Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

3'-Azido-2',3'-dideoxy-5-methylcytidine (CS-92, AzddMeC) is an antiviral nucleoside analogue structurally related to 3'-azido-3'-deoxythymidine (AZT). CS-92 is a potent and selective inhibitor of HIV-1 reverse transcriptase and HIV-1 replication in human lymphocytes and macrophages. The EC50 for CS-92 in HIV-1-infected human PBM cells was 0.09 microM. In HIV-1-infected human macrophages, the EC50 was 0.006 microM. This compound was also effective against human immunodeficiency virus type 2 in lymphocytes. The replication of Friend murine virus was only weakly inhibited, and no effect was observed against herpes simplex virus type 1 and type 2 and coxsackievirus B4. CS-92 was not toxic to PBM or Vero cells when tested up to 200 microM and was, furthermore, at least 40 times less toxic to granulocyte-macrophage and erythroid precursor cells in vitro than was AZT. The interaction of the 5'-triphosphate of CS-92 with HIV-1 reverse transcriptase indicated competitive inhibition (the inhibition constant, Kis, was 0.0093 microM) with a 30-fold greater affinity for CS-92-TP than for ddCTP. CS-92-TP inhibited HIV-1 reverse transcriptase by 50% at a concentration 6,000-fold lower than that which was required for a similar inhibition of DNA polymerase alpha. Pharmacokinetic studies showed that CS-92 was not deaminated to AZT in rats, but this compound was found to have a half-life of 2.7 hours. In rhesus monkeys, however, a compound with a retention time and ultraviolet spectra characteristics similar to AZT was detected. The mean half-life in rhesus monkeys for CS-92 was 1.52 and 1.74 h after intravenous and oral administration, respectively, and the oral bioavailability was about 21 percent. Additional preclinical studies with CS-92 will determine the ultimate utility of this antiviral agent for the treatment of HIV-1 infections.
 ...
PMID:Antiretroviral activity, biochemistry, and pharmacokinetics of 3'-azido-2',3'-dideoxy-5-methylcytidine. 170 74

In these studies, heat radiosensitization in normal human colony-forming unit-granulocyte-macrophage (CFU-GM) and several different leukemic cell lines sensitive or resistant to chemotherapeutic agents were measured. Extent of heat radiosensitization was then correlated with the level of DNA polymerases alpha and beta in control and heat-shocked cells in order to examine whether there is a positive correlation between the degree of heat radiosensitization and the level of these enzymes. Our results show that human bone marrow CFU-GM have an x-ray response with D0 of 1.56 Gy and a small amount of heat radiosensitization with a thermal enhancement ratio (TER) of 1.2. K562, a human erythroleukemic cell, showed a D0 of 1.32 +/- 0.2 Gy and TER of 1.4. However, in contrast to normal CFU-GM which showed no shoulder in the X-ray survival curve, K562 cells showed a small shoulder with a quasi-threshold dose, (Dq) of 2 Gy and n of 2. K562 cells resistant to chemotherapeutic drugs such as 1-beta-D-arabinofuranosylcytosine and etoposide (VP-16) showed D0 of 1.47 +/- 0.13, and 1.77 +/- 0.18 Gy; Dq of 4 and 0 Gy; and n of 5 and 1; and TER of 1.6 and 2, respectively. The level of DNA polymerases alpha and beta activity and their respective mRNA levels were approximately the same in all cells. The reduction in the level of DNA polymerase beta after heat treatment however, correlated with the TER obtained for various leukemic cells. These studies indicate that normal CFU-GM and variety of human leukemic cells show only a small amount of heat radiosensitization. However, drug-resistant leukemic cells show a higher amount of heat radiosensitization than their drug-sensitive parent line. This suggests that hyperthermia may be beneficial in eradicating drug-resistant leukemic cells when combined with X-ray. Furthermore, the inactivation of DNA polymerase beta activity results in a higher amount of heat radiosensitization.
 ...
PMID:Heat radiosensitization and the level of DNA polymerases alpha and beta of human colony-forming unit-granulocyte-macrophage and myeloid leukemias sensitive and resistant to chemotherapeutic agents. 231 94

Estrogens have been reported to modulate immunologic responses at both physiologic and pharmacologic concentrations. Treatment of experimental animals with the synthetic estrogen, diethylstilbesterol (DES), markedly decreases thymic cellularity, manifested histologically as a progressive loss of cortical thymic lymphocytes. In the present report thymic atrophy after prenatal DES exposure was found to be more severe than has been reported following adult exposure, indicating a possible greater sensitivity of the developing immune system to estrogenic hormones. DES exposure resulted in a limited alteration of cell maturation within the fetal thymus as evidenced by only slight alterations in the expression of CD4 and CD8 cell-surface antigens. To examine the possibility that DES targets hematopoietic stem cells in the fetal liver, cytometric analysis was conducted using a panel of fluorescent antibodies to quantitate the hematopoietic subpopulations present in control and DES-exposed Gestational Day (gd) 18 fetal mouse liver. There were no significant DES-induced alterations in the number of hematopoietic stem cells, or in fetal liver cells expressing CD44 (hematopoietic precursors), Mac-1 (granulocyte-macrophage lineage precursors), or CD45R (B-lineage lymphocytes) surface antigens. However, DES selectively reduced the number of fetal liver precursors containing the lymphocyte stem cell-specific DNA polymerase, terminal deoxynucleotidyl transferase, which suggested that DES may specifically target the fetal liver prothymocyte. Reconstitution of irradiated hosts with gd 18 fetal liver from vehicle and DES-exposed syngeneic donors demonstrated an impaired ability of the DES-treated fetal liver to repopulate the thymus of irradiated hosts. In addition, fetal liver cells enriched for prelymphoid cells contained potentially significant levels of estrogen specific receptors. Taken together these data, in conjunction with the lack of direct thymocyte injury (necrosis, apoptosis, and/or inhibition of cell proliferation) by DES treatment, suggest that estrogen-mediated thymic atrophy may result, at least in part, from a specific alteration in the lymphocyte stem cell population responsible for colonizing the thymus.
 ...
PMID:Selective prothymocyte targeting by prenatal diethylstilbesterol exposure. 824 56