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 developed an in vitro model for studying the cytotoxicity of pharmacologic agents on corneal epithelium employing 3H-thymidine incorporation. Primary rabbit corneal epithelial cell cultures were established, and the cells plated prior to each experiment. 3H-thymidine incorporation was measured after the addition of drug or vehicle to these confluent cells, and dose-response curves were generated. Marked inhibition of 3H-thymidine incorporation was reached at chemotherapeutic concentrations achieved clinically for cytosine arabinoside (10(-7) M), methotrexate (10(-3) M), and 5-fluorouracil (10(-6) M). A 10(-4) M concentration of 2-deoxycytidine, a naturally occurring competitive inhibitor of cytosine arabinoside, protected cells up to a concentration of 10(-5) M. We utilized these data to undertake an in vivo prophylaxis study in 13 leukemia patients receiving high-dose iv cytosine arabinoside. Topical deoxycytidine 10(-4) M and 1% prednisolone phosphate, given 12 hours prior to the start of antileukemic therapy, were effective in reducing symptoms and signs of keratitis; both were better than historical placebo-treated eyes. Ophthalmic preservatives were studied in vitro at concentrations used clinically: benzalkonium chloride (BAC) (0.004-0.02%) was the most toxic, thimerosal (TMS) (0.001-0.004%) intermediate, and chlorobutanol (CHB) (0.2-0.5%) the least toxic. Antiviral agents (final concentration) included: trifluridine (TFT) (1.0%), ethyldeoxuridine (EDU) (2.0%), and idoxuridine (IDU) (0.1%). Dose but not time-dependent concentrations of these 3 agents were noted to cause toxicity; however, (E)-5(2-bromovinyl)-2'-deoxyuridine (BVDU) (0.1%) was non-toxic. Similarly, tobramycin and amikacin were significantly less toxic than gentamicin and neomycin in this system. These in vitro cytotoxicity data correlate well with previous in vivo and pre-clinical corneal epithelial toxicity studies. Our model may be useful in the toxicologic study of future topical ophthalmic agents.
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PMID:An in vitro method which assesses corneal epithelial toxicity due to antineoplastic, preservative and antimicrobial agents. 248 34

The antitumor activity of 1-beta-D-arabinofuranosylcytosine-5'-alkylphosphates (CnPCAs) against L1210 leukemia in mice after oral administration was demonstrated. The optimum length of the alkyl group on the phosphate moiety of CnPCA for exhibiting a high antitumor activity was found to be between tetradecyl (C14) and tricosyl (C23). The most active alkyl derivative in this system was found to be 1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate (C18PCA). The optimum and minimum effective doses of C18PCA were 100 and 6.25 mg/kg/day (q1d, day 1 to day 5), respectively. The maximum T/C% of C18PCA was approximately 220. The antitumor activity of C18PCA was not greatly dependent on the treatment schedule and route. Plasma concentration of 1-beta-D-arabinofuranosylcytosine (ara-C) remained in the range of 0.4 to 0.75 nmol/ml [corrected] for 24 h after oral administration of 100 mg/kg (170 mumol/kg) of C18PCA. These results indicate that C18PCA administered per orally is absorbed intact through the gastrointestinal tract and area-C is released of long period of time. C18PCA is regarded as an orally active depot form of ara-C.
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PMID:Antitumor activity and pharmacology of 1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate: an orally active derivative of 1-beta-D-arabinofuranosylcytosine. 250 91

We have optimized the conditions for efficient NIH3T3 focus formation by calcium phosphate transfection of proviral Abelson-murine leukemia virus (A-MuLV) plasmid DNA. Linearized pA-MuLV, P120 or P160 strains, when transfected with calf thymus carrier DNA, will produce 40-50 foci/100 ng pA-MuLV without co-transfecting Moloney-murine leukemia virus (Mo-MuLV) plasmid DNA.
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PMID:Transformation of NIH3T3 cells by A-MuLV proviral DNA: effect of plasmid linearization and carrier DNA on transformation efficiency. 255 40

1. APP is activated by adenosine kinase to its 5'-phosphate (APP-MP). 2. APP-MP inhibits PRPP synthetase, and depletes cellular PRPP and purine and pyrimidine nucleotides. 3. APP inhibits synthesis of DNA and RNA, and blocks cells in G1 phase of the cell cycle. 4. APP retains full activity against MDR cells. 5. APP is equally active against quiescent and proliferating CHO cells. 6. APP has only weak activity against L1210 leukemia in vivo, but has substantial activity against mammary carcinoma 16/c. 7. In vitro, APP has a relatively high ratio of solid tumor: leukemia activity.
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PMID:Biochemical pharmacology and antitumor properties of 4-amino-8-[beta-D-ribofuranosylamino]pyrimido-[5,4-d]pyrimidine. 256 Mar 25

Growth of human hematopoietic cell lines showed a 100-fold range of sensitivity to inhibition by 2-chloro-2'-deoxyadenosine (CldAdo), with highly sensitive lines in all three groups: T-lymphoblastic, B-lymphoblastic, and non-T, non-B. Formation of nucleotides from [8-3H]CldAdo was investigated in ten lines. In cells exposed to 0.15 microM CldAdo, CldAdo 5'-phosphate (CldAMP) reached 0.7-14 microM and CldAdo 5'-triphosphate (CldATP) reached 0.05-6 microM in 1 h. In most cases these nucleotide concentrations at 1 h were close to the steady-state concentrations, and the latter concentrations were approximately proportional to extracellular CldAdo concentration. On removal of extracellular CldAdo, intracellular CldAMP and CldATP declined rapidly with half times of 0.56-0.9 and 0.64-1.46 h, respectively. There was no correlation between these rates of catabolism and steady-state levels. The different sensitivities of the lines to CldAdo is explained only in part by the different steady-state concentrations of CldATP, and must be more directly related to differential effects on target enzymes. Mice inoculated with L1210 leukemia were treated with 2-bromo-2'-deoxyadenosine (BrdAdo) paired with one of 18 other therapeutic agents. Eight of the drugs paired with BrdAdo gave therapeutic responses from the combination greater than the sum of the responses of members of the pair. They included alkylating agents, antimetabolites blocking deoxyribonucleotide synthesis, and DNA polymerase inhibitors. Toxic dosages of CldAdo caused damage chiefly to the hemic-lymphatic systems and the kidneys.
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PMID:Biochemical pharmacology of 2-chlorodeoxyadenosine in malignant human hematopoietic cell lines and therapeutic effects of 2-bromodeoxyadenosine in drug combinations in mice. 256 29

Acivicin [L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid; NSC 163501] is a fermentation-derived amino acid antibiotic antagonistic to L-glutamine which exhibits potent oncolytic properties. We have developed a variant of P388 leukemia resistant to acivicin (P388/ACIA) and compared its properties with those of the parent line (P388/S). An examination of the enzymes utilizing L-glutamine revealed that the basal specific activities of L-asparagine synthetase and L-glutaminase were 1-to 3-fold higher in the parent line. The activities of carbamoyl phosphate synthetase II, L-asparagine synthetase, formylglycinamide ribonucleotide amidotransferase, and guanosine monophosphate synthetase were about equally inhibited in the two cell lines, while there was a partial inhibition of 5-phosphoribosyl-1-pyrophosphate amidotransferase, fructose-6-phosphate amidotransferase, and L-glutaminase activities, found only in the sensitive line. Cytidine triphosphate synthetase activity was not inhibited in either line. There was no difference in the dose response or restitution of L-glutamine utilizing enzyme activities between the two lines. Acivicin treatment produced a 2- to 3-fold augmentation of the L-glutamine pools only in the sensitive line. Drug injection induced increased 5-phosphoribosyl-1-pyrophosphate levels in both lines. Acivicin perturbed guanosine nucleotide pools only in the sensitive line, indicating that the primary mechanism of action of acivicin in P388 leukemia may be directed at guanosine monophosphate synthetase. Transport studies demonstrated a restricted uptake of acivicin by the resistant cells. These studies suggest that the transport of acivicin and L-glutamine plays an important role in determining the sensitivity or resistance to acivicin in these tumors.
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PMID:Mechanism of resistance of a variant of P388 leukemia to L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin). 257 92

Colloidal [51Cr]chromic phosphate uptake is considerably increased by preincubation of P388 ascites leukemia cells with poly(DL-lysine). The uptake increase is in direct relationship with the concentration and the degree of polymerization of poly(DL-lysine). The probable implication of cell surface electrical charge modification in these phenomena is discussed.
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PMID:Enhancement of colloid uptake by tumor cell surface electrical charge modification. 275 31

Two peaks of phosphoinositide-specific phospholipase C (PI-PLC) activity were resolved when guinea pig uterus cytosolic proteins were chromatographed on a DEAE-Sepharose column. The first peak of enzyme activity eluting from the DEAE-Sepharose column (PI-PLC I) was further purified to homogeneity, whereas the second peak of enzyme activity was enriched 300-fold. PI-PLC I migrated as a 62-kDa protein on sodium dodecyl sulfate-polyacrylamide gels. Antibodies prepared against PI-PLC I failed to react with PI-PLC II. PI-PLC I hydrolyzed all three phosphoinositides, exhibiting a greater Vmax for phosphatidylinositol 4,5-bisphosphate greater than phosphatidylinositol 4-phosphate greater than phosphatidylinositol. Hydrolysis of phosphatidylinositol was calcium-dependent, whereas significant hydrolysis of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate occurred in the presence of 2.5 mM EGTA. At physiological concentrations of calcium, phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate were the preferred substrates. Antibodies specific for PI-PLC I reacted with a 62-kDa protein in both the cytosol and membrane fractions from guinea pig uterus. Quantitation of the immunoblots revealed that 25% of the 62-kDa protein was membrane-associated, whereas only 5% of the total enzyme activity was membrane-associated. Approximately 20% of the membrane-bound phospholipase C activity and immunoreactive material were loosely bound, whereas the remainder required detergent extraction for complete solubilization. The 62-kDa protein associated with the membrane fractions did not bind lectin affinity columns, suggesting that it was not glycosylated. PI-PLC I was identified as a phosphoprotein in [32P]orthophosphate-labeled rat basophilic leukemia (RBL-1) cells by two-dimensional gel electrophoresis followed by immunoblotting. In untreated cells, 32P-labeled PI-PLC I was found in the cytosolic fraction. Treatment of RBL-1 cells with those phorbol esters which are known to activate the Ca2+/phospholipid-dependent enzyme protein kinase C, resulted in a time-dependent increase in the phosphorylation of both membrane-bound and cytosolic PI-PLC I. Thus, in RBL-1 cells, protein kinase C may play an important role in the regulation of phospholipase C through protein phosphorylation.
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PMID:Purification and characterization of a phosphoinositide-specific phospholipase C from guinea pig uterus. Phosphorylation by protein kinase C in vivo. 282 Sep 80

The synthetic "C" nucleoside, tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide), its selenium analogue selenazofurin, and the related inhibitor of inosine 5'-phosphate (IMP) dehydrogenase, mycophenolic acid, are effective inducers of the terminal differentiation of HL-60 promyelocytic leukemia cells. The inhibition of cellular replication and the induced maturation produced by these agents appears to be a consequence of the inhibition of IMP dehydrogenase, since growth inhibition is partially reversed and differentiation is completely prevented by the simultaneous exposure of cells treated with inhibitors of IMP dehydrogenase to exogenous guanosine, which serves to circumvent the effects of the blockage of IMP dehydrogenase. The exposure of HL-60 leukemia cells to inhibitors of IMP dehydrogenase caused a marked reduction in the incorporation of [3H]mannose into both cellular glycoproteins and their lipid-linked oligosaccharide precursors; these effects are presumably due to the pronounced decrease in intracellular levels of guanosine triphosphate produced by blockage of IMP dehydrogenase. Maximum effects on glycoprotein biosynthesis occurred within 8 h of exposure to the inhibitors of IMP dehydrogenase. The simultaneous incubation of cells with guanosine and these inducers of differentiation partially prevented the reduction in [3H]mannose incorporation into glycoproteins, supporting a relationship between glycoprotein biosynthesis and guanosine triphosphate formation in the induction of differentiation by inhibitors of IMP dehydrogenase.
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PMID:Alterations in glycoprotein synthesis and guanosine triphosphate levels associated with the differentiation of HL-60 leukemia cells produced by inhibitors of inosine 5'-phosphate dehydrogenase. 287 Jul 96

The synthesis and testing of potential multisubstrate inhibitors of tyrosine-specific protein kinases are described. One of the substrates, ATP, was mimicked by the known kinase inhibitor 5'-[4-(fluorosulfonyl)benzoyl]adenosine, which was covalently linked via the sulfonyl moiety to tyrosine mimics. The resulting multisubstrate inhibitors were tested for their ability to inhibit the transfer of phosphate from ATP to a protein acceptor by p60v-abl, the tyrosine kinase encoded by the transforming gene (v-abl) of the Abelson murine leukemia virus (A-MuLV). Although the series of inhibitors displayed moderately potent activity (IC50 values as low as 19 microM), the absence of large effects produced by modification of the tyrosine mimic suggests that they do not behave as multisubstrate inhibitors but bind primarily through the adenosine moiety common to all the inhibitors. This interpretation is strengthened by the finding that the inhibitors lack specificity, inhibiting a serine kinase at comparable concentrations.
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PMID:Synthesis and evaluation of multisubstrate inhibitors of an oncogene-encoded tyrosine-specific protein kinase. 1. 297 May 50


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