Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vorozole (R83842) is a potent and selective, non-steroidal aromatase inhibitor. It is the dextro-enantiomer of the triazole derivative R 76,713. In FSH-stimulated rat granulosa cells, vorozole inhibited aromatase activity with an IC50-value of 1.4 +/- 0.5 nM. In pregnant mare serum gonadotropin (PMSG)-primed female rats, plasma estradiol levels measured 2 h after single oral administration of vorozole were significantly reduced by drug doses of 0.001 mg/kg and higher, with an ED50-value of 0.0034 mg/kg. In ovariectomized nude mice, bearing an estrogen-producing JEG-3 choriocarcinoma, 5 days treatment with vorozole, dose-dependently reduced uterus weight and completely inhibited tumor aromatase, measured ex vivo. Vorozole showed IC50-values higher than 10 microM for inhibition of progesterone synthesis in rat granulosa cells, for inhibition of steroid biosynthesis in isolated rat testicular and adrenal cells and for inhibition of steroid binding to estrogen-, progestin-, androgen- and gluco- and mineralocorticoid-receptors. In LHRH/ACTH-injected male rats and in rats fed a sodium-deprived diet, single oral administration of up to 10 mg/kg vorozole did not affect plasma levels of testicular and adrenal steroids. The compound also had no in vivo estrogen or androgen (ant)agonistic properties. In the DMBA-induced rat mammary carcinoma model, vorozole at an oral dose of 2.5 mg/kg b.i.d. inhibited tumor growth similarly to ovariectomy.
J Steroid Biochem Mol Biol 1993 Mar
PMID:Pharmacology of vorozole. 838 40

To characterize the effect(s) of transforming growth factor alpha (TGF alpha) during multistage carcinogenesis, we examined tumor development in pancreas and liver of transgenic mice that coexpressed TGF alpha with either viral (simian virus 40 T antigens [TAg]) or cellular (c-myc) oncogenes. In pancreas, TGF alpha itself was not oncogenic, but it nevertheless dramatically accelerated growth of tumors induced by either oncogene alone, thereby reducing the host life span up to 60%. Coexpression of TGF alpha and TAg produced an early synergistic growth response in the entire pancreas together with the more rapid appearance of preneoplastic foci. Coexpression of TGF alpha and c-myc also accelerated tumor growth in situ and produced transplantable acinar cell carcinomas whose rate of growth was TGF alpha dependent. In liver, expression of TGF alpha alone increased the incidence of hepatic cancer in aged mice. However, coexpression of TGF alpha with c-myc or TAg markedly reduced tumor latency and accelerated tumor growth. Significantly, expression of the TGF alpha and myc transgenes in hepatic tumors was induced up to 20-fold relative to expression in surrounding nonneoplastic liver, suggesting that high-level overexpression of these proteins acts as a major stimulus for tumor development. Finally, in both pancreas and liver, combined expression of TGF alpha and c-myc produced tumors with a more malignant (less differentiated) appearance than did expression of c-myc alone, consistent with an influence of TGF alpha upon the morphological character of c-myc-induced tumor progression. These findings demonstrate the importance of TGF alpha expression during multistage carcinogenesis in vivo and point to a major role for this growth factor as a potent stimulator of tumor growth.
Mol Cell Biol 1993 Jan
PMID:Transforming growth factor alpha dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver. 841 34

Thyrotropic tumors (TtT97) contain mRNA transcripts for three T3-receptor (TR) isoforms, alpha 1, beta 1 and beta 2, and a non-receptor alpha 2-variant. We administered T4 (5 mg/l of drinking water) for one month to TtT97-bearing mice, to examine its effect on tumor growth and tumor TR isoform steady-state mRNA levels. Baseline mice were killed at the start of the experiment, and placebo mice were maintained hypothyroid. The treated tumors were 30-35% smaller than the baseline tumors (p = NS), while the placebo tumors were 2- to 7-fold larger than the baseline tumors (p < 0.05). TR beta 1 mRNA increased 5- to 6-fold, while TR beta 2 mRNA decreased by 76%. TR alpha 1 and the alpha 2-variant decreased by 52% and 70%, respectively. Therefore, the tumors decreased their growth rate in response to T4 administration, and increased the ratio of TR beta 1 to TR beta 2 mRNA. This raises the intriguing possibility of a correlation between the relative abundance of the TR beta isoforms and tumor growth.
Mol Cell Endocrinol 1993 Feb
PMID:Effect of thyroid hormone on T3-receptor mRNA levels and growth of thyrotropic tumors. 847 56

The influence of estrogens and tamoxifen on estrogen receptor (ER)-positive human breast cancer (MCF-7) cells transplanted into athymic nude mice was investigated. The mice were divided into the following three groups: (1) an E2 group with mice receiving 17 beta-estradiol dipropionate; (2) a TAM group with mice receiving tamoxifen; (3) a control group with mice given no hormone. (1) Tumor growth was significantly increased in the E2 group, but significantly decreased in the TAM group compared to control; (2) the tumor contents of insulin-like growth factor-I (IGF-I) and the rate of IGF-I-positive cells were significantly lower in the E2 group, but significantly higher in the TAM groups compared to control; (3) the IGF-I-positive cell rates were in significant inverse correlation with the [3H]thymidine-labeled cell rates in the E2, TAM and control groups. Thus, the tumor contents of IGF-I and the rate of IGF-I-positive cells were inversely correlated to the tumor growth and the [3H]thymidine-labeled cell rate in this in vivo study, although IGF-I is known to be a mitogen for breast cancer cells in vitro. Further studies are necessary to answer the questions as to the in vivo roles of immunoreactive IGF-I in ER-positive breast cancer.
Mol Cell Endocrinol 1993 Mar
PMID:Influence of hormones on tumor growth, cell kinetics, estrogen receptor and insulin-like growth factor-I-related protein of human breast cancer (MCF-7) cells transplanted in nude mice. 847 69

While hormone-dependent, mammary tumors induced with carcinogens (DMBA or NMU) in intact rats have been used extensively for studying aromatase inhibitors, there is currently no suitable model to investigate their effects in human breast cancers in vivo. While hormone responsive tumors can be formed in the athymic mouse using human breast carcinoma MCF-7 cells, due to the low ovarian estrogen production, tumor growth is induced with estradiol supplementation. Thus, this model is unsuitable for studies of aromatase inhibitors. We have induced tumors without the need for estrogen supplementation by co-inoculating MCF-7 cells with Matrigel, a basement membrane preparation, into intact athymic mice. In one experiment, 45 days after inoculation, mice were assigned to the control group or 4-hydroxyandrostenedione (4-OHA) (1 mg/day s.c.) treatment for 52 days. Tumor volumes in the control mice increased 672%, whereas tumor volumes in the treated mice did not change significantly (178.9 +/- 16.2 to 336.6 +/- 120 mm3). In the second experiment, 55 days after inoculation, groups of mice were treated with the antiestrogen, tamoxifen (5 micrograms/day s.c.) or vehicle (controls). Tumor volumes in the control mice increased 325% in 58 days, whereas there was no significant change in tumor volume in the tamoxifen treated group (338.8 +/- 55.3 to 330.6 +/- 84.9 mm3). The results suggest that (1) the tumors resulting from MCF-7 cells co-inoculated with Matrigel are estrogen-dependent and (2) tamoxifen and 4-OHA were effective in suppressing growth of these tumors. The results suggest that this model should be useful for evaluating the effects of aromatase inhibitors and for comparing breast cancer treatments.
J Steroid Biochem Mol Biol 1993 Mar
PMID:MCF-7 human breast carcinomas in nude mice as a model for evaluating aromatase inhibitors. 847 81

It has been proposed that local production of estrogen may contribute to breast tumor growth, in part by regulating growth factor production. In view of this, we studied the expression of mRNAs for aromatase cytochrome P-450, the enzyme which catalyzes estrogen synthesis, and keratinocyte growth factor (KGF), a heparin-binding growth factor specific for epithelial cells, in breast tumors. In order to detect mRNAs of low-abundance, reverse transcription-polymerase chain reaction (RT-PCR) was used. RNA from breast tumors and normal breast tissue was reverse transcribed and then amplified using oligonucleotide primers for human aromatase or KGF. Twelve of 15 breast tumor samples yielded variable amounts of aromatase PCR product, but consistently strong KGF PCR signals. Of the three aromatase mRNA-negative samples, two gave weak KGF signals while one was negative for KGF. Both aromatase and KGF transcripts were also detected in all five normal breast tissue samples examined. These results indicate that a high proportion of breast tumors have the potential to produce aromatase and KGF, both of which could play important roles in their growth. The results also suggest that RT-PCR can be used to evaluate local expression of growth mediators in tumors.
J Steroid Biochem Mol Biol 1993 Apr
PMID:Detection of aromatase and keratinocyte growth factor expression in breast tumors using reverse transcription-polymerase chain reaction. 849 30

This review of angiogenesis aims to describe (a) stimuli that either elicit or antagonize angiogenesis, (b) the response of the vasculature to angiogenic or anti-angiogenic stimuli, i.e., processes required for the formation of new vessels, (c) aspects of angiogenesis relating to tissue remodeling and disease, and (d) the potential of angiogenic or antiangiogenic therapeutic measures. Angiogenesis, the formation of new vessels from existing microvessels, is important in embryogenesis, wound healing, diabetic retinopathy, tumor growth, and other diseases. Hypoxia and other as yet ill-defined stimuli drive tumor, inflammatory, and connective tissue cells to generate angiogenic molecules such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), transforming growth factor-beta (TGF-beta), platelet-derived growth factor (PDGF), and others. Natural and synthetic angiogenesis inhibitors such as angiostatin and thalidomide can repress angiogenesis. Angiogenic and antiangiogenic molecules control the formation of new vessels via different mechanisms. VEGF and FGF elicit their effects mainly via direct action on relevant endothelial cells. TGF-beta and PDGF can attract inflammatory or connective tissue cells which in turn control angiogenesis. Additionally, PDGF may act differently on specific phenotypes of endothelial cells that are engaged in angiogenesis or that are of microvascular origin. Thus phenotypic traits of endothelial cells committed to angiogenesis may determine their cellular responses to given stimuli. Processes necessary for new vessel formation and regulated by angiogenic/antiangiogenic molecules include the migration and proliferation of endothelial cells from the microvasculature, the controlled expression of proteolytic enzymes, the breakdown and reassembly of extracellular matrix, and the morphogenic process of endothelial tube formation. In animal models some angiogenesis-dependent diseases can be controlled via induction or inhibition of new vessel formation. Life-threatening infantile hemangiomas are a first established indication for antiangiogenic therapy in humans. Treatment of other diseases by modulation of angiogenesis are currently tested in clinical trials. Thus the manipulation of new vessel formation in angiogenesis-dependent conditions such as wound healing, inflammatory diseases, ischemic heart and peripheral vascular disease, myocardial infarction, diabetic retinopathy, and cancer is likely to create new therapeutic options.
J Mol Med (Berl) 1995 Jul
PMID:Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects. 852 Sep 66

1. Cellular expression and distribution of the stress response small heat shock protein 27 (hsp27) in 39 high-grade astrocytomas (27 glioblastoma multiformes, 12 anaplastic astrocytomas) and in 27 low-grade astrocytomas (grade I-II) were analyzed immunohistochemically. 2. The correlation between hsp27 expression and tumor growth fractions of the astrocytomas was examined following Ki-67 immunostaining. 3. The hsp27 staining was cell cytoplasmic. The hsp27 immunopositive rate was significantly higher in high-grade astrocytomas; the rates was 74% for glioblastomas, 58% for anaplastic astrocytomas, and 37% for low-grade astrocytomas. The small and large tumor cells, especially in glioblastomas, multinucleated tumor giant cells, tumor cells in the pseudopalisading and necrotic areas, cells of the microvascular endothelial proliferations, and tumor vascular smooth muscles were usually hsp27 positive. The mean percentage of hsp27-positive cells was significantly higher in the glioblastomas alone and in the combined high-grade astrocytomas, compared to the low-grade, and in recurrent rather than in primary high-grade astrocytomas. 4. The high-grade astrocytomas had a highly statistical significant Ki-67 labeling index. The Ki-67 labeling indices were significantly higher in the hsp27-positive than the hsp27-negative astrocytomas, irrespective of the histological grade. In the high-grade astrocytomas with a Ki-67 labeling index of five and above, 81% of those tumors were hsp27 positive. 5. Thus, a large number of human astrocytomas express hsp27, and hsp27 expression correlates with histological grades of astrocytoma and with tumor growth fractions. This being the case, hsp27 is likely to have a role in the growth of human astrocytomas.
Cell Mol Neurobiol 1995 Apr
PMID:Expression of the small heat shock protein (hsp) 27 in human astrocytomas correlates with histologic grades and tumor growth fractions. 859 Apr 55

Several laboratories have described estrogen receptor mRNA variants created by skipping internal exons. Some of the putative proteins encoded for by these variants have been functionally characterized by transfection analyses. The variant lacking exon 5 would lead, if translated, to a truncated receptor which shows dominant positive transactivation activity in the absence of hormone. It has been postulated that the variant could account for anti-estrogen resistant tumor growth and for expression of the progesterone receptor in estrogen negative tumors. In order to understand the possible role this and other variants may have in the tumorigenesis of mammary tissue we have carried out a thorough analysis of variants expressed in a tumor cell line (MCF-7), in a tumor sample and in a sample of normal breast tissue derived from mammary reduction surgery. We performed rt-PCR analyses followed by hybridization with exon specific oligonucleotide probes. By these means we have detected nine different variants co-expressed in MCF-7 cells and at least the major variants were equally expressed in normal and neoplastic breast tissue. The same is true for the variant lacking exon 5 which, however, resulted to be a variant of low expression in the three samples analyzed. Variant formation appeared to be restricted to the estrogen receptor messenger since several other members of the superfamily of nuclear receptors did not show variant formation. We also have analyzed the effect of the most abundantly expressed variant, the exon 4 lacking variant, on normal estrogen receptor function, on the growth and on the response to estradiol and to tamoxifen of MCF-7 cells. Although over-expressed at high levels this variant has, if any, only marginal effects on the expression of endogenous estrogen regulated genes and on growth and response to the hormone and its antagonist. Although the lack of function of this variant cannot be extrapolated to other variants, their involvement in tumor formation appears rather unlikely since they are also expressed in normal tissue and the single variant is expressed in addition to many others, some of which might have opposing effects. Variant formation is, however, specific for the estrogen receptor and apparently regulated with tissue specificity as our expression analysis in normal mouse tissues shows. Therefore the variants probably have a physiological significance yet to be discovered.
J Steroid Biochem Mol Biol 1996 Jan
PMID:Alternative splicing of the estrogen receptor primary transcript normally occurs in estrogen receptor positive tissues and cell lines. 860 53

Prostaglandin A2 (PGA2) potently inhibits cell proliferation and suppresses tumor growth in vivo, but little is known regarding the molecular mechanisms mediating these effects. Here we demonstrate that treatment of breast carcinoma MCF-7 cells with PGA2 leads to G1 arrest associated with a dramatic decrease in the levels of cyclin D1 and cyclin-dependent kinase 4 (cdk4) and accompanied by an increase in the expression of p21. We further show that these effects occur independent of cellular p53 status. The decline in cyclin D and cdk4 protein levels is correlated with loss in cdk4 kinase activity, cdk2 activity is also significantly inhibited in PGA2-treated cells, an effect closely associated with the upregulation of p21. Immunoprecipitation experiments verified that p21 was indeed complexed with cdk2 in PGA2-treated cells. Additional experiments with synchronized MCF-7 cultures stimulated with serum revealed that treatment with PGA2 prevents the progression of cells from G1 to S. Accordingly, the kinase activity associated with cdk4, cyclin E, and cdk2 immunocomplexes, which normally increases following serum addition, was unchanged in PGA2-treated cells. Furthermore, the retinoblastoma protein (Rb), a substrate of cdk4 and cdk2 whose phosphorylation is necessary for cell cycle progression, remains underphosphorylated in PGA2-treated serum-stimulated cells. These findings indicate that PGA2 exerts its growth-inhibitory effects through modulation of the expression and/or activity of several key G1 regulatory proteins. Our results highlight the chemotherapeutic potential of PGA2, particularly for suppressing growth of tumors lacking p53 function.
Mol Cell Biol 1996 Mar
PMID:Inhibition of G1 cyclin-dependent kinase activity during growth arrest of human breast carcinoma cells by prostaglandin A2. 862 77


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