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

The structural parameters necessary for the antineoplastic potency of a new class of anticancer agents, arylsulfonylhydrazones of 2-formylpyridine N-oxide, were examined in mice bearing Sarcoma 180 ascites cells. The findings indicated that (a) replacement of the pyridine ring with benzene, quinoline, or isoquinoline resulted in loss of activity (b) movement of the formylhydrazone side chain from the 2 to the 3 or 4 positions of the pyridine N-oxide produced inactive agents (c) the pyridine N-oxide function was essential for anticancer activity, except for 4-substituted derivatives which were active without the N-oxide group, (d) replacement of the SO2 group by CO resulted in complete loss of activity, and (e) a carbon atom could be inserted between the SO2 and aryl ring with retention of anticancer potency. One of the most active members of this series, 1-oxidopyridine-2-carboxaldehyde p-toluenesulfonylhdrazone, exhibited antineoplastic activity against a broad spectrum of transplanted tumors including Sarcoma 180, Hepatoma 129, Ehrlich carcinoma, leukemia L1210, and a subline of Sarcoma 180 resistant to alpha-(N)-heterocyclic carboxaldehyde thiosemicarbazones. This agent caused inhibition of thymidine-3H and uridine-3H incorporation into DNA and RNA, respectively, of Sarcoma 180 ascites cells; protein biosynthesis was relatively insensitive to the action of this compound.
 ...
PMID:Antineoplastic and biochemical properties of arylsulfonylhydrazones of 2-formylpyridine N-oxide. 18 76

The synthesis of the N,N-bis-(acetylhomoveratrylamido)-1-hydroxymethyl and 1-carboxypropylamines (III a) and (III b) is described. Until now, these molecules could not been cyclized to the corresponding isoquinoline compounds. An attempted synthesis of 3-azaemetine by condensing homoveratrylamine with acetonedicarboxylic acid or its esters did not yield the expected diamide (XIV). However, by subjecting 1,3-bis-(1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl)acetone (XV) to a reducing aminoalkylation, one obtained the corresponding ethylamino derivative (XVI) which could be cyclized through Mannich reaction to give 3-azaemetine. The pharmacological screening showed 3-azaemetine to be less toxic than emetine in the mouse and without antiamebic and antitumor activity against P 388 Leukaemia in the mouse (25).
 ...
PMID:[Azotized emetine analogues: synthesis and evaluation of the anti-amebic and anti-tumoral action of aza-3 emetine and attempted synthesis of aza-2 emetine]. 21 76

Antitumor activity of N-heterocyclic carboxaldehyde thiosemicarbazone derivatives was examined in ascites sarcoma-180 system. Among isoquinoline-1-carboxaldehyde thiosemicarbazone derivatives, the parent compound, IQ-1, was the most active and less toxic. On the other hand, among the pyridine-2-carboxaldehyde thiosemicarbazone derivatives tested, 5-acetoxymethyl and 5-isonicotinoyl derivatives were active, and their therapeutic indices were 190 and 54, respectively. In other tumor systems, acetoxymethyl derivative was markedly active against Ehrlich ascites carcinoma, leukemia L-1210, and leukemia C-1498, while moderately effective against Nakahara-Fukuoka sarcoma, but it was not active against adenocarcinoma-755. Isonicotinoyl derivative was markedly active against Ehrlich ascites carcinoma, leukemia L-1210, and leukemia C-1498, while moderately active against adenocarcinoma-755, and slightly active against Nakahara-Fukuoka sarcoma.
 ...
PMID:Antitumor activity of N-heterocyclic carboxaldehyde thiosemicarbazone derivatives. 89 96

We investigated the effects of seven isoquinoline derivatives in overcoming resistance to vinblastine in Adriamycin-resistant mouse leukemia P388/ADR cells and human myelogeneous leukemia K562/ADR cells. N-(2-Methylpiperazyl)-5-isoquinoline-sulfonamide (H-7), N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide (H-8), and N-(2-aminoethyl)-5-isoquinolinesulfonamide (H-9) did not reverse resistance to vinblastine in these resistant cells. N-[2-[N-[3-(4-Chlorophenyl)-2-propenyl]amino]ethyl]-5- isoquinolinesulfonamide (H-86) and N-[2-[N-[3-(4-chlorophenyl)-1-methyl-2-propenyl]- amino]ethyl]-5-isoquinolinesulfonamide (H-87) caused significant accumulation of intracellular vinblastine and marked reversal of the resistance to vinblastine in both resistant cell lines. Addition of a formyl group at the terminal amino group of H-86 (H-85) or addition of an aminoethyl group to the nitrogen atom at the sulfonamide group of H-86 (W-66) reduced those activities. The activity on vinblastine accumulation seems to correlated with the hydrophobicity of the compounds. The compounds that effectively reversed resistance to vinblastine inhibited [3H]vinblastine efflux and photoaffinity labeling of P-glycoprotein with a photosensitive analogue of vinblastine, N-(p-azido-(3-[125I]iodo)-salicyl)-N'-beta-aminoethylvindesine. Although these isoquinoline derivatives inhibited protein kinase A and protein kinase C with various potencies, these inhibitory activities did not correlate with the reversal of drug resistance. These results indicate that hydrophobic isoquinoline derivatives reverse multidrug resistance due to the suppression of drug binding to P-glycoprotein, without involvement of their activities on protein kinase A and protein kinase C.
 ...
PMID:Overcoming of vinblastine resistance by isoquinolinesulfonamide compounds in adriamycin-resistant leukemia cells. 161 7

The combination of tumour necrosis factor alpha (TNF alpha) and gamma-interferon induced transcription of class I HLA genes in chronic myelogenous leukaemia (CML) cell lines through the formation of a complex between nuclear proteins and the transcriptional enhancers associated with these genes. Although gamma-interferon or TNF-alpha stimulated expression of class I HLA antigens in the EM2 and K562 CML cell lines when used alone, the effect of the combination of TNF-alpha and gamma-interferon was greater than that observed with either agent alone. The induction of class I HLA expression by gamma-interferon and TNF-alpha was inhibited completely by the isoquinoline sulfonamide H7, an inhibitor of protein kinase C. We conclude that the enhancement of the gamma-interferon induced transcriptional activation of class I HLA gene expression by TNF-alpha involves a protein kinase C-dependent pathway.
 ...
PMID:Activation of class I HLA expression by TNF-alpha and gamma-interferon is mediated through protein kinase C-dependent pathway in CML cell lines. 190 10

A newly synthesized compound, H-87, N-[2-(p-bromo cinnamylmethylamino)ethyl]-5-isoquinolinesulfonamide was found to be a potent and selective inhibitor of cyclic AMP-dependent protein kinase. The effects of H-87 on in vitro sensitivities of various P388 murine leukemia cell lines resistant to several antitumor agents were examined. H-87 significantly potentiated the cytotoxic effects of Adriamycin (ADR), daunorubicin (DAU), vincristine (VCR) and vinblastine (VBL) on P388 cells resistant to these antitumor agents but hardly influenced the effects of mitomycin C (MMC), 5-fluorouracil (5-FU) and cisplatin (CDDP) on ADR-resistant P388 cells (P388/ADR) and P388 phenotypes resistant to the corresponding antitumor agents. H-87 promoted the accumulation of VBL much more in P388/ADR cells than in the sensitive cells by inhibiting the energy-dependent extrusion of the antitumor agent from the cells. These results suggest that this novel isoquinoline-sulfonamide derivative, H-87, overcomes the multidrug resistance by inhibiting the phosphorylation of an outward drug transport system through cyclic AMP-dependent protein kinase.
 ...
PMID:Circumvention of multidrug resistance in P388 murine leukemia cells by a novel inhibitor of cyclic AMP-dependent protein kinase, H-87. 233 96

The human erythroid myeloid leukaemia cell line K562 was used as target for human neutrophil cytotoxicity. Neutrophils demonstrated cytotoxicity against K562 only in the presence of a second stimulus, tetradecanoyl phorbol acetate (TPA), a result consistent with previous observations. We now demonstrate that antibody-coated K562 (using OKT9 and 345 monoclonal antibodies) are similarly only sensitive to neutrophils when TPA is added. The presence of both antibody and TPA in the cytotoxic assay resulted in significantly higher levels of cytotoxicity than in the absence of antibody; the result being consistent with a synergistic action between protein kinase C activation and Fc receptor perturbation in the neutrophil. The cytotoxicity against non-coated and antibody-coated targets was markedly inhibited, particularly against the former, by the protein kinase C inhibitor, 1-(5-isoquinoline-sulfonyl)-2-methyl piperazine (H-7). There were marked differences in the extracellular calcium dependency of the two types of cytotoxicity reactions. TPA-activated respiratory burst was unaffected by the presence of non-coated and OKT9-coated targets, whereas TPA-induced lysosomal enzyme release was significantly increased by non-coated targets and a further increase occurred in the presence of OKT9-coated K562.
 ...
PMID:Triggering of neutrophil cytotoxicity against an antibody-coated tumour target by TPA. 256 Apr 63

Pharmacokinetics and urinary excretion of Amonafide (5-amino-2-[2-(dimethylamine)ethyl]-1H-benz[de]isoquinoline-1,3-(2H)- dione) were examined in seven patients who were administered 400 mg/m2 of drug as a 30-min infusion on a daily schedule for 5 consecutive days. Amonafide concentrations in plasma and urine were determined using reversed phase HPLC. Amonafide was eliminated from plasma with a terminal half-life of 3.5 hr. Renal excretion accounted for 23% of the administered dose. Amonafide pharmacokinetic parameters after the initial dose (day 1) were similar to those calculated after the fifth daily dose. Amonafide undergoes a significant amount of metabolism and eight urinary metabolites have been identified using a thermospray liquid chromatography-mass spectrometry (LC/MS) technique. Various N-acetylated species appear to be the major metabolites, although no evidence of N-acetylation was found in urine obtained from two patients. Two of the primary metabolites, the N(N5)-acetyl and N'(N1)-oxide metabolites of Amonafide, were tested in vitro for cytotoxicity against P388 murine leukemia cells. In this test system, the N-acetyl metabolite was observed to be only slightly less cytotoxic than the parent compound. The N'-oxide of Amonafide, however, proved to be inactive. These results are discussed together with the pharmacokinetic and metabolism data of this new investigational antitumor drug.
 ...
PMID:Pharmacokinetics and metabolism of the antitumor drug amonafide (NSC-308847) in humans. 289 1

Phosphorylation of a 36,000-dalton (36k-Da) protein of rat basophilic leukemia (RBL-2H3) cell membranes was investigated. This phosphoprotein has been suggested to be the beta-subunit protein of the immunogloblin E (IgE) receptor of RBL-2H3 cells [Teshima et al., Biochem. biophys. Res. Commun. 125, 867-874 (1984)]. Phospholipids such as phosphatidyl serine, phosphatidyl inositol and phosphatidyl ethanolamine, which are known to be activators of protein kinase C, enhanced the phosphorylation of the 36K-Da protein. In contrast, 1-(5-isoquinoline sulfonyl)-2-methylpiperazine (H-7) which has been identified as a potent inhibitor of protein kinase C in vitro decreased incorporation of radioactive phosphate from [gamma-32P]ATP into this protein. These results indicate that the phosphorylation of the 36K-Da protein of RBL-2H3 cell membranes is catalyzed by protein kinase C. H-7 also inhibited the release of serotonin from RBL-2H3 cells stimulated with an antigen or calcium ionophore A23187 and 12-O-tetradecanoyl phorbol 13-acetate (TPA). Treatment of the antigen-stimulated cells with TPA caused a synergistic effect on the serotonin release. A similar effect was obtained by treatment of A23187-stimulated cells with TPA or 1-oleoyl-2-acetyl glycerol.
 ...
PMID:Possible involvement of phosphorylation of a 36,000-dalton protein of rat basophilic leukemia (RBL-2H3) cell membranes in serotonin release. 308 12

A series of mono-, di-, and trimethoxystyryl derivatives of heterocyclic nitrogen compounds were prepared to test the N-O-O triangulation hypothesis of Zee-Cheng and Cheng. Of 29 free bases submitted for KB cell culture test, only 2-(3,4-methylenedioxystyryl)benzoxazole and 4-(2,5-dimethoxystyryl)cinnoline were active (ED50 of 4 microgram/ml or less). Methiodide salts were more potent: 8 of 14 were active. 2-(2,4,6-Trimethoxystyryl)quinoline methiodide and 4-(2,4,5-trimethoxystyryl)quinoline methiodide had ED50 of 0.4 and 0.9 microgram/ml, respectively. The methiodides of 2-(2,3,4-, 4-(2,4,5-, 4-(2,4,6-, and 2,4-bis-(2,4,6-trimethoxystyryl)quinoline and 1-(2,4,6-trimethoxystyryl) isoquinoline and the propiodide of 4-(2,4,6-trimethoxystyryl)quinoline were active against P388 leukemia. Several of the active compounds do not conform to the dimensions of the Zee-Cheng and Cheng triangle.
 ...
PMID:Di- and tri-methoxystyryl derivatives of heterocyclic nitrogen compounds. 719 62


1 2 3 4 Next >>