we were not surprised to find that SP500263 binds to both ERs equally well. In contrast, SP500263 acts as a strong estrogen agonist in a strictly ER-alpha-specific manner in U2OS osteosarcoma cell lines blocking the production of interleukin (IL) 6 and granulocyte macrophage colony-stimulating factor. SP500263 also blocked IL-6 production in primary bone cells. The mechanism of this inhibition is different from the classic estrogen stimulation involving an estrogen response element (ERE). SP500263 does not activate gene expression through an ERE. In contrast to the results observed in U2OS cells, SP500263 acts as a strong estrogen antagonist in an MCF-7 breast cancer proliferation assay. Therefore, SP500263 is a member of a series of next-generation SERMs with functional selectivity toward ER-alpha and a mixed agonist/antagonist profile in a bone cell assay versus a breast cancer assay. The panel of assays described herein allow for the development of receptor-specific ligands that may be further developed into novel pharmaceuticals with an improved profile for the treatments of osteoporosis and breast cancer.
Mol Pharmacol 2002 Mar
PMID:Differential response of estrogen receptors alpha and beta to SP500263, a novel potent selective estrogen receptor modulator. 1185 36

This study investigated the value of fluorine-18 2'-deoxy-2-fluoro- D-glucose (FDG) imaging with a double-headed gamma camera operated in coincidence (hybrid PET) detection mode in patients with suspected spondylitis. Comparison was made with conventional nuclear medicine imaging modalities and magnetic resonance imaging (MRI). Sixteen patients with suspected spondylitis (nine male, seven female, mean age 59 years) prospectively underwent FDG hybrid PET (296 MBq) and MRI. For intra-individual comparison, the patients were also imaged with technetium-99m methylene diphosphonate (MDP) (555 MBq) ( n=13) and/or gallium-67 citrate (185 MBq) ( n=11). For FDG hybrid PET, two or three transverse scans were performed. Ratios of infected (target) to non-infected (background) (T/B) vertebral bodies were calculated. MR images were obtained of the region of interest. Patients found positive for spondylitis with MRI and/or FDG hybrid PET underwent surgical intervention and histological grading of the individual infected foci. Twelve out of 16 patients were found to be positive for spondylitis. Independent of the grade of infection and the location in the spine, all known infected vertebrae ( n=23, 9 thoracic, 12 lumbar, 2 sacral) were detected by FDG hybrid PET. T/B ratios higher than 1.45+/-0.05 (at 1 h p.i.) were indicative of infectious disease, whereas ratios below this value were found in cases of degenerative change. FDG hybrid PET was superior to MRI in patients who had a history of surgery and suffered from a high-grade infection in combination with paravertebral abscess formation ( n=2; further computed tomography was needed) and in those with low-grade spondylitis ( n=2, no oedema) or discitis ( n=2, mild oedema). False-positive 67Ga citrate images ( n=5: 2 spondylodiscitis, 1 aortitis, 1 pleuritis, 1 pulmonary tuberculosis) and 99mTc-MDP SPET ( n=4: 1 osteoporosis, 2 spondylodiscitis, 1 fracture) were equally well detected by FDG hybrid PET and MRI. No diagnostic problems were seen in the other patients ( n=5). In this study, FDG hybrid PET was superior to MRI, 67Ga citrate and (99m)Tc-MDP, especially in patients with low-grade spondylitis (as compared with MRI), adjacent soft tissue infections (as compared with 67Ga citrate) and advanced bone degeneration (as compared with 99mTc-MDP).
Eur J Nucl Med Mol Imaging 2002 Apr
PMID:18F-FDG hybrid PET in patients with suspected spondylitis. 1191 90

The active form of vitamin D, 1,25-dihydroxyvitamin D(3)[1,25(OH)(2)D(3)], is a secosteroid hormone that regulates calcium and bone metabolism, controls cell proliferation and differentiation, and exerts immunoregulatory activities. This range of functions has been exploited clinically to treat a variety of conditions, from secondary hyperparathyroidism to osteoporosis, to autoimmune diseases such as psoriasis. Recent advances in understanding 1,25(OH)(2)D(3) functions and novel insights into the mechanisms of its immunomodulatory properties suggest a wider applicability of this hormone in the treatment of autoimmune diseases and allograft rejection.
Trends Mol Med 2002 Apr
PMID:The coming of age of 1,25-dihydroxyvitamin D(3) analogs as immunomodulatory agents. 1192 75

Phosphorylation of eukaryotic initiation factor 2 alpha (eIF-2 alpha) is typically associated with stress responses and causes a reduction in protein synthesis. However, we found high phosphorylated eIF-2 alpha (eIF-2 alpha[P]) levels in nonstressed pancreata of mice. Administration of glucose stimulated a rapid dephosphorylation of eIF-2 alpha. Among the four eIF-2 alpha kinases present in mammals, PERK is most highly expressed in the pancreas, suggesting that it may be responsible for the high eIF-2 alpha[P] levels found therein. We describe a Perk knockout mutation in mice. Pancreata of Perk(-/-) mice are morphologically and functionally normal at birth, but the islets of Langerhans progressively degenerate, resulting in loss of insulin-secreting beta cells and development of diabetes mellitus, followed later by loss of glucagon-secreting alpha cells. The exocrine pancreas exhibits a reduction in the synthesis of several major digestive enzymes and succumbs to massive apoptosis after the fourth postnatal week. Perk(-/-) mice also exhibit skeletal dysplasias at birth and postnatal growth retardation. Skeletal defects include deficient mineralization, osteoporosis, and abnormal compact bone development. The skeletal and pancreatic defects are associated with defects in the rough endoplasmic reticulum of the major secretory cells that comprise the skeletal system and pancreas. The skeletal, pancreatic, and growth defects are similar to those seen in human Wolcott-Rallison syndrome.
Mol Cell Biol 2002 Jun
PMID:The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. 1199 20

To elucidate the molecular mechanism in relation to vascular supply and osteoporosis, we investigated the effect of hypoxia on Runx2 expression in MG63 cells. Also investigated was expression of type I collagen and osteocalcin, which are regulated by Runx2, alkaline phosphatase (ALPase) to see if they are affected by hypoxia. Quiescent cultures of MG63 cells were exposed to hypoxia (2% O(2)) and normoxia (18% O(2)) for 24, 48, 72 and 96 h. In cells exposed to hypoxia, reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that mRNA expression of Runx2, type I collagen, osteocalcin, and ALPase were decreased in a time dependent manner to 96 h. Activity of ALPase was also reduced in the same manner. Western blotting showed a marked decrease in Runx2 protein at 96 h in cells under hypoxia compared to normoxia. These data indicate that Runx2 expression in osteoblasts is reduced by hypoxia, and may be a mechanism of osteoporosis by decreased vascular supply.
Mol Cell Endocrinol 2002 Jun 28
PMID:Hypoxia decreases Runx2/Cbfa1 expression in human osteoblast-like cells. 1208 80

Patients with pycnodysostosis, a rare skeletal dysplasia, present with bone abnormalities such as short stature, acroosteolysis of distal phalanges, and skull deformities. The disease is caused by a deficiency of the cysteine protease cathepsin K which is responsible for degradation of collagen type I and other bone proteins. Osteoclasts, bone cells of hematopoietic origin responsible for bone mineral as well as protein matrix degradation, are dysfunctional in patients with pycnodysostosis due to mutations in the cathepsin K gene. Cathepsin K deficient osteoclasts can demineralize bone but cannot degrade the protein matrix. Mutations in the cathepsin K gene disrupting wild type cathepsin K activity have been described in patients with pycnodysostosis. Animal models of cathepsin K deficiency have been created and provide a valuable tool to study osteoclast function and treatment for cathepsin K deficiency. Understanding the regulation and role of cathepsin K in osteoclast function is important for designing future therapies for pycnodysostosis. Cathepsin K inhibitors will be useful in pathological processes involving excess osteoclast activation and bone resorption such as osteoporosis, bone metastasis and multiple myeloma. This review will discuss the bone remodeling cycle, the human disease pycnodysostosis caused by cathepsin K deficiency and cathepsin K activity and regulation.
Curr Mol Med 2002 Aug
PMID:Pycnodysostosis: role and regulation of cathepsin K in osteoclast function and human disease. 1212 7

Osteoporosis is a common skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. In the past years, twin and family study have shown that this disease recognizes a strong genetic component and that genetic factors play an important role in regulating bone mineral density (BMD). While in few isolate conditions osteoporosis can be inherited in a simple Mendelian pattern, due to single gene mutations, in the majority of cases has to be considered a multifactorial polygenic disease in which genetic determinants are modulated by hormonal, environmental and nutritional factors. Given the important role that steroid hormones play in bone cell development and in the maintenance of normal bone architecture, polymorphisms at receptor of the steroid/thyroid hormone receptor superfamily, such as estrogen receptor alpha (ERalpha) and Vitamin D receptor (VDR) have been thoroughly investigated in the last years and appeared to represent important candidate genes. The individual contribution of these genetic polymorphisms to the pathogenesis of osteoporosis remains to be universally confirmed and an important aim in future work will be to define their functional molecular consequences and how these polymorphisms interact with each other and with the environment to cause the osteoporotic phenotype. A further promising application of genetic studies in osteoporosis comes from their pharmacogenomic implications, with the possibility to give a better guidance for therapeutic agents commonly used to treat this invalidating disorder or to identify target molecules for new therapeutic agents.
J Steroid Biochem Mol Biol 2002 May
PMID:Genetics of osteoporosis: role of steroid hormone receptor gene polymorphisms. 1212 38

Genetic factors play an important role in the pathogenesis of osteoporosis. The genes involved are, however, still largely unknown. In the present study, we have investigated whether sequence variations in the estrogen receptor beta (ERbeta) gene are associated with bone mineral density (BMD) and biochemical markers of bone turnover in 79 Slovenian postmenopausal women with osteoporosis. We also assessed the response by BMD and bone markers to antiresorptive therapy with bisphosphonate alendronate. All eight exons of ERbeta gene were amplified by polymerase chain reaction and screened for mutations by single-strand conformation polymorphism analysis. Potentially mutated samples were found only in exon 5 and sequence analysis identified the presence of a silent mutation in codon 328 with a nucleotide substitution GTG to GTA. For easier detection of this silent mutation, the RsaI restriction fragment length polymorphism analysis was developed. The frequencies of genotypes were as follows: Rr 5.1% and RR 94.9%. Between both genotypes, no significant differences in baseline lumbar spine and femoral neck BMD or in bone markers osteocalcin and deoxypyridinoline were observed. Similarly, no significant difference between RR and Rr genotypes in BMD or bone markers after 1 year of therapy was found. The increase in lumbar spine BMD after therapy was the only parameter that approached statistical significance (P=0.099). Patients with genotype Rr showed a smaller increase compared to those with RR. Our results suggest that RsaI polymorphism of ERbeta gene is probably not an important genetic determinant of BMD and does not significantly influence the responsiveness to alendronate therapy.
J Steroid Biochem Mol Biol 2002 Jun
PMID:No major effect of estrogen receptor beta gene RsaI polymorphism on bone mineral density and response to alendronate therapy in postmenopausal osteoporosis. 1213 4

Aromatase, the enzyme responsible for the conversion of androgens to estrogens, is present in the mouse gonads, brain, adipose tissue and bone. Depletion of endogenous estrogens in the aromatase deficient mouse (ArKO) caused by the targeted disruption of the Cyp19 gene resulted in an impairment of sexual behaviour and an age-dependent disruption of spermatogenesis. This disruption occurred during early spermiogenesis, due possibly to increased number of apoptotic round spermatids. Development of obesity was associated with ageing, decrease in lean mass, hypercholesterolemia, hyperleptinemia, and insulin resistance and hepatic steatosis. However, it was not correlated with hyperphagia but to decreased physically-active behaviour. ArKO mice also developed osteoporosis. Thus, studies using the ArKO mice model has led to several insights into the multiple roles played by estrogens in the development and maintenance of fertility, sexual behaviour, lipid metabolism and bone remodelling.
Mol Cell Endocrinol 2002 Jul 31
PMID:Effect of estrogen deficiency in the male: the ArKO mouse model. 1216 Sep 96


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