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)

Suramin--a well-known antitrypanosomal agent--was found to exert a strong inhibitory effect on the RNA-directed DNA polymerase (reverse transcriptase) activity of several oncornaviruses such as Moloney murine leukemia virus, murine Rauscher leukemia viruses, Moloney murine sarcoma virus and avian myeloblastosis virus. Inhibition of enzyme activity was obtained with both endogenous viral RNA and (A)n . oligo(dT) as the template-primer. Suramin effected a 50% inhibition of the reverse transcriptase activity of oncornaviruses at a concentration range of 0.1--1 microgram/ml. In this aspect it compared favorably to ethidium bromide, another trypanocide drug which is considered as one of the most powerful inhibitors of oncornaviral DNA polymerases. The inhibition of reverse transcriptase activity by suramin was competitive with the template-primer, (A)n . oligo(dT), suggesting that the drug may interact with the template-primer binding site of the enzyme.
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PMID:Suramin: a potent inhibitor of the reverse transcriptase of RNA tumor viruses. 9 62

The new antiviral substance phosphonoformate (PFA) has been tested in a cell-free system for its effect on reverse transcriptases from an avian retrovirus (avian myeloblastosis virus, AMV) and from mammalian retroviruses (Rauscher leukaemia virus, RMuLV; bovine leukaemia virus; baboon endogenous virus; simian sarcoma virus; visna virus). The observed inhibitory effect of PFA has been compared with that of a structurally related substance, phosphonoacetate (PAA). Phosphonoformate, at a concentration of 100 microM, reduced the activities of all the above mentioned polymerases by 90% when (rA)n.(dT)10 was used as a template/primer. The dose-response curves for AMV and RMuLV polymerases primed with (rA)n.(dT)10 showed PFA to be a 1000-fold more active than PAA; the RMuLV polymerase activity was reduced to 50% after incubation with 0.7 microM-PFA and 0.7 mM-PAA, respectively. There was no difference in PFA inhibition of virus-associated and purified reverse transcriptase activity. Results with various synthetic templates showed that both the RNA- and the DNA-dependent polymerase activities of reverse transcriptase were inhibited by PFA. The endogenous polymerase activity of AMV was inhibited to 50% at 100 microM-PFA, while PAA had no effect. The PFA inhibition was dependent on whether Mg2+ or Mn2+ was used as divalent cation in the assay. Phosphonoformate arrested DNA synthesis immediately after being added to the assay system. The mechanism of inhibition of the AMV polymerase was non-competitive with respect to substrate and template and the apparent inhibition constants were 16 microM and 9 microM, respectively.
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PMID:Phosphonoformate inhibits reverse transcriptase. 9 44

The nucleotide sequence of a tRNA primer molecule for initiation of Moloney murine leukemia virus DNA synthesis has been determined. The sequence is heterogeneous in two positions but both forms, when drawn in a cloverleaf structure, have anticodon specificities for proline. We have termed these isoacceptors tRNA1Pro and tRNA2Pro. Aminoacylation studies confirmed the specificity for proline. The two forms occur in approximately equal amounts in uninfected mouse and chicken cells and in Moloney leukemia virus particles.
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PMID:The primer tRNA for Moloney murine leukemia virus DNA synthesis. Nucleotide sequence and aminoacylation of tRNAPro. 11 65

Chlorozotocin, 2-(3-(2-chloroethyl)-3-nitrosoureido)-D-glucopyranose, is a newly synthesized, water-soluble nitrosourea antitumor agent that is active against L1210 leukemia in mice. A 701% and a 401% increase in life-span were attained with a dose that was lethal to 10% of the animals (15 to 20 mg/kg, i.p.) in mice treated on Day 2 or Day 6 of L1210 tumor growth, respectivley. Sixity % of Day 2-treated mice and 30% of Day 6-treated mice survived for 90 days. At the maximally effective dose against L1210, chlorozotocin produced no significant depression in normal bone marrow DNA synthesis nor in peripheral neutrophil count, in contrast to a sustained greater than 90% inhibition in L1210 ascites cell DNA synthesis. If the antitumor activity and reduced bone marrow toxicity of chlorozotocin are confirmed in man the use of this compound would facilitate treatment of patients with neoplastic disease who have preexisting abnormal bone marrow function or would allow for the more effective use of a nitrosourea agent in combination with anticancer agents possessing more potent myelosuppressive properties.
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PMID:Chlorozotocin, 2-(3-(2-chloroethyl)-3-nitrosoureido)-D-glucopyranose, an antitumor agent with modified bone marrow toxicity. 12 70

The role of the macrophage in the guinea pig mixed leukocyte culture was investigated. Macrophages obtained from oil-induced peritoneal exudates, peritoneal wash-out cells, spleen, and alveolar washings were found to be effective stimulators of allogeneic lymph node and splenic lymphocyte DNA synthesis. The stimulatory properties of macrophages proved radioresistant but viability dependent. Unfractionated lymph node cells or adherence column purified lymph node lymphocytes and thymocytes were only minimally active as stimulators, even in the presence of macrophages syngeneic to the responder lymphocytes. Allogeneic fibroblasts, polymorphonuclear leukocytes, L2C leukemia cells, and xenogeneic (murine) macrophages failed to simulate. These data provide evidence that the macrophage is the predominant stimulator of the mixed leukocyte culture in the guinea pig.
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PMID:Macrophage activation of allogeneic lymphocyte proliferation in the guinea pig mixed leukocyte culture. 12 44

DNA-repair and the frequency of chromosome aberration after u.v. and X-ray irradiation was studied on leukocytes from patients with Down's syndrome. The u.v.-induced DNA-repair synthesis was followed by the incorporation of [3H]thymidine in the presence of hydroxyurea. Similar dose-response curves were established for Down's syndrome leukocytes and controls. The cells from patients with Down's syndrome incorporated 70-75% of the activity of control cells at the various doses (32-196 erg/mm.2). This difference was significant for the two highest u.v.-doses (P less than 0-01). The yield of dicentric chromosomes after X-ray exposure (150 rad.) was 35% higher in Down's syndrome leukocytes than in the control cells (P less than 0-001). Combined u.v. and X-ray irradiation caused a twofold increase in the frequency of dicentric chromosomes in control cells, while the increase was only 27% in Down's syndrome leukocytes. This synergistic effect of u.v. and X-ray irradiation on the yield of dicentric chromosomes suggests that healing of X-ray and u.v.-induced DNA lesions may partly utilize the same repair enzymes. The results also indicate that DNA repair mechanisms are impaired in leukocytes from patients with Down's syndrome, which may contribute to the increased incidence of leukemia and the susceptibility to X-ray irradiation in this disorder.
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PMID:DNA repair and frequency of x-ray and u.v.-light induced chromosome aberrations in leukocytes from patients with Down's syndrome. 13 31

Structure-activity studies of nitrosourea pharmacology have resulted in the synthesis of a new water-soluble agent,chlorozotocin, which has significant antitumor activity against the L1210 leukemia system and produces only a minor degree of inhibition of mouse and human bone marrow DNA synthesis compared to BCNU. It is important to emphasize that the bone marrow sparing feature of chlorozotocin is relative and that if the drug is administered at lethal dose levels in mice, myelosuppression is observed. The potential importance of these studies is the identification of a new and active nitrosourea antiumor agent with modified bone marrow toxicity. If aminoglucose modification of nitrosourea bone marrow toxicity can be confirmed in man without significant loss of antitumor activity, the use of such a compound could facilitate treatment of patients with neoplastic disease who have pre-existing abnormal bone marrow function. It would also allow the more effective use of a nitrosourea agent in combination with anticancer agents possessing more potent myelosuppressive properties.
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PMID:Pharmacology of chlorozotocin Nsc-178248), a new nitrosourea antitumor agent. 13 56

1-4-Amino-2-methylpyrimidin-5-yl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) is a water-soluble nitrosourea that has produced delayed hematological toxicity in man during Phase 1 clinical trials. ACNU has in vitro alkylating activy 40% less than that of 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose (chlorozotocin) but shares the property of negligible carbamoylating activity with the latter compounds. ACNU is highly active against murine L1210 leukemia. However, the maximum therapeutic dose, 30 mg/kg (a dose lethal to 10% of the animals), produced a 64% reduction in peripheral WBC and an 85% decrease in circulating neutrophils in normal mice. This was correlated with a 76% inhibition of normal mouse bone marrow DNA synthesis within 24 hr after treatment, followed by full recovery within 48 hr after treatment, followed by full recovery within 48 hr. In contrast, DNA synthesis in L1210 cells was suppressed to less than 10% of control for a minimum of 72 hr. While ACNU, a pyrimidine analog, possesses many of the chemical properties of chlorozotocin, it does not share with the latter compound its reduced myelotoxicity at therapeutic doses. The glucose carrier of the chlorozotocin molecule appears to impart the selective sparing of normal bone marrow.
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PMID:A comparison of the biological and biochemical properties of 1-(4-amino-2-methylpyrimidin-5-yl)methyl-3-(2-chloroethyl)-3-nitrosourea and 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose. 14 14

Murine leukemia cells transformed by in vivo treatment with 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC) are rejected by histocompatible recipients following inocula of 10(7) cells i.p. Progressive tumor growth or tumor growth and regression was monitored measuring the extent of DNA synthesis in the peritoneal cavity of mice using the [125I]5-iodo-2'-deoxyuridine uptake method. In addition, the results were confirmed by cell count and mortality data. Comparable growth rate was found initially in both DTIC and parental lines in histocompatible hosts. Later, mice challenged with parental lines died, whereas hosts inoculated with DTIC-treated sublines rejected the tumor. On the other hand, lethal growth occurred in mice inoculated with DTIC-treated sublines when immunodepressed by cyclophosphamide given before tumor challenge, or by methotrexate given after challenge of a methotrexate-resistant DTIC-treated subline. The similarity between the growth rate of the parental and DTIC-treated lines in histocompatible hosts does not support the hypothesis of impaired "oncogenic potential" of such DTIC-treated lines. Furthermore, the growth and rejection pattern of a parental line in H-2-incompatible hosts was similar to that observed for DTIC-treated lines in histocompatible hosts, suggesting that comparable immune mechanisms were involved in both cases.
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PMID:Growth and rejection patterns of murine lymphoma cells antigenically altered following drug treatment in vivo. 14 82

Psoralen photosensitization of L 1210 cells has a strong effect on DNA and RNA syntheses and this result appears connected with the psoralen photobinding to DNA. Protein synthesis is less sensitive and its inhibition seems due to a different photochemical interaction, very likely to the psoralen photobinding to RNA. A combined therapy using cyclophosphamide and L 1210 cells psoralen-photoinactivated was performed after the leukaemia transplant, showing a significant decrease in mortality, even in comparison with the simple treatment with the alkilating drug.
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PMID:Psoralen photosensitization of L 1210 leukaemia cells: an approach to a new combined therapy. 14 53


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