Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Seven patients with adult T-cell leukaemia/lymphoma (ATL) were treated with a combination of zidovudine (AZT) and interferon after failed chemotherapy. One patient showed a major response for nine months. The remainder showed progressive disease further complicated by drug toxicity. The poor responses could be explained by patient selection, since most patients had advanced disease refractory to chemotherapy. A larger more protracted study is required for further evaluation of this treatment option.
 ...
PMID:Zidovudine and interferon therapy for adult T-cell leukaemia/lymphoma. Results of a preliminary study at UHWI-Mona. 903 28

At present, 3'-azido-3'-deoxythymidine (AZT; zidovudine) remains the drug of choice for initiating AIDS therapy. This drug in itself is inactive; it needs to be converted intracellularly by a series of cellular kinases to AZT 5'-triphosphate (AZT-TP) to exert antiviral activity. The purpose of this study was to examine the in vivo disposition of the phosphorylated AZT anabolites in different target tissues and to investigate the effects of chronic retrovirus infection on the tissue disposition of AZT anabolites. Female C57BL/6 mice at 20 weeks after inoculation with LP-BM5 murine leukemia virus, as well as age-matched control animals, were dosed subcutaneously with 25 mg/kg of AZT. The dosing solution contained [3H]AZT with a specific activity of 87 mCi/mmol. The levels of AZT and its phosphorylated anabolites were determined in tissues collected at different times after AZT administration using an analytical method coupling an ion-pair HPLC separation procedure with radioactivity detection after the separation. The tissue-to-plasma AZT ratios in control mice could be ranked in the following order: kidneys > muscle approximately equal to spleen approximately equal to liver approximately equal to heart approximately equal to lung > thymus > lymph nodes > brain. Similar rank order was observed in infected animals, with the exception that significantly higher AZT levels were found in the lymph nodes, where the tissue-to-plasma AZT ratios in lymph nodes were higher than those in thymus tissues. Tissue AZT 5'-monophosphate profiles tended to parallel the AZT profiles in most tissues examined. Delays in the appearance of AZT 5'-diphosphate and AZT-TP were observed in all tissues tested. AZT-TP content was not detectable in any of the brain samples analyzed. The conversion of AZT to AZT anabolites was found to be highest in the spleen and bone marrow samples from both control and infected animals. Lymph nodes of the control animals showed poor ability to phosphorylate AZT to its active triphosphate moiety. This ability was significantly enhanced in infected animals. We concluded that the in vivo disposition of AZT anabolites after a single dose administration of AZT is tissue-specific in mice and that experimentally induced chronic retrovirus infection resulted in the most significant changes in the distribution of AZT into the lymph nodes and in the phosphorylation of AZT in this important target tissue. Further studies are needed to relate the tissue-specific disposition of AZT anabolites to the therapeutic problems encountered with AZT treatment.
 ...
PMID:In vivo tissue disposition of 3'-azido-3'-deoxythymidine and its anabolites in control and retrovirus-infected mice. 910 39

Originally designed as an antitumor agent, zidovudine (AZT) has exhibited only marginal tumor growth inhibitory activity. Recently, three abstracts have described positive clinical outcomes for a small number of patients with advanced breast cancer treated with weekly infusions of either methotrexate or cisplatin and AZT. Consequently, we conducted a preclinical study of the anti-breast cancer and anti-mammary tumor activity of AZT. Here we have demonstrated that AZT, alone, has a preferential in vitro and in vivo effect on breast and mammary cancer cells. It is 1000 times as potent as an inhibitor of the in vitro growth of the human breast cancer cell line MCF-7 (IC50 = 10 +/- 5 nM) than of the growth of the T-cell leukemia cell line CEM (IC50 = 14 +/- 2 microM). A novel mechanism for this preferential effect on growth is indicated by the 3-4-fold increase in production of phosphorylated AZT (mono-, di-, and triphosphate) in MCF-7 relative to CEM. We extended these in vitro observations to in vivo studies in rats and found that AZT is a potent in vivo inhibitor of the growth of methylnitrosourea-induced rat mammary tumors without any apparent toxic effects on internal organs. These preclinical results demonstrate, for the first time, that AZT has significant anti-breast cancer activity and strongly suggest that the clinical usefulness of this drug is worthy of investigation.
 ...
PMID:Potent growth inhibitory activity of zidovudine on cultured human breast cancer cells and rat mammary tumors. 919 4

HIV-infected individuals, who received 3TC monotherapy over one year, generally had lower plasma viral burden than at base-line. This was in spite of high-level resistance to this compound and the appearance of the M184V substitution in the HIV reverse transcriptase (RT) gene, responsible for diminished sensitivity to 3TC. This apparent contradiction is explained by an increase in the fidelity of the HIV RT, conferred by the M184V mutation, on the basis of the following observations. First, titers of viral neutralizing antibodies, as measured against sequential autologous HIV isolates, remained stable in this population in contrast to rapid declines in patients treated with other drugs. This suggests that increased fidelity of M184V RT may limit variability in the HIV env gene and result in protracted effectiveness of anti-viral immune responsiveness. Second, recombinant HIV, that contained the M184V substitution in RT, could not replicate in the presence of d4T, AZT, Nevirapine, Delavirdine or Saquinavir, using previously described protocols for the generation of drug resistance in vitro.
Leukemia 1997 Apr
PMID:Increased fidelity of drug-selected M184V mutated HIV-1 reverse transcriptase as the basis for the effectiveness of 3TC in HIV clinical trials. 920 7

AZT has induced a macrocytic anemia in AIDS patients on long term AZT therapy. It is generally assumed that DNA elongation is stopped by the insertion of AZT into the chain in place of thymidine thus preventing the phosphate hydroxyl linkages and therefore suppresses hemopoietic progenitor cell proliferation in an early stage of differentiation. CBA/Ca male mice started on AZT 0.75 mg/ml H2O at 84 days of age and kept on it for 687 days when dosage reduced to 0.5 mg/ml H2O for a group, another group removed from AZT to see recovery, and third group remained on 0.75 mg. At 687 days mice that had been on 0.75 mg had average platelet counts of 2.5 x 10(6). Histological examination on 9 of 10 mice with such thrombocytopenia showed changes compatible with myelodysplastic syndrome (MDS). A variety of histological patterns was observed. There were two cases of hypocellular myelodysplasia, two cases of hypersegmented myelodysplastic granulocytosis, two cases of hypercellular marrow with abnormal megakaryocytes with bizarre nuclei, one case of megakaryocytic myelosis associated with a hyperplastic marrow, dysmyelopoiesis and a hypocellular marrow and two cases of myelodysplasia with dyserythropoiesis, hemosiderosis and a hypocellular marrow. Above mentioned AZT incorporation may have induced an ineffective hemopoiesis in the primitive hemopoietic progenitor cells, which is known to be seen commonly in the myelodysplastic syndrome.
Leukemia 1997 Apr
PMID:Lifetime treatment of mice with azidothymidine (AZT) produces myelodysplasia. 920 18

The effect of zidovudine (3'-azido-3'-deoxythymidine; AZT) was investigated in four breast cancer cell lines, a T4 cell leukemia, and a normal breast cell line in vitro. AZT inhibited the growth of all tumoral cell lines, but it did so in a wide range of concentrations. The growth of a normal breast cell line was also inhibited, although it required a much higher concentration. Furthermore, AZT inhibited colony formation in soft agar and telomerase activity. These results indicated that AZT can be potentially used, alone or in combination, as an anti-breast cancer agent.
 ...
PMID:Inhibition of cell growth and telomerase activity of breast cancer cells in vitro by 3'-azido-3'-deoxythymidine. 953 39

Several 2,4-diaminopyrimidines have been synthesized and tested for their anticancer and anti-HIV activities. Out of these, eight compounds displayed significant activity against leukemia, melanoma, non-small cell and CNS cancer. Two compounds were active against leukemia P388. One compound has been found to be moderately active as compared to AZT.
 ...
PMID:Synthesis of some new pyrimidine derivatives as potential anticancer and anti-HIV agent. 956 52

Murine AIDS in C57BL/6 mice is caused by a unique mixture of murine leukemia viruses. We report the use of a competitive PCR to detect and quantitate BM5d proviral DNA. This assay allowed discrimination among endogenous wild-type murine retroviruses and BM5d sequences. Furthermore, the method was subsequently used to evaluate the amount of BM5d in infected mice and in infected AZT (zidovudine)-treated mice, providing an effective way to quantitatively evaluate drug efficacy in the murine AIDS model.
 ...
PMID:Competitive PCR for quantification of BM5d proviral DNA in mice with AIDS. 966 28

LP-BM5 murine leukemia virus (MuLV) infection causes severe immunodeficiency termed murine AIDS (MAIDS). The acyclic nucleoside phosphonates, (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA) were examined, in comparison with zidovudine (AZT), for their inhibitory effect on the development of MAIDS. Although no significant difference in inhibition of LP-BM5 MuLV replication was identified between PMPA and PMEA in cell cultures, PMPA was obviously less cytotoxic to the host lymphocytes. None of the mice treated in vivo with 5 or 25 mg/kg of PMPA or 25 mg/kg of PMEA developed MAIDS at 5 weeks after viral infection. However at 9 weeks, none of the 25 mg/kg PMPA-treated mice progressed to MAIDS, except for one that developed mild MAIDS, whereas PMEA, even at 100 mg/kg, could not prevent disease progression. MAIDS-associated activation of lymphocytes and viral replication were drastically inhibited by PMPA treatment. These results indicate that PMPA is a highly effective antiretroviral agent in vivo.
 ...
PMID:Prevention of murine AIDS development by (R)-9-(2-phosphonylmethoxypropyl)adenine. 970 36

Human T-cell lymphotropic virus type I (HTLV-I) is the causative agent of adult T-cell leukemia/lymphoma (ATL). ATL is an aggressive proliferation of mature activated T cells associated with a poor prognosis. The combination of the antiviral agents, zidovudine (AZT) and interferon (IFN), is a potent treatment of ATL. Recently, arsenic trioxide (As) was shown to be an effective treatment of acute promyelocytic leukemia (APL). We have tested the effects of the combination of As and IFN on cell proliferation, cell cycle phases distribution, and apoptosis in ATL-derived or control T-cell lines. A high synergistic effect between IFN and As was observed in ATL-derived cell lines in comparison to the control cell lines, with a dramatic inhibition of cell proliferation, G1 arrest, and induction of apoptosis. Similar results were obtained with fresh leukemia cells derived from an ATL patient. Although the mechanisms involved are unclear, these results could provide a rational basis for combined As and IFN treatments in ATL.
 ...
PMID:Arsenic trioxide and interferon-alpha synergize to induce cell cycle arrest and apoptosis in human T-cell lymphotropic virus type I-transformed cells. 986 71


<< Previous 1 2 3 4 5 6 7 Next >>