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)

For the rational design of more specific alkylating agents, we suggested new biological platforms able to deliver the alkylating moieties to specific target site and on the other hand we hoped to lead in compounds with synergistic activity. As biological platforms have been used steroidal lactams of A and D- ring and as alkylating agents carboxylic derivatives of N,N-bis (2-Chloroethyl) aniline which combine to the steroid by an easily cleaved ester bond. These homo-aza-steroidal esters gave satisfactory results in early and advanced P388, L1210 leukemias and solid tumors. Whereas unmodified steroidal esters have generally been reported to be inactive in treatment of L1210 leukemia. The steric arrangement of the alkylating moiety greatly effects toxicity and activity of the drugs, while the steric arrangement of the hydrogen atom at position 5 influences these parameters. Isosterism of alkylating agent is the factor for biological action. The amide group of the lactam molecule may be essential for activity.
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PMID:Hybrid anticancer compounds. Steroidal lactam esters of carboxylic derivatives of N,N-bis (2-chloroethyl) aniline (review). 176 51

Methylation of Micrococcus lysodeikticus DNA by purified DNA methylase isolated from L1210 leukaemia cells is potently and specifically inhibited by both hetero and homoribo and deoxyribopolynucleotides containing guanine residues. The inhibitory effect is unaffected by chain length, but is abolished when the O6 residue of guanine is substituted as in poly[d(O6MeG)]20. Potent inhibition is also shown by polyinosinic and polyxanthylic acids, but not by polyadenylic acid or by heteropolymers containing adenine and thymine. These results suggest that the 6-position of the purine nucleus is important in binding of the DNA methylase to a particular region of the DNA duplex and that the hydrogen bonding properties of this group are important in enzyme recognition.
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PMID:Importance of the O6 position of guanine residues in the binding of DNA methylase to DNA. 201 98

Oxidative biotransformation of xenobiotics and endogenous substances involves glutathione in reduced form as an integral component through two mechanisms: glutathione peroxidase catalysing the reduction of hydrogen peroxide and organic hydroperoxides, and glutathione-S-transferases catalysing the conjugation of oxygenated derivatives with glutathione. We studied glutathione and glutathione-related enzyme activities in haemolysed venous blood samples from 49 healthy children and from 11 children with diabetes mellitus, 10 children with rheumatoid arthritis, seven children with active coeliac disease, and seven children with acute lymphoblastic leukaemia. Among the healthy children glutathione content and the activities of glutathione reductase, glutathione peroxidase, and glutathione-S-transferase were unrelated to sex; age-dependent differences were also minor. The patients with diabetes mellitus had decreased activity of glutathione reductase. The patients with acute lymphoblastic leukaemia had increased activity of both glutathione peroxidase and glutathione-S-transferase, possibly reflecting an adaptive response to free-radicals. The patients with active coeliac disease had control levels of all measured parameters of glutathione-related reactions indicating, since we earlier found decreased activities of glutathione peroxidase in intestinal mucosa of celiacs, that blood may not always reflect tissue-specific changes.
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PMID:Glutathione and glutathione-metabolizing enzymes in the erythrocytes of healthy children and in children with insulin-dependent diabetes mellitus, juvenile rheumatoid arthritis, coeliac disease and acute lymphoblastic leukaemia. 204 16

A series of 1,2,3-triazole (2), pyrazole (3 and 5), and pyrrole (4) ribonucleosides with two adjacent carbamoyl groups have been synthesized and evaluated for cell growth inhibition and induction of cellular differentiation of HL-60 cells in culture. Glycosylation of the TMS derivatives of dimethyl 1,2,3-triazole-4,5-dicarboxylate (6) and diethyl pyrazole-3,4-dicarboxylate (7) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D- ribofuranose (8) in the presence of TMS triflate gave predominantly the beta-nucleosides 9 and 14, respectively. Ammonolysis of 9 and 14 furnished 2-beta-D-ribofuranosyl-1,2,3-triazole-4,5-dicarboxamide (2) and 1-beta-D-ribofuranosylpyrazole-3,4-dicarboxamide (3), respectively. Stereoselective ring annulation of 1-deoxy-1-hydrazinyl-2,3-O-isopropylidene-D- ribose (16) with tetracyanoethylene (15) gave 5-amino-1-(2,3-O-isopropylidene-beta-D-ribofuranosyl)pyrazole-3,4- dicarbonitrile (17). Deisopropylidenation of 17, followed by oxidative hydrolysis of the reaction product (18), gave the 5-amino derivative of 3 (5). Stereospecific glycosylation of the sodium salt of preformed diethyl pyrrole-3,4-dicarboxylate (22) with 1-chloro-2,3-O-isopropylidene-5-O-(tert-butyldimethylsilyl)-alpha-D- ribofuranose (23) was accomplished to furnish blocked nucleoside 24, which on ammonolysis and deisopropylidenation gave 1-beta-D-ribofuranosylpyrrole-3,4-dicarboxamide (4). The structures of 2 and 3 were assigned by single-crystal X-ray diffraction studies, which showed extensive inter- and intramolecular hydrogen bonding. Nucleosides 2-5 are devoid of significant cytotoxic properties against L1210 and WI-L2 leukemia cells in culture. However, these compounds were found to be inducers of cellular differentiation of HL-60 cells in the range of 30-60 microM and were comparable to ribavirin in this regard.
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PMID:Growth inhibition and induction of cellular differentiation of human myeloid leukemia cells in culture by carbamoyl congeners of ribavirin. 229 29

The antitumor and DNA-binding properties of a group of oligomeric platinum(II) and platinum(IV) complexes are described. The compounds, having the stoichiometry [cis-PtII(X)2(mu-OH)]2(NO3)2, where X is NH3, NH2CH2CH3, and NH2CH(CH3)2, were found to be inactive or only weakly active against L-1210 leukemia. In vitro studies involving PM2-DNA show that these compounds bind to and unwind closed circular DNA in a manner similar to cis-PtII-(NH3)2Cl2. The Pt(IV) complexes produced by hydrogen peroxide oxidation of the Pt(II) dimers are inactive as antitumor agents and are incapable of unwinding PM2-DNA. The cyclotrimer [cis-PtII(RR-DACH)(mu-OH)]3(NO3)3, where RR-DACH is (R,R)-1,2 diaminocyclohexane, exhibits potent antitumor activity against L-1210 leukemia and modest activities with B-16 and M5076 tumor lines. This compound platinates DNA, causing DNA unwinding and mobility shifts.
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PMID:Antitumor and DNA-binding properties of a group of oligomeric complexes of Pt(II) and Pt(IV). 237 44

In order to study a new antitumor platinum complex, various platinum complexes were prepared from 2-amino-methylpyrrolidine derivatives synthesized to serve as carrier ligands and tested for their antitumor activity against Colon 26 carcinoma (s.c.-i.p. system) and P388 leukemia (i.p.-i.p. system) in mice. 2-Aminomethylpyrrolidine proved to be the most effective carrier ligand in its amine derivatives. The structure-activity relationships of the carrier ligands in the platinum complexes with dichloro, oxalato, 1,1-cyclobutanedicarboxylato and dichlorodihydroxo as leaving group were clearly shown on the Colon 26 carcinoma screen and were as follows: the antitumor activity of the platinum complexes with any leaving groups was considerably decreased by the substitution of hydrogen by alkyl group (Me, Et) on nitrogen of aminomethyl and the effects of 1,1-cyclobutanedicarboxylato Pt(II) complexes completely disappeared with the same substitution on nitrogen of pyrrolidine. In all the tested platinum complexes 2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato)platin um(II) (15) exhibited the most potent antitumor activity. 15 was superior to 1,1-cyclobutanedicarboxylatodiammineplatinum(II) (CBDCA) and similar to cis-diamminedichloroplatinum(II) (CDDP) on the Colon 26 carcinoma screen but it was inferior to CBDCA and CDDP on the P388 leukemia screen. Furthermore, 15 showed more potent antitumor activity than CBDCA against Colon 38 carcinoma (s.c.-i.p. system).
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PMID:Synthesis of platinum complexes of 2-aminomethylpyrrolidine derivatives for use as carrier ligands and their antitumor activities. 237 86

Xylanpoly-(hydrogen sulphate) disodium salt with a molecular weight of about 6000 daltons (HOE/BAY 946) completely inhibited syncytium formation induced by the infection of T lymphocytes with HIV as well as viral replication at concentrations above 25 micrograms/ml. This dose was found to be inhibitory for several strains of HIV-1 and HIV-2. Low molecular weight fractions of the compound were less active against HIV, and high molecular derivatives were as active as HOE/BAY 946. A direct influence of the drug on the infectivity of the virus could not be demonstrated. The drug inhibited the reverse transcriptase of HIV. Treatment of permanently HIV-infected U937 cells resulted in a drastic reduction of virus particles released into the supernatant and points to an additional mode of action. A therapeutic effect of HOE/BAY 946 against retroviruses in vivo could be demonstrated in Friend leukaemia virus-infected mice. A clinical pilot study with the compound was started recently in Germany with AIDS patients who did not tolerate or refused to take zidovudine and with asymptomatic virus carriers.
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PMID:Inhibition of HIV and virus replication by polysulphated polyxylan: HOE/BAY 946, a new antiviral compound. 246 49

P388 leukemia sublines were isolated from leukemia-cell-bearing CD2F1 mice that had been treated in vivo with increasing amounts of diaziquone (AZQ). The sublines isolated for in vitro studies were AZQ19 and AZQ30 which corresponded to the 19th and 30th in vivo passages, respectively. The AZQ19 subline displayed a very low degree of resistance to AZQ (1.5-fold), whereas the AZQ30 subline was sensitive. Both sublines, however, had much higher degrees of resistance to Adriamycin than to AZQ (24-fold for AZQ30 cells and 10-fold for AZQ19 cells). Both cell lines were also more resistant to actinomycin D, colchicine, and vincristine than to AZQ. The AZQ19 line was resistant to the alkylator thio-TEPA to the same degree that it was to AZQ, but the AZQ30 line was sensitive to thio-TEPA. On the other hand, AZQ30 cells were resistant to hydrogen peroxide with a very low degree of resistance (1.27-fold, P less than 0.05), whereas the AZQ19 line was sensitive. Drug accumulation experiments indicated that AZQ-resistant cells differed from the parental line in that they did not accumulate Adriamycin or vinblastine. In the case of AZQ, however, resistant and parental lines accumulated the same amounts of exchangeable AZQ. Using the immunoblotting technique, no P-glycoprotein was found in resistant cells. The resistant lines consumed oxygen at greater rates than the parental line. Oxygen consumption (Mean +/- SD) in sensitive cells was 2.0 +/- 0.4% O2 consumed/min, whereas in resistant cells it was nearly 3.1 +/- 0.6% O2 consumed/min. The increase in oxygen consumption with drug resistance was statistically significant (P less than 0.01). The kinetics of production of hydroxyl free radicals and of AZQ free radicals were faster in the resistant lines reflecting, in essence, their increased oxygen consumption. It appears that the two sublines analyzed here show resistance mechanisms that may have been elicited by the two distinct chemical constituents of AZQ. Therefore, in the AZQ19-resistant line, the alkylating aspect of AZQ was emphasized, whereas in the AZQ30 line, the quinone and, thus, free radical aspect was emphasized. This is consistent with AZQ30 cells being sensitive to the alkylator thio-TEPA and resistant to hydrogen peroxide, and the AZQ19 line being resistant to thio-TEPA and sensitive to hydrogen peroxide. In addition, the AZQ30 cell line was relatively more resistant than the AZQ19 line to Adriamycin.
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PMID:In vitro multidrug resistance of P388 murine leukemia selected for resistance to diaziquone. 257 72

The growth inhibitory effect on human leukemia HL-60 cells of hydrogen peroxide as an oxidative stress and the possibility of adaptation of the cells to this stress were examined. When HL-60 cells were treated with various concentrations of hydrogen peroxide, concentrations of 5-200 microM were found to be sublethal. When HL-60 cells were repeatedly exposed to 50 and 100 microM hydrogen peroxide, they began to grow stably in the medium with the drug after a few months, indicating that they had become adapted to the drug. Sublines HP50-2 and HP100-1 cloned from these cultures were approximately 40-fold and 340-fold more resistant, respectively, than the parent cells. These resistant sublines tended to form cell aggregates in stationary culture, suggesting an alteration in their surface membrane. The HP50-2 and HP100-1 lines will be useful in the studies of many cellular mechanisms associated with reactive oxygens.
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PMID:Adaptation of human leukemia HL-60 cells to hydrogen peroxide as oxidative stress. 279 82

Preliminary experiments have suggested that guinea pig L2C B-cell leukemia cells were able to evade macrophage-mediated lysis. To determine whether the L2C cells were resistant to macrophage cytotoxic activity or whether factors associated with the L2C leukemia contributed to a generalized inhibition of macrophage cytotoxic activity, pulmonary macrophages from strain 2 guinea pigs with L2C leukemia were tested for their ability to lyse the susceptible K562 cell line after activation by lipopolysaccharide (LPS) or lymphokines. In addition, the potential presence of soluble inhibitors of macrophage tumoricidal activity in serum-free culture supernatants and in serum from strain 2 guinea pigs terminally ill with the leukemia was tested by determining the effects of leukemic guinea pig serum (LGPS) or L2C-conditioned medium (CM) on the tumoricidal activity of normal pulmonary macrophages. Macrophages from guinea pigs terminally ill with L2C leukemia were demonstrated to be depressed in their cytotoxic activity against the K562 cell after stimulation by either LPS or lymphokines when compared to normal macrophages. The lymphokine-stimulated cytotoxic activity of normal macrophages was inhibited in the presence of LGPS or CM. Oxidative burst activity of normal macrophages, as measured by zymosan-stimulated production of superoxide and hydrogen peroxide, was also inhibited under these conditions. The data presented here suggests that soluble factors associated with L2C leukemia cells can suppress oxidative burst activity of macrophages in vitro and that this effect may contribute to the ability of the leukemia cells to evade macrophage-mediated cytotoxicity.
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PMID:Effects of L2C leukemia on macrophage-mediated responses. 282 44


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