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)

1. Isolated perfused livers from starved mice inoculated with myeloproliferative leukemia virus exhibited similar rates of consumption of [3-13C]alanine and of synthesis of glutamine and glutamate labeled at the C-2 or C-3 positions as livers from uninfected mice. 2. Leukemic livers also formed glutamine and glutamate labeled at the C-4 position. This is related to their lower content of triglyceride as compared to that of control livers which do not produce these isotopomers. 3. The glucose synthesis rate was much lower in livers from leukemic mice. This is explained by the glycolytic properties of the leukemic infiltrating cells.
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PMID:Modification of the gluconeogenic/glycolytic balance in isolated perfused liver of myeloproliferative leukemia infected mice: a 13C NMR study. 215 73

Tetrahydronaphthoquinones and tetrahydroanthraquinones bearing an amido group have been prepared by Diels-Alder reactions between (E)-1-(N-carbobenzyloxyamino)-1,3-butadiene (2) or (E)-1-(N-benzoyl-N-benzylamino)-1,3-butadiene (5) and benzoquinone or 5-substituted naphthoquinones. The stereochemistry of the cycloadditions was investigated. A high regioselectivity was observed in the reaction of the diene carbamate 2 with 5-methoxy and 5-acetoxy naphthoquinones. This latter gave the unexpected 1,8-regioisomer 3d. The cycloadditions of the dienamide 5 with naphthoquinones 1 (R = OH, OMe, OAc) are regiospecific. Assignment of the structure of the tetrahydroanthraquinone 6b is in good agreement with the known directing effect of the 5-hydroxy group of juglone 1b in analogous Diels-Alder reactions. With 5-methoxy and 5-acetoxy naphthoquinones, the opposite regiochemistry observed is consistent with the electron-donating influence of the methoxy or acetoxy group, making the C-3 carbon atom more electron deficient. Aromatization of the adducts 6b and 7c was accompanied by an unusual elimination of the amido moiety. Thus, 1-hydroxy and 1-methoxy anthraquinones were obtained. Reactions of the dienes 2 and 5 with benzoquinone gave the tetrahydronaphthoquinones 9 and 10 with an endo stereospecificity. Oxidation of 9 by activated manganese dioxide gave the naphthoquinone 11. These compounds were submitted to in vitro cytotoxic assays towards murine L 1210 leukemia cells and clonogenic human tumor cell line MDA-MB 231. The naphthoquinone derivatives 9, 10 and 11 had significant activities with IC50 less than or equal to 0.4 microgram/ml towards these two tumor cell systems.
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PMID:Diels-Alder reactions between dienamides and quinones: stereochemistry of the cycloadditions and cytotoxic activity of the adducts. 234 11

The cytotoxicity of T-2 toxin and related trichothecenes was studied in Adriamycin-sensitive and -resistant P388 leukemia cells in vitro. The structure-activity relationship indicated that a free hydroxyl in the C-3 position contributed to the activity. Free hydroxyls at the 4, 8, and 15 positions interfered with the activity, and their estrification resulted in improved cytotoxicity. The cytotoxic activity of these trichothecenes did not seem to be related to their degree of lipophilicity. Adriamycin-resistant P388 cells were cross-resistant to the trichothecenes, and this resistance could be circumvented by verapamil.
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PMID:The cytotoxicity of T-2 toxin and related 12,13-epoxytrichothecenes to Adriamycin-sensitive and -resistant P388 leukemia cells. 275 9

Two different tetracyclic chromophoric analogues of actinomycin D have been synthesized by engaging two chromophoric DNA-binding functions in actinomycin D, i.e., 2-amino and 3-oxo, into either a 1,4-oxazin-2-one or an oxazole ring system. A third analogue has an extra quinone function at C-8 of the oxazole analogue. In all the analogues the chemical integrity of the peptide lactones of the parent antibiotic is kept intact, but their sterochemistry is altered. The analogues are designed as transport-modified prodrug forms of either the tricyclic active analogues of actinomycin D or actinomycin D itself. All analogues exhibit cytotoxicity that is several-fold less potent than AMD; they also have no binding affinity toward extracellular DNA. Nonetheless, the analogues of the first and the third series show improved antitumor activities (P388 leukemia, CDF1 mice). In fact, two of these analogues having a phenyl substituent at the C-3 site of the oxazinone ring or the C-2 position of the 8-oxo-8H-oxazole ring exhibit the highest antitumor effects. Most of the analogues are active over a broader dose range than actinomycin D and are 6- to 16-fold less cytotoxic to human lymphoblastic leukemia (CCFR-CEM) cells in vitro. The analogues with the most pronounced antitumor activity are those that retain most elements in the peptide stereochemistry of actinomycin D and have a quinone function or demonstrate susceptibility of their chromophores to biotransformation.
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PMID:Tetracyclic chromophoric analogues of actinomycin D: synthesis, structure elucidation and interconvertibility from one form to another, antitumor activity, and structure-activity relationships. 657 6

A multidisciplinary methodology was applied to study 6 patients with acute leukemia (AL) following treatment for Hodgkin's disease. All 6 patients developed acute monocytic leukemia according to cytochemical criteria; morphologically, 3 cases were undifferentiated monoblastic leukemia; 3 cases were partially differentiated monocytic leukemia. In 3 of the 6 cases, cell suspensions from peripheral blood and/or bone marrow bore predominantly surface receptors for the Fc fragment of IgG and/or C-3 fraction of complement and exhibited variable degrees of phagocytosis. Two cases lacked any recognizable membrane markers or phagocytic activity. Terminal transferase enzymatic activity was not diagnostically elevated. Soft agar bone marrow culture studies revealed no growth or a characteristic leukemic cluster pattern. Chromosome analysis done in 1 of the 2 patients studied revealed hypodiploidy and structural rearrangement. Prospective studies, done serially, will help determine whether development of AL in patients with Hodgkin's disease results from the influence of intensive and potentially oncogenic therapy or represents progression from a preleukemic stage inherent to the original tumor.
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PMID:Analysis of multiple cell markers in acute leukemia complicating Hodgkin's disease. 693 Sep 87

Benzene is a carcinogen in rodents and a cause of bone marrow toxicity and leukemia in humans. p-Benzoquinone (p-BQ) is one of the stable metabolites of benzene, as well as of a number of drugs and other chemicals. 2'-Deoxycytidine (dC) and 2'-deoxyadenosine (dA) were allowed to react with p-BQ in aqueous solution at pH 7.4 and 4.5. The yields were considerably higher at pH 4.5 than at pH 7.4, as indicated by HPLC analysis. The desired products were isolated by column chromatography on silica gel or cellulose. Identification was done by FAB-MS, 1H NMR, and UV spectroscopy. The reaction of p-BQ with dC and dA at pH 4.5 produced the exocyclic compounds 3-hydroxy-1,N4-benzetheno-2'-deoxycytidine (p-BQ-dC), and 9-hydroxy-1,N6-benzetheno-2'-deoxyadenosine (p-BQ-dA), respectively, in a large scale and high yield. These adducts have been previously made in a microgram scale as the 3'-phosphate for 32P-postlabeling studies of their incidence in DNA. The p-BQ-dC and p-BQ-dA adducts have, in addition to the two hydroxyl groups of deoxyribose, one newly formed hydroxyl group at the C-3 or C-9 of the exocyclic base of each product respectively. Incorporation of these adducts into oligonucleotides as the phosphoramidite requires the protection of all three hydroxyl groups in these compounds. The exocyclic hydroxyl on the base has been successfully protected by acylation after protecting the 5'- and the 3'-hydroxyl groups of the sugar moiety with a 4,4'-dimethoxytrityl group and a cyanoethyl N,N-diisopropylphosphoramidite group, respectively. For the first time, to our knowledge, the fully protected phosphoramidites of p-BQ-dC and p-BQ-dA were prepared and incorporated site-specifically into a series of oligonucleotides. The coupling efficiency was very high (> 98%). However, deprotection of the DNA oligomers with ammonia produced only 50% of the desired oligomers containing the adduct. In contrast, when 10% of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in methanol at room temperature was used, only the desired oligomers were detected by HPLC. Thus, by deprotecting the oligomers with methoxide ions (DBU/methanol) and avoiding the use of ammonia, a high yield of modified DNA was obtained. After purification of these oligomers by HPLC, they were hydrolyzed enzymatically and analyzed by HPLC, which confirmed the base composition and the incorporation of the adducts. The mass spectroscopic analysis of the DNA oligomers was confirmed by electrospray MS. These oligomers are now under investigation for their biochemical properties.
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PMID:Large scale synthesis of p-benzoquinone-2'-deoxycytidine and p-benzoquinone-2'-deoxyadenosine adducts and their site-specific incorporation into DNA oligonucleotides. 749 36

Synthesis and cytotoxicity of the new analogs (11-13) of docetaxel possessing cyclohexyl groups instead of phenyl groups at the C-3' and/or C-2 benzoate positions are described. The C-2 cyclohexanecarboxylate analog of paclitaxel (15) is also synthesized for comparison. The potency of these new taxoids were examined for their inhibitory activity for microtubule disassembly and also for their cytotoxicity against murine P388 leukemia cell line as well as doxorubicin-resistant P388 leukemia cell line (P388/Dox). It is found that 3'-dephenyl-3'-cyclohexyldocetaxel (11) (0.72T) and 2-(hexahydro)docetaxel (12) (0.85T) possess strong inhibitory activity for microtubule disassembly equivalent to docetaxel (0.7T), which is more potent than paclitaxel (1.0T). The results clearly indicate that phenyl or an aromatic group at C-3' or C-2 is not a requisite for strong binding to the microtubules. This finding has opened an avenue for development of new nonaromatic analogs of docetaxel and paclitaxel. 3'-Dephenyl-3'-cyclohexyl-2-(hexahydro)docetaxel (13) (2T) turns out to be a substantially weaker inhibitor. The cytotoxicities of 11-13 against P388 are, however, in the same range that is 8-12 times weaker than docetaxel and 4-6 times weaker than paclitaxel, i.e., 13 shows equivalent cytotoxicity to that of 11 or 12 in spite of much lower microtubule disassembly inhibitory activity. The cytotoxicities of these new taxoids against the P388/Dox cell line are only 2-2.5 times lower than that of docetaxel. The potency of 2-(hexahydro)paclitaxel (15) for these assays is much lower than the docetaxel counterpart 12. The significant loss of activity in vivo against B16 melanoma is observed for 11-13, i.e., 11 is only marginal (T/C = 38% at 20 mg/kg/day), and 12 and 13 are inactive (T/C = 76% and 79%, respectively). This could be ascribed to faster metabolism, faster excretion or other bioavailability problems.
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PMID:Synthesis and structure-activity relationships of new antitumor taxoids. Effects of cyclohexyl substitution at the C-3' and/or C-2 of taxotere (docetaxel). 791 41

Cosalane (3), a novel anti-HIV agent having a disalicylmethane unit linked to C-3 of cholestane by a three-carbon linker, was synthesized from commercially available starting materials by a convergent route. Cosalane proved to be a potent inhibitor of HIV with a broad range of activity against a variety of laboratory, drug-resistant, and clinical HIV-1 isolates, HIV-2, and Rauscher murine leukemia virus. The cytotoxicity of cosalane is relatively low as reflected by an in vitro therapeutic index of > 100. Although cosalane inhibits HIV-1 reverse transcriptase and protease, time of addition experiments indicate that it prevents the cytopathic effect of HIV by acting earlier than reverse transcription in the viral replication cycle. The available evidence indicates that the primary mechanism of action of cosalane involves inhibition of gp120-CD4 binding as well as inhibition of a postattachment event prior to reverse transcription.
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PMID:Design, synthesis, and biological evaluation of cosalane, a novel anti-HIV agent which inhibits multiple features of virus reproduction. 793 26

Hydroxyrubicin, a synthetic doxorubicin analog in which the basic amino group at C-3' is replaced by a hydroxyl group, was used as a prototype compound to study the effects of basicity of the sugar moiety on the toxicity and antitumor activity of anthracycline antibiotics. Compared with doxorubicin, hydroxyrubicin showed similar or superior in vitro cytotoxicity against P388, L1210, and M5076 cells, as determined by an MTT assay, and against 8226 and CEM cells, as determined by a growth inhibition assay. Hydroxyrubicin was 5 and 13 times more effective than doxorubicin in inhibiting the growth of multidrug-resistant CEM (CEMvbl) and 8226 (8226R) cells, respectively. Hydroxyrubicin was not cross-resistant with doxorubicin in a cytotoxicity assay against KB 3-1 and KB V1 cells (resistance index 1.1 for hydroxyrubicin versus > 15.6 for doxorubicin). Cellular uptake and retention of hydroxyrubicin were studied by flow cytometry in parent and multidrug-resistant 8226 cells, and compared with those of doxorubicin. In 8226 sensitive cells, 2 h uptake and retention of doxorubicin were similar or higher than those of hydroxyrubicin. In 8226R cells, uptake and retention of hydroxyrubicin were about 3-fold higher than those of doxorubicin. In mice, the acute LD50 of hydroxyrubicin was about 3-fold higher than that of doxorubicin (79.1 versus 25.7 mg/kg). At equitoxic doses, hydroxyrubicin was as myelosuppressive as doxorubicin but less cardiotoxic, as assessed by the Bertazzoli test. In contrast to doxorubicin, hydroxyrubicin, due to the lack of basic amine function, showed no selective interaction with negatively-charged cardiolipin (CL). The observed decrease of affinity to CL might be responsible for the reduced cardiotoxicity of hydroxyrubicin. In in vivo antitumor activity studies, hydroxyrubicin at the optimal dose (37.5 mg/kg, i.p., on day 1) had significant activity against intraperitoneal P388 leukemia resistant to doxorubicin, whereas doxorubicin (10 mg/kg, i.p., on day 1) was inactive (%T/C 163-200 versus 118-120). These studies indicate that: (i) the amino group at position 3' is not essential for doxorubicin to exert its biological activity, (ii) removal of the basic center (deamination at the C-3') results in an increased cellular uptake and retention, (iii) the increased cellular uptake and retention of hydroxyrubicin in multidrug-resistant cells correlate with a partial or total lack of cross-resistance of this analog with the parent compound, doxorubicin, and (iv) deamination at position 3' confers a reduced cardiotoxicity and diminished affinity for CL.
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PMID:Removal of the basic center from doxorubicin partially overcomes multidrug resistance and decreases cardiotoxicity. 845 13

From ethyl acetate and methanolic extracts of Lethedon tannaensis leaves, which were cytotoxic against murine leukemia (P-388) and human nasopharynx carcinoma (KB) cells, one new and six known 5-hydroxy-7-methoxyflavones variously substituted on the B ring were isolated and their structures determined by spectral analysis. Compounds active against KB cells were velutin (4) (IC50 4.8 microM), 7,3',5'-tri-O-methyltricetin (2) (IC50 22.2 microM), genkwanin (6) (IC50 30.6 microM), and the novel compound, 7,3',4'-tri-O-methyltricetin, named lethedocin (1) (IC50 47.6 microM). These flavones required the presence of hydroxyl groups at C-5 and C-4' and methoxyl groups at C-7 and C-3' for inhibition of calf thymus DNA topoisomerase I activity.
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PMID:DNA topoisomerase I inhibitors: cytotoxic flavones from Lethedon tannaensis. 875 70


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