Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Androgens have significant beneficial effects on the skeleton. However, studies on the effects of androgens on osteoblasts are limited due to the absence of appropriate model systems that combine completeness of the osteoblastic phenotype, rapid proliferation rate, and stable expression of the androgen receptor (AR). Thus, we stably transfected the conditionally immortalized human fetal osteoblastic cell line (hFOB) with the human wild-type AR (hAR) cDNA. Compared to nontransfected hFOB cells, constitutive hAR mRNA expression in three independent hAR-transfected hFOB clones (hFOB/AR) was 15-fold higher in hFOB/AR-16, 62-fold higher in hFOB/AR-2, and 72-fold higher in hFOB/AR-6 cells, respectively, as assessed by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Detectable constitutive levels of hAR mRNA by Northern blot analysis were present in hFOB/AR-2 and hFOB/AR-6 cells, but not in hFOB/AR-16 or hFOB cells, respectively. Treatment with 5 alpha-dihydrotestosterone (5 alpha-DHT) (10(-8) M) for 24 h did not alter hAR mRNA steady state levels in the hFOB/AR cell lines. Nuclear binding studies demonstrated 152 +/- 73 (mean +/- SEM) functional hARs/nucleus in non-transfected hFOB cells, 3,940 +/- 395 functional hARs/nucleus in hFOB/AR-2 cells, and 3,987 +/- 823 hARs/nucleus in hFOB/AR-6 cells, respectively. Treatment with 5 alpha-DHT increased the expression of a transiently transfected androgen response element-chloramphenicol acetyltransferase (ARE-CAT) reporter construct in hFOB/AR-6 cells in a dose- and time-dependent manner; no such effect was observed in transiently transfected hFOB cells lacking exogenously transfected hARs. Moreover, 5 alpha-DHT-induced ARE-CAT expression was inhibited by the selective androgen receptor antagonist, hydroxyflutamide. In summary, we have developed and characterized androgen-responsive osteoblastic cell lines derived from normal human fetal bone that express physiological levels of functional hARs. These cell lines should provide a suitable model for further studies on the effects of androgens on osteoblast function, including the identification of potential androgen-regulated growth factors and cytokines.
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PMID:Development and characterization of a conditionally immortalized human osteoblastic cell line stably transfected with the human androgen receptor gene. 928 32

The intact cervicovaginal mucosa is a relative barrier to the sexual transmission of human immunodeficiency virus type 1 (HIV-1). In the simian immunodeficiency virus (SIV) macaque model of HIV infection, seronegative transient viremia (STV; virus isolation positive followed by repeated negative cultures) occurs after intravaginal inoculation of a low dose of pathogenic SIVmac251 (C. J. Miller, M. Marthas, J. Torten, N. Alexander, J. Moore, G. Doncel, and A. Hendrickx, J. Virol. 68:6391-6400, 1994). Thirty-one adult female macaques that had been inoculated intravaginally with pathogenic SIVmac251 became transiently viremic. One monkey that had been culture negative for a year after SIV inoculation became persistently viremic and developed simian AIDS. No other STV monkey developed persistent viremia or disease. Results of very sensitive assays showed that 6 of 31 monkeys had weak SIV-specific antibody responses. SIV-specific antibodies were not detected in the cervicovaginal secretions of 10 STV monkeys examined. Twenty of 26 monkeys had lymphocyte proliferative responses to p55(gag) and/or gp130(env) antigens; 3 of 6 animals, including the monkey that became persistently viremic, had detectable cytotoxic T-lymphocyte (CTL) responses to SIV. At necropsy, lymphoid tissues and vaginal mucosa were virus culture negative, but in 10 of 10 animals, SIV provirus was detected by PCR using gag-specific primer pairs. Fifty percent of the PCR-positive tissue samples were also positive for SIV gag RNA by reverse transcriptase PCR. Thus, transient viremia following intravaginal inoculation of pathogenic SIV is associated with persistent, systemic infection, either latent or very low level productive. Atypical immune responses, characterized by lymphocyte proliferation and some CTL responses in the absence of conventionally detectable antibodies, develop in transiently viremic monkeys.
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PMID:Occult systemic infection and persistent simian immunodeficiency virus (SIV)-specific CD4(+)-T-cell proliferative responses in rhesus macaques that were transiently viremic after intravaginal inoculation of SIV. 981 41

The kinetic parameters, steroid substrate specificity and identities of reaction products were determined for four homogeneous recombinant human 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) isoforms of the aldo-keto reductase (AKR) superfamily. The enzymes correspond to type 1 3alpha-HSD (AKR1C4), type 2 3alpha(17beta)-HSD (AKR1C3), type 3 3alpha-HSD (AKR1C2) and 20alpha(3alpha)-HSD (AKR1C1), and share at least 84% amino acid sequence identity. All enzymes acted as NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductases and as 3alpha-, 17beta- and 20alpha-hydroxysteroid oxidases. The functional plasticity of these isoforms highlights their ability to modulate the levels of active androgens, oestrogens and progestins. Salient features were that AKR1C4 was the most catalytically efficient, with k(cat)/K(m) values for substrates that exceeded those obtained with other isoforms by 10-30-fold. In the reduction direction, all isoforms inactivated 5alpha-dihydrotestosterone (17beta-hydroxy-5alpha-androstan-3-one; 5alpha-DHT) to yield 5alpha-androstane-3alpha,17beta-diol (3alpha-androstanediol). However, only AKR1C3 reduced Delta(4)-androstene-3,17-dione to produce significant amounts of testosterone. All isoforms reduced oestrone to 17beta-oestradiol, and progesterone to 20alpha-hydroxy-pregn-4-ene-3,20-dione (20alpha-hydroxyprogesterone). In the oxidation direction, only AKR1C2 converted 3alpha-androstanediol to the active hormone 5alpha-DHT. AKR1C3 and AKR1C4 oxidized testosterone to Delta(4)-androstene-3,17-dione. All isoforms oxidized 17beta-oestradiol to oestrone, and 20alpha-hydroxyprogesterone to progesterone. Discrete tissue distribution of these AKR1C enzymes was observed using isoform-specific reverse transcriptase-PCR. AKR1C4 was virtually liver-specific and its high k(cat)/K(m) allows this enzyme to form 5alpha/5beta-tetrahydrosteroids robustly. AKR1C3 was most prominent in the prostate and mammary glands. The ability of AKR1C3 to interconvert testosterone with Delta(4)-androstene-3,17-dione, but to inactivate 5alpha-DHT, is consistent with this enzyme eliminating active androgens from the prostate. In the mammary gland, AKR1C3 will convert Delta(4)-androstene-3,17-dione to testosterone (a substrate aromatizable to 17beta-oestradiol), oestrone to 17beta-oestradiol, and progesterone to 20alpha-hydroxyprogesterone, and this concerted reductive activity may yield a pro-oesterogenic state. AKR1C3 is also the dominant form in the uterus and is responsible for the synthesis of 3alpha-androstanediol which has been implicated as a parturition hormone. The major isoforms in the brain, capable of synthesizing anxiolytic steroids, are AKR1C1 and AKR1C2. These studies are in stark contrast with those in rat where only a single AKR with positional- and stereo-specificity for 3alpha-hydroxysteroids exists.
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PMID:Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones. 1099 48

The experimental reverse transcriptase inhibitor FddA (lodenosine) has shown promise in early studies. The drug was originally developed by the National Cancer Institute (NCI) and appears to have little in vitro cross-resistance with other drugs in its class, including AZT (Retrovir), ddI (Videx), and d4T (Zerit). Drug trials are in the early stages, and there is limited data on the drug to date. The NCI is planning a Phase I/II trial. U.S. Bioscience is planning a Phase II trial to study FddA in combination with a protease inhibitor plus a nucleoside analog in treatment-naive patients. Contact information is provided.
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PMID:FddA: antiretroviral in development. 1136 97

We examined the pharmacokinetics and metabolism of the experimental nucleoside reverse transcriptase inhibitor compound stampidine in mice, dogs, and cats. Also reported is the identification of p-bromophenyl sulfate (p-Br-Ph-S) as a major in vivo phase II metabolite of stampidine. Liver cytosol was shown to take part in the hydrolysis of stampidine to form alaninyl-STV-monophosphate (Ala-STV-MP), 2',3'-didehydro-3'-deoxythymidine (STV), and p-bromophenol; p-bromophenol was further sulfonated by sulfotransferase to form p-Br-Ph-S. Notably, plasma concentrations of stampidine >4 logs higher than its IC(50) value can be achieved in both dogs and cats after its p.o administration at a 100-mg/kg dose level. In dogs as well as cats, stampidine was metabolized to yield micromolar concentrations of the active metabolites ala-STV-MP and STV, which is similar to the metabolism of stampidine in mice. These findings encourage the further development of this new antiviral agent for possible clinical use in human immunodeficiency virus-infected patients.
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PMID:Metabolism of stavudine-5'-[p-bromophenyl methoxyalaninyl phosphate], stampidine, in mice, dogs, and cats. 1243 28

For the last several years, the combination of ddI (didanosine, Videx) and d4T (stavudine, Zerit) as a backbone of three-drug therapy has been popular both in treatment and in research. Together, the two nucleoside analog reverse transcriptase inhibitor (NARTI) drugs offered relatively high strength and fairly simple use. Despite this, some researchers have long questioned the wisdom of the combination as it violates one of the key rules of combining drugs: combine only drugs with different side effect profiles. Both drugs are associated with the development of peripheral neuropathy and pancreatitis. Pancreatitis is more commonly seen with ddI and neuropathy with d4T, but both occur to a significant degree with each drug and to a higher degree than was seen with other drugs of their class. However, few if any studies were run comparing the ddI/d4T combination to alternatives such as AZT/3TC (Combivir) or even 3TC/d4T. Both ddI and d4T come from the same company, Bristol Myers Squibb.
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PMID:New questions about an old combination--ddI + d4T. 1264 75

Androgen independence is the major cause of endocrine therapy failure in advanced prostate cancer (PC). To examine the effects of human androgen receptor (AR) expression on growth of human PC cells, transfection of full-length AR cDNA in an androgen-insensitive human prostatic adenocarcinoma cell line (DU145) was performed. Transcriptional activity of AR was confirmed by the MMTV luciferase assay and AR expression was assessed by reverse transcriptase polymerase chain reaction, Western blotting, and immunocytochemistry. Two stable transfectant cell lines expressing functional AR were established and passaged over 60 times. Under standard culture conditions, AR expression in transfected cells was predominantly cytoplasmic. Exposure to dihydrotestosterone (DHT; 60 pM-10 nM) resulted in a rapid (maximal at 30 minutes) translocation of AR to the nucleus. Treatment with DHT (5 nM) caused a significant reduction in cell-cell adhesion and aggregation accompanied by a decrease in E-cadherin expression. This was associated with up to 40% inhibition of proliferation and approximately two-fold increase in apoptosis. These results suggest that gene transfer-mediated AR expression in DU145 cells confers sensitivity to DHT, modulates cell-cell adhesion through E-cadherin, and suppresses cell growth by inhibiting proliferation and promoting apoptosis. This provides amodelfor studies ofAR-regulated cell signalling and identification of novel androgen-regulated genes in PC.
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PMID:Ligand activation of the androgen receptor downregulates E-cadherin-mediated cell adhesion and promotes apoptosis of prostatic cancer cells. 1451 6

Hearts from 1-yr-old Erythrocebus patas monkeys were examined after in utero and 6-wk-postbirth exposure to antiretroviral nucleoside reverse transcriptase inhibitors (NRTIs). Protocols were modeled on those given to human immunodeficiency virus (HIV)-1-infected pregnant women. NRTIs were administered daily to the dams for the last 20% or 50% of gestation, and to the infants for 6 wk after birth. Exposures included: no drug (n = 4); Zidovudine, 3'-azido-3'-deoxythymidine (AZT; n = 4); AZT/Lamivudine, (-)-beta-L-2', 3'-Dideoxy-3'-thiacytidine (Epivir, 3TC) (n = 4); AZT/Didanosine (Videx, ddI) (n = 4); and Stavudine (Zerit, d4T)/3TC (n = 4). Echocardiograms and clinical chemistry showed no drug-related changes, but the d4T/3TC-exposed fetuses at 6 and 12 mo had increased white cell counts (p < 0.05). At 1 yr of age, oxidative phosphorylation (OXPHOS) enzyme activities were similar in heart mitochondria from all groups. Mitochondrial pathology, that included clones of damaged mitochondria (p < 0.05), was found in hearts of all 1-yr drug-exposed infants. Levels of mtDNA were elevated (p < 0.05) in hearts of all NRTI-exposed monkeys in the following order: control < d4T/3TC < AZT < AZT/3TC < AZT/ddI. The clinical status of NRTI-exposed infants, as evidenced by behavior, clinical chemistry, OXPHOS activity and echocardiogram, was normal. However, extensive mitochondrial damage with clusters of similar-appearing damaged heart mitochondria observed by electron microscopy, and an increase in mtDNA quantity, that persisted at 1 yr of age, suggest the potential for cardiotoxicity later in life.
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PMID:Cardiac mitochondrial compromise in 1-yr-old Erythrocebus patas monkeys perinatally-exposed to nucleoside reverse transcriptase inhibitors. 1624 78

Stavudine (STV, d4T, 2',3'-didehydro-3'-deoxythymidine, CAS 3056-17-5) is a standard anti-HIV drug. Stampidine (STAMP, DDE-113, HI-113, N-[p-(4-bromophenyl)-2',3'-didehydro-3'-deoxy-5'-thymidylyl]-L-alanine methyl ester, CAS 217178-62-6) is a novel aryl phosphate derivative of stavudine with more potent anti-HIV activity and more favorable pharmacodynamic features. The remarkable potency of stampidine against clinical HIV-1 isolates with NRTI- or NNRTI-resistance (NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor) warrants the further development of this new anti-HIV agent.
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PMID:Stampidine as a novel nucleoside reverse transcriptase inhibit with potent anti-HIV activity. 1657 Aug 21

The in vitro potency of stampidine (STAMP, DDE-113, HI-113, N-[p-(4-bromophenyl)-2',3'-didehydro-3'-deoxy-5'-thymidylyl]-L-alanine methyl ester, CAS 217178-62-6) was examined against 8 clinical non-B subtype HIV-1 isolates with resistance to stavudine (STV, d4T), adefovir and tenofovir, 19 clinical zidovudine-resistant HIV-1 isolates, and 6 recombinant HIV-1 clones with multi-resistance against nucleoside reverse transcriptase inhibitors. Stampidine exhibited potent anti-HIV activity against each one of these 33 HIV-1 isolates with subnanomolar to nanomolar IC50 values.
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PMID:Potency of stampidine against multi-nucleoside reverse transcriptase inhibitor resistant human immunodeficiency viruses. 1657 Aug 27


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