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)

We have studied the virus-like 30S (VL30) RNA sequences of mice. Previous work has shown that these sequences are coded in the mouse genome, expressed in some normal cells and released as pseudotypic particles from cells producing murine C-type retroviruses. VL30 sequences have some similarities to standard retrovirus RNA, but differences also exist. To further assess the similarities and differences, several aspects of VL30-specific metabolism were investigated. We studied the initiation of VL30-specific DNA synthesis during an endogenous reverse transcriptase reaction. Short initial VL30-specific cDNA transcripts were covalently attached to RNA as measured by equilibrium banding in caesium sulphate density gradients. Therefore, reverse transcription of VL30-specific cDNA is initiated by an RNA primer. The intracellular synthesis of VL30 RNA was investigated by pulse labelling uninfected JLS-V9 cells with 3H-uridine. Hybridization of the pulse-labelled nuclear RNA indicated that the major VL30-specific RNA evident after a 15 min label was the same size as the mature VL30 RNA. Thus, VL30 RNA is apparently not synthesized via a higher mol. wt. precursor. Both of these results demonstrate similarity of VL30 RNA sequences to standard retroviruses. One unique feature of VL30 RNA was detected. JLS-V9 cells contained both the monomeric VL30 RNA and a hydrogen-bonded 38S form which yielded the monomer when denatured. This contrasts with standard murine leukaemia virus which is only found as a monomer within cells.
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PMID:Further characterization of virus-like 30S (VL30) RNA of mice: initiation of reverse transcription and intracellular synthesis. 616 92

The arylsulfonyl-hydrazones of 2-pyridinecarboxaldehyde 1-oxide represent a relatively new class of antineoplastic agents with the potential for clinical usefulness. The requirement for spontaneous chemical transformation of these agents to exert anticancer activity was evaluated using as the prototype the most potent member of this class synthesized to date, the 3,4-dimethoxybenzene sulfonylhydrazone of 2-pyridinecarboxaldehyde 1-oxide (3,4-DSP. 3,4-DSP was chemically unstable, decomposing with a half-life of 19 min in 0.01 M potassium phosphate buffer (pH 7.4) at 37 degrees. The major chemical decomposition product was identified as 2-pyridylcarbinol 1-oxide by comparison with the authentic compound. This carbinol is hypothesized to be formed via the intramolecular abstraction of hydrogen from the arylsulfonyl-hydrazone, a process that leads to the release of 3,4-dimethoxybenzenesulfinic acid and the formation of 1-oxidopyridin-2-yldiazomethane, which subsequently reacts with water. The diazomethane intermediate is a potent alkylating agent which, if generated in cells, would have the potential to alkylate nucleophilic groups of biologically important macromolecules. The proposed reactive species was trapped using both 4-(4-nitrobenzyl)pyridine (NBP) and morpholine, and the latter product was characterized by mass spectroscopy. The importance of the chemical formation of an alkylating species to cytotoxicity was demonstrated by studies in which solutions of 3,4-DSP were "aged" prior to addition to L1210 leukemia cells in culture and prior to incubation with NBP. The "aging" of 3,4-DSP for 20 min resulted in a 4-fold decrease in cytotoxicity, and aging for 1 to 3 hr led to complete loss of cytotoxicity. Correspondingly, a 20-min aging period decreased alkylation of NBP by 51%, and 3-hr aging resulted in essentially no alkylation of the nucleophile. Further support for the above proposed chemical activation pathway was provided by correlations between in vitro cytotoxicity, in vivo antineoplastic activity, chemical stability, and the degree of alkylation of NBP by a wide variety of arylsulfonyl-hydrazones. The lack of the 1-oxide, envisioned to be required for intramolecular hydrogen abstraction, the steric prevention of the abstraction, or the replacement of the proton of the nitrogrn of the side-chain by a methyl group resulted in a marked increase in chemical stability and a corresponding loss of the ability to alkylate NBP and to inhibit the replication of L1210 leukemia cells in culture.
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PMID:Relationship of spontaneous chemical transformation of arylsulfonylhydrazones of 2-pyridinecarboxaldehyde 1-oxide to anticancer activity. 683 33

Three new modified steroidal alkylating agents, 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam-p-bis(2-chloroethyl)aminophenylacetate, 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam-p-bis-(2-chloroethyl)aminophenylbutyrate, and 17 beta-hydroxy-3-aza-A-homo-4 alpha-androsten-4-one-p-N,N-bis(2-chloroethyl)aminophenylacetate are active in treatment of L1210 and P388 leukemias. A stereoisomer of the first compound, 3 alpha-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13, 17-lactam-p-bis(2-chloroethyl)aminophenylacetate, was tested in L1210 leukemia. This stereoisomer, in which the alkylating agent is linked to the modified steroid in the axial position, is active only as much higher doses in L1210 leukemia. The results of testing these compounds and previous results from similar compounds allow certain conclusions to be drawn regarding structure-activity relationships. The presence of the lactam moiety is the major structural feature that confers activity in the murine leukemias. The steric arrangement of the alkylating moiety at position 3 and the hydrogen atom at position 5 influence toxicity and antileukemic activity.
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PMID:Antitumor activity of homo-aza-steroidal esters of [p-[bis(2-chloroethyl)amino]phenyl]acetic acid and [p-[bis(2-chloroethyl)amino]phenyl]butyric acid. 683 26

The key intermediate 9-(2,3,5,-tri-O-acetyl-beta-D-arabinofuranosyl)purine-6-carbonitrile (7) was synthesized in four steps from 9-beta-D-arabinofuranosylpurine-6-thione (3) via 6-(methylsulfonyl)-9-(2,3,5-tri-O-acetyl-beta-D-arabinofuranosyl)purine (6). Reaction of compound 7 with methanolic ammonia provided the rearranged compound 4-amino-8-(beta-D-arabinofuranosylamino)pyrimido[5,4-d]pyrimidine (8). Treatment of 7 with ammonium hydroxide and hydrogen peroxide provided 9-beta-D-arabinofuranosylpurine-6-carboxamide (9). Compound 7 was also treated with sodium hydrosulfide to yield 9-beta-D-arabinofuranosylpurine-6-thiocarboxamide (10). Similarly, 9-(2-deoxy-3,5-di-O-acetyl-beta-D-erythro-pentofuranosyl)purine 6-carbonitrile (17) was prepared from 6-chloro-9-(2-deoxy-beta-D-erythro-pentofluranosyl)purine (11) via 9-(2-deoxy-beta-D-erythro-pentofuranosyl)purine-6-thione. Compound 17 was converted into 4-amino-8-[(2-deoxy-beta-D-erythro-pentofuranosyl)amino]pyrimido[5,4-d]pyrimidi ne (18) and 9-(2-deoxy-beta-D-erythro-pentofuranosyl)purine-6-carboxamide (20), respectively. Compound 2 showed immunosuppressive activity and also inhibited the growth of L-1210 leukemia in mice. Arabinonucleoside analogues 8-10 were inactive when tested against RNA and DNA viruses in cell culture.
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PMID:Synthesis and biological evaluation of certain 2'-deoxy-beta-D-ribo- and -beta-D-arabinofuranosyl nucleosides of purine-6-carboxamide and 4,8-diaminopyrimido[5,4-d]pyrimidine. 726 26

Hydrogenolysis of 3-(benzyloxy)cyclophosphamide (10) using Pd/C catalyst and ethyl acetate as solvent leads to the formation of 3-hydroxycyclophosphamide (3, approximately 20%) and cyclophosphamide (1, approximately 10%), accompanied by regioselective hydrogen-exchange reactions at the C-4 and C-5 positions in 3 and 1. A variety of oxidizing reagents and liver microsomal incubation failed to provide evidence (31P NMR) for conversion of 1 into 3, whereas identical incubation of 3 led to its reduction to 1. Compound 3 is stable at pH 6.5-8.2, 37 degrees C, and exhibits anticancer activity comparable to 1 when tested against L1210 leukemia in mice. Data are discussed with regard to a previously reported suggestion that metabolism of 1 may involved oxidation to give 3 followed by rearrangement of 3 to 2.
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PMID:Synthesis of 3-hydroxycyclophosphamide and studies related to its possible role in the metabolism of cyclophosphamide. 731 Aug 17

Nitrosourea derivatives 18-22 which utilize either a piperidine or pyridine ring as a carrier group were synthesized and evaluated for anticancer activity. N'-(1-Benzyl-4-piperidinyl)-N-(2-chloroethyl)-N-nitosourea hydrogen maleate (19) exhibited good activity against intracranial L1210 leukemia as well as the mouse ependymoblastoma brain tumor system. Compound 19 exhibited comparable activity in the Lewis lung carcinoma system to N,N'-bis(2-chloroethyl)-N-nitrosourea. Replacement of the N-benzyl group in both the 3-piperidinyl- and 4-piperidinylnitrosoureas resulted in less active compounds in all tumor systems tested. The 3-pyridylnitrosourea 22 was inactive in the L-1210 leukemia system.
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PMID:Synthesis of nitrosourea derivatives of pyridine and piperidine as potential anticancer agents. 740 Nov 13

A new class of tricyclic nucleosides in which the aglycon has a linear [6:5:6] geometry has been synthesized using certain pyrrolo[2,3-d]pyrimidine nucleosides as the starting materials. An adenosine-adenosine analogue (12) has been prepared from 6-aminotoyocamycin using two different synthetic routes. An adenosine-guanosine analogue (4) and several adenosine-6-mercaptopurine ribonucleoside-type tricyclic nucleoside derivatives have also been synthesized. Structural assignments have been based on 1H NMR spectral studies, as well as an unequivocal chemical proof of structure. An interesting chemical shift for the 2' hydrogen of certain tricyclic nucleosides was observed and is discussed. The in vitro cytotoxicity of these nucleosides against leukemia L-1210 has been determined. The in vivo evaluation of these tricyclic nucleosides against mouse leukemia will also be discussed.
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PMID:Synthesis of certain [6:5:6] linear tricyclic nucleosides as potential antitumor agents. 745 64

The natural product of the Red Sea sponge Verongia sp., identified as 3,5,8-trihydroxy-4-quinolone, was found to be a potent inhibitor of the RNA-directed DNA synthesis of the reverse transcriptases (RTs) of human immunodeficiency viruses type 1 and type 2 (HIV-1 and HIV-2, respectively). This inhibition was unaffected by the nature of the primer template used for DNA synthesis. The DNA-dependent DNA polymerase activity was inhibited to a lesser extent, whereas the ribonuclease H (RNase H) function associated with both HIV RTs was only slightly inhibited. The inhibition by the trihydroxyquinolone is reversible and noncompetitive with respect to both substrates--dTTP and the template primer poly(rA)n.oligo(dT)12-18. The inhibitor binds HIV-1 RT with a high affinity (Ki = 0.46 microM). This compound was shown also to inhibit the catalytic activities of the RT of murine leukemia virus, establishing the general inhibitory effect on retroviral RTs. Introductions of acetyl or methoxy moieties at positions with potential activity have generated three synthetic analogs of the natural compound. Only one analog, 5,8-dimethoxy-4-quinolone, exhibited an inhibition potency similar to that of the unmodified compound. Analysis of the three analogs has led us to the conclusion that the hydroxyl group at the ortho position to the carbonyl group in the pyridinone ring is a key structural element for the inhibitory activity. Thus, it could well be that the inhibitor interacts with the enzyme through a hydrogen bond of this hydroxyl group. We hope that the identification of the inhibitory site of the compound might be an important step toward the rational design of new potent anti-HIV RT drugs.
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PMID:3,5,8-Trihydroxy-4-quinolone, a novel natural inhibitor of the reverse transcriptases of human immunodeficiency viruses type 1 and type 2. 751 Sep 44

Six new analogues of 5,8-dideazaisofolic acid and 5,8-dideazaisoaminopterin were synthesized in an effort to obtain enhanced antitumor activity. The modifications included the replacement of the 2-amino group by hydrogen or methyl as well as the inclusion of a methyl substituent at position 9. Based upon activity against L1210 leukemia cells in culture, three of the new analogues together with one compound described previously were evaluated for cytotoxicity in vitro using three human tumor cell lines (Colo 320 DM, Hep G2 and HL-60). The most effective compound was 2-desamino-N9-methyl-5,8-dideazaisoaminopterin (2c) with the HL-60 cells being the most sensitive to its cytotoxic effects. These analogues were evaluated in vitro as inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS) from human as well as bacterial (Lactobacillus casei) sources. All four of the 4-amino analogues were most effective toward L. casei DHFR compared with human DHFR, with 2-desamino-2-methyl-5,8-dideazaisoaminopterin (2d) and its 9-methyl derivative (2e) having 818- and 430-fold greater selectivity (L. casei/human). Most of the compounds studied were found to be only modest inhibitors of human TS (I50 values = 1.5 to 20 microM) and were therefore at least 40-fold less inhibitory than 10-propargyl-5,8-dideazafolic acid. Nevertheless, reversal of cytotoxicity studies with thymidine, hypoxanthine and folinic acid using the HL-60 cell line suggested that TS is the primary target for these analogues.
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PMID:Studies on the antitumor effects of analogues of 5,8-dideazaisofolic acid and 5,8-dideazaisoaminopterin. 757 41

Adult T cell leukemia-derived factor (ADF), originally defined as an interleukin 2 receptor/alpha (alpha) chain inducer produced by human T-lymphotropic virus type-I transformed cells, is identical to human thioredoxin (TRX). In this study, the protective effect of ADF/TRX on the cytotoxicity of endothelial cells caused by phorbol myristate acetate (PMA)-activated neutrophils or hydrogen peroxide (H2O2) was examined. When murine endothelial F-2 cells established from an ultraviolet light-induced tumor on a nude mouse were incubated with PMA-activated neutrophils or with 1 mM H2O2 for 6 hours, the cytotoxicity of F-2 cells was respectively 51 +/- 4% or 40 +/- 8% by the 51Cr releasing assay. Recombinant ADF/TRX (rADF/TRX) inhibited this cytotoxicity in a dose-dependent manner, although mutant ADF/TRX (cysteine 31 to serine), 2-mercaptoethanol and dithiothreitol did not. On a molar basis, rADF/TRX was more effective than glutathione but less effective than catalase. Immunoblotting analysis showed that treatment with 0.1 mM H2O2 induced murine TRX on F-2 cells. These findings indicate that ADF/TRX is an oxidative stress-inducible endogenous protein and rADF/TRX plays a protective role against activated neutrophils- or H2O2-induced endothelial cytotoxicity.
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PMID:Adult T cell leukemia-derived factor/human thioredoxin protects endothelial F-2 cell injury caused by activated neutrophils or hydrogen peroxide. 782 34


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