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)

AZT is widely used in combination with other potentially myelotoxic drugs. Bone marrow suppression may limit the vigor of therapy directed at HIV itself, opportunistic infections, and/or AIDS-associated malignancies. Evidence from an HL60 model suggests that toxicity is of most concern with simultaneous use of multiple agents, and that staggered use of different agents may in some cases be a more effective strategy.
Res Commun Mol Pathol Pharmacol 1995 Dec
PMID:AZT modulation of trimetrexate myelotoxicity: evidence from an HL60 model. 874 86

Mutations that confer resistance to nucleoside analogs do not cluster around the deoxynucleotide triphosphate (dNTP) binding site. Instead, these mutations appear to lie along the groove in the enzyme where the template-primer binds. Based on such structural data and on complementary biochemical analyses, it has been suggested that resistance to nucleoside analogs involves repositioning of the template-primer. We have prepared mutations in HIV-2 RT that are the homologs of mutations that confer resistance to nucleoside analogs in HIV-1 RT. Analysis of the behavior of HIV-2 RT mutants (Leu74Val, Glu89Gly, Ser215Tyr, Leu74Val/Ser215Tyr and Glu89Gly/Ser215Tyr) in vitro confirms the results obtained with HIV-1 RT: resistance is a function of the length of the template overhang. These analyses also suggest that the homolog in HIV-2 RT of one of the mutations that confers resistance to AZT in HIV-1 RT (Thr215Tyr) confers resistance by repositioning of the template-primer.
J Mol Biol 1997 May 09
PMID:Analysis of HIV-2 RT mutants provides evidence that resistance of HIV-1 RT and HIV-2 RT to nucleoside analogs involves a repositioning of the template-primer. 917 Dec 88

We have conducted a retrospective study of 100 HIV-infected patients enrolled in an AZT monotherapy clinical study at the Medical College of Georgia (MCG) in Augusta, Georgia. When compared to the national trends, our results confirm previous studies that describe an overall increase in the burden of HIV infections among blacks, and, in particular, black women in the rural Southeast. In our cohort, infections due to homosexual contact accounted for approximately 40% of all cases while heterosexual contact and intravenous drug use (IDU) comprised 33% and 13%, respectively. Infections attributable to all other risk factors accounted for the remaining 14%. Relative to national surveillance data, we observed an increase in the prevalence of HIV infections among blacks, and heterosexually acquired infections, particularly among black women. Our analysis illustrates the dynamic nature of the current U.S. epidemic which appears to be shifting both in terms of its demographic and epidemiological profile. These data may indicate that national surveillance data may not reflect the dynamic nature of current demographic trends in HIV incidence, particularly as evidenced in the rural Southeast. This suggests that hospital or laboratory based cross-sectional studies, like ours, that analyze demographic variables of HIV-infected clinic attendees may be necessary to more accurately assess the leading edge of the HIV epidemic in rural, non-metropolitan areas.
Cell Mol Biol (Noisy-le-grand) 1997 Nov
PMID:Epidemiology of HIV-1 infection in rural Georgia: demographic trends and analysis at the Medical College of Georgia. 944 42

Resistance of HIV-1 reverse transcriptase (RT) to nucleoside analogs (e.g. AZT, ddC and 3TC) is conferred by various amino acid substitutions or combinations thereof on the RT molecule. The M184V mutation, that confers high and low-level resistance to 3TC and ddC, respectively, can restore sensitivity to AZT when introduced into RT against a background of AZT-resistance. The K65R mutation, that confers low level resistance to both 3TC and ddC, can also restore sensitivity to AZT. This information is of potential utility in choosing combinations of anti-viral drugs for clinical use. To explore this subject further, we have used an endogenous RT reaction to study mutated viruses containing M184V alone or M184V combined with each of the K65R, E89G or both the M41L and T215Y substitutions. Endogenous assays possess the advantage of utilizing genomic RNA as template in a reaction mixture that includes each of tRNALys.3 and viral nucleocapsid protein, necessary for specific initiation of reverse transcription, as well as all other viral proteins that might impact on this process. We now show that viruses containing both M184V and K65R displayed synergistic resistance to 3TC triphosphate (3TCTP), while the same combination yielded the same level of resistance to ddC triphosphate (ddCTP) as that manifested by K65R alone. The combination of M184V and E89G displayed synergistic resistance against ddCTP but not 3TCTP, while viruses containing only E89G were highly resistant to 3TCTP and displayed low-level resistance to ddCTP. The results show that endogenous RT assays can reveal variable synergistic, antagonistic, or neutral effects in regard to drug sensitivity, depending on the presence of specific amino acid substitutions in RT itself.
J Mol Biol 1998 Mar 27
PMID:Endogenous reverse transcriptase assays reveal synergy between combinations of the M184V and other drug resistance-conferring mutations in interactions with nucleoside analog triphosphates. 951 45

The key factor for the treatment of post-transfusion graft-versus-host disease (PT-GVHD) is the successful eradication of donor-derived cytotoxic T cells (CTLs) which are thought to be a main cause of the disease, with no effects on either peripheral blood mononuclear cells (PBMCs) or tissues of the recipient. In this study, we examined the effect of azidothymidine (AZT: Zidovudine) on resting PBMCs and cultured fibroblast cells which are assumed to be patient cells, and alloreactive CD8(+)-CTL clones which are imagined to be donor-derived activated CTLs, in vitro. We show here that AZT has no effect on resting PBMCs and cultured fibroblast cells, but greatly inhibited the growth of CTL clones.
Res Commun Mol Pathol Pharmacol 1998 May
PMID:Differential effect of azidothymidine on resting and activated cells: potentiality of this drug for treatment of post-transfusion graft-versus-host disease. 966 67

AZT, a widely-utilized drug for the treatment of HIV infection, inhibits the polymerase responsible for mitochondrial DNA replication (mtDNA). The aim of this study was to assess myocardial alterations caused by this action. Ventricular muscle from rats treated for > or = 35 days with 1 mg/ml of AZT in their drinking water was analysed for cytochrome oxidase activity and the content of mRNAs for the nuclear-encoded cytochrome oxidase (COX) subunit VIc and the mitochondrial-encoded COX subunit III. In addition contractile protein expression was assessed by examining mRNA levels for alpha- and beta-myosin heavy chains (MHC). Changes in MHC mRNA levels were correlated with changes in alpha- and beta-MHC proteins and changes in myofibrillar ATPase activity. Results show that AZT caused a reduction in COX activity, COX subunit III mRNA, and mtDNA levels. There was no decrease in the COX subunit VIc mRNA. MHC expression was altered such that the relative content of beta-MHC protein and mRNA were increased. Accumulation of beta-MHC was reflected in the reduction of myofibrillar ATPase activity at pCa values of 5.875 and 6.125. These data demonstrate that AZT induces a reorganization of cardiac gene expression indicative of changes in cardiac contractile properties. The observed decreases in mtDNA levels along with mRNA for a mitochondrial-encoded protein and COX activity is consistent with the postulated mechanism whereby AZT induces a myopathy by diminishing mtDNA replication.
J Mol Cell Cardiol 1998 Oct
PMID:AZT decreases rat myocardial cytochrome oxidase activity and increases beta-myosin heavy chain content. 979 52

Biology of HIV-1 associated neoplasias is modulated by viral and host factors. In addition the development of tumors and their response to therapy may be further influenced by long-term treatment of HIV-1 patients with nucleoside analogs such as AZT (3'-azido-3'deoxythymidine), ddI (2',3'-dideoxyinosine), ddC (2',3'-dideoxycytidine), d4T (2',3'-didehydro-2'3'-dideoxythymidine), and 3TC [(-)-beta-L-2',3'-dideoxy-3'-thiacytidine] alone or in combination. As these compounds can trigger mechanisms involved in chemoresistance, we tested whether prolonged in vitro treatment of H9 cells (T-cell lymphoma) with AZT alters sensitivity of lymphoma cells to antitumor agents used for AIDS-associated malignancies. H9 cells grown for more than two years in medium containing 250 microM AZT developed resistance to the toxic effects of AZT while retaining sensitivity for other nucleoside analogs including ddC or cytosine arabinoside (ARA-C). These cells designated H9rAZT250 were 2 to 10-fold less sensitive to the toxic effects of antitumor agents, including cisplatin (CDDP), vincristine (VCR), doxorubicin (DOX) and etoposide (VP-16), when compared with parental H9 cells. The resistance of H9rAZT250 cells to antitumor agents was associated with inhibition of apoptosis as demonstrated by ultrastructural investigations and DNA-fragmentation assay (ELISA). The expression of the antiapoptotic gene bcl-2 was increased in H9rAZT250 cells while expression of other genes involved in the regulation of apoptosis such as c-myc, p53 and Fas was not changed. These results demonstrate that prolonged in vitro treatment of H9 lymphoma cells with AZT results in the development of resistance to antitumor agents in association with inhibition of apoptosis and increased expression of bcl-2. Therefore AZT long-term treatment of some HIV-1 patients with malignancies may have affected behavior of tumor cells including response to therapy.
Int J Mol Med 1998 Dec
PMID:Azidothymidine resistance of H9 human T-cell lymphoma cells is associated with decreased sensitivity to antitumor agents and inhibition of apoptosis. 985 Jul 37

The mitochondrial myopathy associated with long-term AZT therapy limits the clinical efficacy of this drug in AIDS therapy. Thus, in order to determine how AZT can affect mitochondria bioenergetics, the capability of AZT to both uncouple oxidative phosphorylation and inhibit electron flow in isolated rat liver mitochondria was investigated. The failure of AZT to oxidize intramitochondrial pyridine nucleotides, to stimulate mitochondrial swelling in K+-acetate plus valinomycin or to cause ATP hydrolysis shows that AZT is not an uncoupler.
Int J Mol Med 1998 Mar
PMID:AZT side effect on mitochondria does not depend on either inhibition of electron flow or mitochondrial uncoupling. 985 71

The replication of recombinant multidrug-resistant HIV-1 clones modeled on clinically derived resistant HIV-1 strains from patients receiving long-term combination therapy with zidovudine (AZT) plus 2',3'-dideoxycytidine was found to regain sensitivity to AZT and stavudine (D4T) as a consequence of a pharmacologically induced decrease in de novo dTMP synthesis. The host-cell system used was phytohemagglutinin-stimulated peripheral blood mononuclear cells; dTMP and dTTP depletion were induced by single exposures to a low level of the thymidylate synthase inhibitor 5-fluorouracil (5-FU) or its deoxynucleoside, 2'-deoxy-5-fluorouridine. The host-cell response to the latter was biphasic: a very rapid decrease in the rate of de novo dTMP formation and, consequently, in intracellular dTTP pools, followed by slower recovery in both indices over 3 to 24 h. With the additional presence of AZT or D4T, however, replication of the multidrug-resistant HIV-1 strains remained inhibited, indicating dependence of HIV DNA chain termination by AZT-5'-monophosphate or 2',3'-didehydro-2', 3'-dideoxythymidine-5'-monophosphate in these resistant strains on simultaneous inhibition of host-cell de novo synthesis of thymidine nucleotides. No effect on viability of control (uninfected) phytohemagglutinin-stimulated/peripheral blood mononuclear cells was noted on 6-day exposures to 5-FU or 2'-deoxy-5-fluorouridine alone or in combination with AZT or D4T, even at drug levels severalfold higher than those used in the viral inhibition studies. These studies may provide useful information for the potential clinical use of AZT/5-FU or D4T/5-FU combinations for the prevention or reversal of multidrug resistance associated with long-term dideoxynucleoside combination therapy.
Mol Pharmacol 1999 Mar
PMID:Suppression of replication of multidrug-resistant HIV type 1 variants by combinations of thymidylate synthase inhibitors with zidovudine or stavudine. 1005 38

The administration of CycloSaligenyl 3'-azido-2',3'-dideoxythymidine monophosphate (CycloSal-AZTMP) to CEM cells resulted in a concentration- and time-dependent conversion to the 5'-monophosphate (AZTMP), 5'-diphosphate (AZTDP), and 5'-triphosphate (AZTTP) derivatives. High ratios of AZTMP/AZTTP were found in the CEM cell cultures treated with CycloSal-AZTMP. The intracellular T(1/2) of AZTTP in CEM cell cultures treated with either AZT and CycloSal-AZTMP was approximately 3 h. A variety of human T- and B-lymphocyte cell lines efficiently converted the prodrug to the AZT metabolites, whereas peripheral blood lymphocytes and primary monocyte/macrophages showed at least 10-fold lower metabolic conversion of the prodrug. CycloSal-AZTMP failed to generate marked levels of AZT metabolites in thymidine kinase-deficient CEM/TK(-) cells, an observation that is in agreement with the substantial loss of antiviral activity of CycloSal-AZTMP in CEM/TK(-) cells. The inability of CycloSal-AZTMP to generate AZTMP in CEM/TK(-) cells is presumably due to a relatively high hydrolysis rate of AZTMP to the parent nucleoside AZT, combined with the inability of CEM/TK(-) cells to phosphorylate AZT to AZTMP through the cytosolic salvage enzyme thymidine kinase.
Mol Pharmacol 1999 Dec
PMID:Intracellular metabolism of CycloSaligenyl 3'-azido-2', 3'-dideoxythymidine monophosphate, a prodrug of 3'-azido-2', 3'-dideoxythymidine (zidovudine). 2008 Sep 48


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