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

Revistin, a substance that strongly inhibits the reverse transcriptase activity of murine leukemia virus in our screening system, was obtained from a cultured broth of a soil streptomyces which was closely related to Streptomyces filipinensis. The assay method for the activity was based on the inhibition by a test material of the incorporation of 3H-dTMP into DNA synthesized by the reverse transcriptase of an oncogenic RNA virus. Crude revistin was isolated by serial procedures of salting out with ammonium sulfate and precipitation with cetylpyridinium chloride. The crude material showed neither antibacterial nor antifungal activity. It exhibited against splenomegaly in mice caused by Rauscher leukemia virus infection.
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PMID:Revistin found by screening for inhibitors of reverse transcriptase of an oncogenic virus. 5 48

The reverse transcriptase was purified to homogeneity from Rauscher leukemia virus by sequential column chromatography on phosphocellulose and DNA-cellulose. The purified enzyme, a single polypeptide chain with a molecular weight of approximately 70,000, interacts with major internal protein p30 of the same virus. The reverse transcriptase - p30 complex stimulated [3H]TMP incorporation into (dT)12 - (rA)n 2- to 3-fold compared to that observed with the purified enzyme alone. Monospecific antiserum made against either p30 or reverse transcriptase precipitated the entire complex. The sedimentation rate of the reverse transcriptase - p30 complex is approximately 12 S as estimated by glycerol gradient centrifugation, and the molecular weight is approximately 400,000 by chromatography on a Sepharose 6B column. The complex dissociates into its original components when treated with 0.8 M KCl.
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PMID:Effect of Rauscher leukemia virus-specific proteins on reverse transcriptase. Binding between reverse transcriptase and p30. 6 27

Modern advances in the development of antimicrobial agents and in chemotherapy have made available potent aminoglycoside antibiotics, with more effective ones to come. Their effectiveness against P. aeruginosa is a great contribution to patients with cystic fibrosis and other chronic disorders. The development of carbenicillin has augmented the effectiveness of the aminoglycoside antibiotics. Ticarcillin is similar to carbenicillin and will play a similar role in antibiotic therapy. The cephalosporins serve as alternative agents principally for their antistaphylococcal activity. We are urgently in need of a potent antibiotic agent against P. aeruginosa that can be given by the oral route. The TMP-SMX combination is a potent chemotherapeutic agent that can be administered by the oral route. It is effective in the treatment of P. carinii pneumonia, which is very common owing to the extended survival of patients with leukemia and other malignancies or with allografts who are prone to develop infections with immunosuppressive therapy.
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PMID:The use of new antibiotic agents for chronic pulmonary disease. 61 46

Thymidylate synthetase (EC 2.1.1) from in vitro 3-methylcholanthreneor Rauscher leukemia virus-transformed rat embryo cells was studied. The enzyme from control or transformed rat cells exhibited a Km for 2'-deoxyuridylic acid of 4.5 +/- 0.2 muM, but the transformants had a higher level of enzyme activity than did control cells. Titration of the enzyme with tritiated 5-fluoro2'-deoxyuridylic acid indicated that the increased enzyme activity in the transformants was due to a greater level of cellular enzyme. While the level of enzyme activity in control cells was dependent on both the availability of nutrients in the medium and cell density, the level of enzyme activity in the transformants appeared to depend only on the availability of nutrients.
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PMID:Thymidylate synthetase of in vitro chemically and virally transformed rat cells. 124 99

A 45-year-old woman was admitted to our hospital with complaints of fever and lumbago. She was treated for adult T-cell leukemia and thrombocytopenia with 20 mg/day of prednisolone. CT scan showed multiple abscesses in right peri-kidney, right iliopsoas muscle, left subcutaneous region in the abdominal wall and the brain. Left subcutaneous abscess was drained. Gram-positive organisms consisting of filaments were found, and Nocardia farcinica was grown in cultures. After two months of chemotherapy (FMOX, MINO and AMK), all abscesses except one in the brain disappeared. Cerebral abscess was cured fifty days after the start of the treatment with oral administration of Sulfamethoxazole-trimethoprim (SMX/TMP). The mortality of Nocardial cerebral abscess is high. This patient is a very rare case in which multiple Nocardial abscesses including brain abscess was cured by chemotherapy.
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PMID:[A case of adult T-cell leukemia (ATL) complicated with multiple nocardial abscesses]. 179 47

The inhibition of de novo nucleotide, serine, and methionine biosynthesis in mammalian cells treated with antifolates has been attributed generally to a reduction in the levels of tetrahydrofolate cofactors. In L1210 leukemia cells grown in tritiated folic acid (1 microM), most of the endogenous radiolabeled folates were present as formyl-substituted tetrahydrofolates (60-73%, including 10- and 5-formyl and 5,10-methenyl tetrahydrofolate), with lower levels of tetrahydrofolate (including 5,10-methylene tetrahydrofolate), 5-methyl tetrahydrofolate, and non-metabolized folic acid. Trimetrexate (1 microM) caused an elevation of dihydrofolate levels within 5 min following drug addition, from approximately 1 to 20% of the total folates. Whereas total reduced folates were preserved, losses in the levels of individual forms ranged from minor changes in the formyl tetrahydrofolates (approx. 10% decrease), to significant losses in the levels of tetrahydrofolate (approx. 60%) and 5-methyl tetrahydrofolate (95%). Under these conditions, the incorporations of [3H]deoxyuridine into TMP and [14C]glycine into purines or of [14C]formate into biosynthetic products were inhibited (69-95%). The majority (59-100%) of the endogenous radiolabeled folates in L1210 cells grown in various concentrations (0.2 to 3 microM) of [3H]folic acid was bound to soluble intracellular proteins when cell-free extracts were fractionated by rapid gel filtration or charcoal adsorption. Total intracellular folate levels increased in proportion to the changes in medium folic acid concentration; however, cofactor binding was saturable. At low concentrations, below that which supported maximal growth (less than 0.75 microM), all of the intracellular folates were protein-bound; only when maximal growth was achieved, could unbound folates be detected. Incubation with trimetrexate (1 or 10 microM), methotrexate (10 microM), or calcium leuvovorin (50 microM) did not alter significantly the levels of total and protein-bound [3H]folates in cells grown in 1 microM [3H]folic acid. Under all conditions, formyl tetrahydrofolates were the major intracellular derivatives; however, these forms were poorly represented in the bound fraction. Conversely, all of the other intracellular folate forms were completely bound. Tetrahydrofolate was the predominant protein-bound derivative in control cells; in antifolate-treated cells, both bound tetrahydrofolate and 5-methyl tetrahydrofolate were largely replaced by protein-bound dihydrofolate. This interconversion in drug-treated cells was independent of (i) sustained levels of [3H]formyl tetrahydrofolates, or (ii) high extracellular concentrations of unlabeled calcium leucovorin (50 microM). Hence, protein-bound tetrahydrofolates must not only be substrates for enzyme mediated reactions (i.e. TMP synthesis) but also must slowly equilibrate with unbound cofactor. In this fashion, binding of endogenous folates to soluble proteins may function to "segregate' intracellular cofactor pools.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Evidence for a localized conversion of endogenous tetrahydrofolate cofactors to dihydrofolate as an important element in antifolate action in murine leukemia cells. 214 Dec 58

Because trimethoprim-sulfamethoxazole (TMP-SMX) causes neutropenia in children with leukemia, we investigated the possibility that pharmacokinetic interaction between methotrexate (MTX) and TMP-SMX causes accumulation of the antileukemia agent. We studied the pharmacokinetics of MTX given intravenously or orally to nine children with acute lymphoblastic leukemia, once with and once without TMP-SMX. There was an increase in free MTX fraction during TMP-SMX therapy in all patients, from (mean +/- SD) 37.4 +/- 11% without TMP-SMX to 52.2 +/- 6.4% with TMP-SMX (p less than 0.01). Plasma clearance of total MTX did not change significantly, whereas clearance of free MTX decreased significantly (from 12.5 +/- 4 to 7.6 +/- 1.5 ml/kg/min; p less than 0.05). There was a consistent decrease in the renal clearance of free MTX (from 12.1 +/- 6.8 to 5.6 +/- 2.4 ml/kg/min; p less than 0.05). Elimination half-life of MTX was not affected significantly by TMP-SMX. There was a significant correlation between serum concentrations of TMP-SMX and the percentage of decrease in the renal clearance of free MTX (r = 0.91; p less than 0.05). These changes in protein binding and tubular clearance of MTX, caused by competition with TMP-SMX, result in a mean 66% increase in systemic exposure to MTX and may explain the myelotoxicity often observed with the coadministration of the two drugs.
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PMID:Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia. 223 Dec 18

We have studied the roles of 5,10-methylenetetrahydrofolate (5,10-methylene-H4PteGlu) depletion and dihydrofolate (H2PteGlu) accumulation in the inhibition of de novo thymidylate synthesis by methotrexate (MTX) in human MCF-7 breast cancer cells. Using both a high pressure liquid chromatography system and a modification of the 5-fluoro-2'-deoxyuridine-5'-monophosphate radioenzymatic binding assay, we determined that the 5,10-methylene-H4PteGlu pool is 50-60% depleted in human MCF-7 breast cancer cells following exposure to 1 micron MTX for up to 21 h. Similar alterations in the 5,10-methylene-H4PteGlu pools were obtained when human promyelocytic HL-60 leukemia cells and normal human myeloid precursor cells were incubated with 1 micron MTX. The H2PteGlu pools within the MCF-7 cells increased significantly after 15 min of 1 micron MTX exposure, reaching maximal levels by 60 min. Thymidylate synthesis, as measured by labeled deoxyuridine incorporation into DNA, decreased to less than 20% of control activity within 30 min of 1 micron MTX exposure. The inhibition of thymidylate synthesis coincided temporally with the rapid intracellular accumulation of H2PteGlu, a known inhibitor of thymidylate synthase. Furthermore, inhibition of this pathway was associated in a log-linear fashion with the intracellular level of dihydrofolate. These studies provide further evidence that depletion of the thymidylate synthase substrate 5,10-methylene-H4PteGlu is inadequate to account completely for diminished thymidylate synthesis resulting from MTX treatment. Our findings suggest that acute inhibition of de novo thymidylate synthesis is a multifactorial process consisting of partial substrate depletion and direct enzymatic inhibition by H2PteGlu polyglutamates.
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PMID:Mechanism of thymidylate synthase inhibition by methotrexate in human neoplastic cell lines and normal human myeloid progenitor cells. 234 91

A 66-year-old woman was admitted to the Medical College Hospital of Oita on February 23, 1988, because of headache and fever. Chest X-P and chest CT findings showed a coin lesion in r-S4. Cryptococcus neoformans was isolated from the CSF. Abnormal lymphocytes with lobulated nuclei were found in 0-5% of peripheral leukocytes. The ATLA-antibody was positive and bone marrow smear showed normal myelogram. According to these data, we diagnosed the patient as smouldering adult T-cell leukemia accompanied with pulmonary cryptococcosis and cryptococcal meningitis. C. neoformans disappeared from the CSF and cryptococcal antigen was not detectable after Amphotericin B and Flucytosine treatment. On April 1, the patient complained of a dry cough, high fever and dyspnea. A chest X-ray showed bilateral patchy infiltrations. By the methenamine silver staining, cysts of Pneumocystis carinii were found in the specimens of transbronchial lung biopsy and bronchoalveolar lavage fluid. The abnormal shadow on chest X-ray disappeared after TMP-SMX and aerosolised pentamidine treatment.
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PMID:[A case of adult T-cell leukemia with pulmonary cryptococcosis, cryptococcal meningitis and Pneumocystis carinii pneumonia]. 250 95

The therapeutic efficacy of 5-fluorouracil (FUra) and cis-dichlorodiamine-platinum (cis-DDP) in mice bearing transplantable leukemia and solid tumors was evaluated using different sequences of combination of these agents. The optimal sequence was cis-DDP administered 24 h after FUra. The administration of FUra at its maximally tolerated dose (MTD) followed 24 h later by low doses of cis-DDP yielded less toxicity and higher response rate against L1210 and colon 26 than the administration of these two agents in the opposite sequence or concurrently at the MTD. The sequence of administration of these two agents was not therapeutically important when the antitumor activity was evaluated against mice bearing lymphoma P388. These results indicate that the importance of sequencing of FUra and cis-DDP varies among different tumors. The biochemical basis for the therapeutic importance of sequencing in treatments with cis-DDP and FUra was investigated in mice bearing leukemia L1210 cells. While cis-DDP has no significant effects on the activity of thymidylate synthase (dTMP-S), the target enzyme for FUra action, recovery of dTMP-S inhibition following pretreatment with FUra was significantly delayed when cis-DDP was administered 12-24 h after the initial dose of FUra.
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PMID:The role of drug sequence in therapeutic selectivity of the combination of 5-fluorouracil and cis-platin. 262 82


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