Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An initial step in the replication of simian virus (SV40) DNA is the ATP-dependent formation of a double hexamer of the SV40 large tumor (T) antigen at the SV40 DNA replication origin. In the absence of DNA, T antigen assembled into hexamers in the presence of magnesium and ATP. Hexameric T antigen was stable and could be isolated by glycerol gradient centrifugation. The ATPase activities of hexameric and monomeric T antigen isolated from parallel glycerol gradients were identical. However, while monomeric T antigen was active in the ATP-dependent binding, untwisting, unwinding, and replication of SV40 origin-containing DNA, hexameric T antigen was inactive in these reactions. Isolated hexamers incubated at 37 degrees C in the presence of ATP remained intact, but dissociated into monomers when incubated at 37 degrees C in the absence of ATP. This dissociation restored the activity of these preparations in the DNA replication reaction, indicating that hexameric T antigen is not permanently inactivated but merely assembled into a nonproductive structure. We propose that the two hexamers of T antigen at the SV40 origin assemble around the DNA from monomer T antigen in solution. This complex untwists the DNA at the origin, melting specific DNA sequences. The resulting single-stranded regions may be utilized by the T antigen helicase activity to initiate DNA unwinding bidirectionally from the origin.
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PMID:The simian virus 40 T antigen double hexamer assembles around the DNA at the replication origin. 132 Nov 35

The activity of a phosphodiesterase of the phospholipase C (PLC) type and factors influencing its activity were studied in ascites tumor cells. The enzyme confined to the 12,000 x g particulate fraction hydrolyses inositol phospholipids, with preference for phosphatidylinositol 4-phosphate (PtdIns(4)P) over phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), exhibiting maximum values of 61 and 15 nmol/min per mg protein, respectively, at a pH optimum of 5.5. The phosphodiesterase, which is strongly Ca2+ dependent with optimal free Ca2+ concentrations between 20 and 100 nM for both substrates, is almost completely inhibited (93-95%) in the presence of 2 mM EGTA. Only the PLC acting on PtdIns(4,5)P2 is significantly activated in the presence of 6-60 microM GTP gamma S. The low extent of enzymatic activity in the presence of 5 mM MgCl2 or chelating agents is suggestive of inositolphosphatase activity which is supported by the determination of small amounts of myo-inositol during HPLC analyses. Both dioleoylglycerol (DAG) and the membrane-permeable 1-oleoyl-2-acetyl-sn-glycerol (OAG) inhibit PLC activity, exhibiting IC50 values of 5 microM with PtdIns(4)P and approx. 10 microM with PtdIns(4,5)P2 as substrate and maximum inhibition up to 60% (DAG) and 80% (OAG). These data are indicative of a mechanism of direct negative feedback regulation of the enzyme by diglycerides which may explain the observed long-term effects of OAG on PLC activity in cell culture experiments.
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PMID:Ca2+ and partly GTP gamma S-dependent particulate phospholipase C hydrolyzing phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate is inhibited by diacyl(acyl-acetyl) glycerols. 133 19

Multidrug-resistant human tumor cells overexpress the MDR1 gene product P-glycoprotein, which is believed to function as an ATP-dependent efflux pump. In this study we demonstrate that the partially purified P-glycoprotein, when reconstituted in an artificial membrane, catalyzes drug-stimulated ATP hydrolysis. Plasma membrane proteins of a human multidrug-resistant cell line, KB-V1, were solubilized with 1.4% (wt/vol) octyl beta-D-glucopyranoside in the presence of 0.4% phospholipid and 20% (vol/vol) glycerol, and the crude detergent extract was chromatographed on DEAE-Sepharose CL-6B. The 0.1 M NaCl fraction, enriched in P-glycoprotein but devoid of Na,K-ATPase, was reconstituted by the detergent-dilution method. P-glycoprotein constituted 25-30% of the reconstituted protein in proteoliposomes. ATP hydrolysis by proteoliposomes was stimulated 3.5-fold by the addition of vinblastine but was unaffected by the hydrophobic antitumor agent camptothecin, which is not transported by P-glycoprotein. The stimulatory effect of vinblastine was observed only if the protein was reconstituted in proteoliposomes, suggesting that either the substrate binding site(s) was masked by detergent or that the conformation of the soluble P-glycoprotein might not be suitable for substrate-induced activation. Several other drugs that are known to be transported by P-glycoprotein enhanced the ATPase activity in a dose-dependent manner with relative potencies as follows: doxorubicin = vinblastine greater than daunomycin greater than actinomycin D greater than verapamil greater than colchicine. The basal and vinblastine-stimulated ATPase activities were inhibited by vanadate (50% inhibition observed at 7-10 microM) but were not affected by agents that inhibit other ATPases and phosphatases. These data indicate that the P-glycoprotein, similar to other ion-transporting ATPases, exhibits a high level of ATP hydrolysis (5-12 mumol per min per mg of protein).
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PMID:Partial purification and reconstitution of the human multidrug-resistance pump: characterization of the drug-stimulatable ATP hydrolysis. 135 64

A triglyceride analog, glycerol-2-palmitoyl-1,3-di-15-(p-iodophenyl)pentadecanoate (DPPG) was synthesized and radiolabeled for evaluation as a potential functional liver scintigraphic agent. Uptake of DPPG was compared in normal, diabetic, tumor-bearing and heparin pretreated rats, revealing differences in uptake and clearance of radioactivity, correlating with hepatic lipase activity of these groups. Similar results were observed by gamma-camera scintigraphy. Comparing the uptake of DPPG with that of its fatty acid component, 15-(p-iodophenyl)pentadecanoic acid (IPPA), revealed that the peak uptake of IPPA in the liver was about half that of DPPG. Based upon these findings, DPPG warrants further study as a hepatic radiodiagnostic agent.
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PMID:Potential organ or tumor imaging agents. 32. A triglyceride ester of p-iodophenyl pentadecanoic acid as a potential hepatic imaging agent. 152 18

A number of highly lipophilic dineodecanoato(trans-R,R- and trans-S,S-1,2-diaminocyclohexane) platinum (II) complexes were entrapped in multilamellar vesicles composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidyl-glycerol at a molar ratio of 7:3. The entrapment efficiency and stability of liposomal platinum (L-Pt) preparations was greater than 90%. The subacute mouse LD50 of L-Pt preparations tested ranged from 60 to 104 mg/kg. All L-Pt preparations tested had no significant nephrotoxicity at the LD50 dose except for L-Pt 5, which caused renal dysfunctions (as evidenced by elevated blood urea nitrogen levels) at the LD50 dose. L-Pt preparations had shown good in vivo antitumor activity against i.p. L1210 leukemia when an optimal dose was administered i.p. to mice on days 1, 5 and 9 (% T/C 230-300; cisplatin 220). L-Pt preparations were also markedly active, by the i.p. route, against L1210 leukemia resistant to cisplatin (% T/C 237-355; cisplatin 112). All L-Pt preparations exhibited significant antitumor activity against B16 melanoma when administered i.p. on day 1 (% T/C 144-155; cisplatin 161). L-Pt 1, 3 and 5 were all tested by the i.v. route on days 4, 8 and 12 against M5076 reticulosarcoma, but none of these preparations showed any significant antitumor activity against this tumor system (% T/C 120-127; cisplatin 173). Current studies aimed at optimizing the liposomal formulation of these compounds should result in the selection of a single isomeric L-Pt formulation for clinical development.
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PMID:Toxicity and efficacy studies on a series of lipid-soluble dineodecanoato(trans-R,R- and trans-S,S-1,2-diaminocyclohexane) platinum (II) complexes entrapped in liposomes. 152 98

As a common characteristic of tumor cells, as well as of normal proliferating cells in the G1-phase of cell cycle, one finds constitutive high levels of all the glycolytic metabolites arising between glucose 6-phosphate and phosphoenolpyruvate. Thus, it is that the phosphometabolites fructose 1,6-bisphosphate, ribose 5-P, P-ribose-PP, NAD, GTP, CTO, UTP, UDP-glucose, glycerol 3-P, glycerol phosphocholine and glycerol phosphoethanolamine are useful in the 31P-nuclear magnetic resonance (NMR) detection of solid tumors in animals and man. This expansion of phosphometabolites is achieved during tumor formation as a result of reductions in levels of enzymes degrading phosphometabolites, owing to the decline in the glycerol 3-P hydrogen shuttle, and as a consequence of alterations in the glycolytic isoenzyme equipment. Tumor cells typically express a particular isoenzyme of pyruvate kinase called type M2 (K) at high levels. This isoenzyme is subject to a complex regulation by amino acids, by fructose 1,6-bisphosphate, and by hormonal- and oncogene-dependent phosphorylation. Pyruvate kinase type M2 is a substrate for the oncogene encoded PP60v-src-tyrosine kinase. A drastic decrease in the affinity for its substrate phosphoenolpyruvate found after transformation by the src-oncogene can be explained as a consequence of the phosphorylation of pyruvate kinase in serine and tyrosine. These phosphorylations induce the breakdown of tetrameric pyruvate kinase to the trimeric and dimeric forms. Unlike the tetrameric form, the dimeric form as a low affinity for phosphoenolpyruvate. Partial inactivation of pyruvate kinase and enolase on the one hand, and a hyperactivation of hexokinase and phosphofructokinase on the other hand, lead to an expansion of all metabolites. Only when these metabolites attain high levels, thereby assuring a sufficient supply of metabolites for RNA, DNA, lipid, and complex carbohydrate synthesis, can cell proliferation proceed. This accumulation of metabolites in the G1-phase cells has been termed a "metabolic budget system" because it senses not only the actual nutrient levels, but also the supply over a period of time. Monoclonal antibodies specific for the dimeric form of pyruvate kinase type M2 can be used for the immunohistological detection of tumor cells. The amount of the dimeric form in tumor cells closely correlates with the degree of malignancy and can be used for a nonspecific detection of tumors based on assays performed with patient's plasma.
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PMID:Double role for pyruvate kinase type M2 in the expansion of phosphometabolite pools found in tumor cells. 153 31

Fibroblasts represent one of the in vivo sites of insulin-like growth factor-I (IGF-I) production. In this study rat dermal fibroblasts in culture were used as a model system to assess the effect of activation of protein kinase-C on the levels of the mRNAs encoding IGF-I and another growth factor, basic fibroblast growth factor (bFGF). IGF-I and bFGF mRNA levels were determined using a solution hybridization/RNase protection assay. Treatment of cells in serum-free medium containing 0.25% BSA (MEM + BSA) with the tumor-promoting phorbol ester phorbol 12-myristate 13-acetate (PMA) decreased IGF-I and increased bFGF mRNA levels in a time- and dose-dependent fashion. The peak effect of 100 nM PMA on IGF-I mRNA levels occurred at 9 h, whereas the peak effect on bFGF mRNA levels occurred after 3 h of incubation. In dose-response studies, half-maximal inhibition of IGF-I mRNA levels was achieved with approximately 0.08 nM PMA, while half-maximal stimulation of bFGF mRNA levels was achieved with approximately 3 nM PMA. Inhibition of protein synthesis with cycloheximide abrogated the effect of PMA on bFGF mRNA levels, but only partially inhibited the effect of PMA on IGF-I mRNA levels. Studies employing sphingosine or staurosporine to inhibit protein kinase-C or preincubation in high doses of PMA to down-regulate protein kinase-C suggested that the effect of PMA on IGF-I and bFGF mRNA levels was mediated by activation of protein kinase-C, although both staurosporine and sphingosine had independent effects on the levels of these mRNAs and down-regulation of protein kinase-C had a sustained effect on IGF-I mRNA levels. Ligands known to activate protein kinase-C were then tested. Treatment of cells with 100 micrograms/ml of the synthetic diacylglycerol 1-oleoyl-2-acetyl-sn-glycerol decreased IGF-I mRNA levels to 25% and increased bFGF mRNA levels to 520% of the level present in cells maintained in MEM + BSA. Treatment of cells with thrombin or bradykinin also decreased IGF-I mRNA levels and increased bFGF mRNA levels, but whereas the effect of thrombin on IGF-I mRNA levels was marked, the effect of bradykinin was minimal, and whereas the effect of thrombin on bFGF mRNA levels was sustained, the effect of bradykinin was transient.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Activation of protein kinase-C differentially regulates insulin-like growth factor-I and basic fibroblast growth factor messenger RNA levels. 160 84

The 14-O-palmitoyl ester of 3'-deamino-3'-hydroxydoxorubicin was synthesized to study the liposomal formulation and biological activity properties conferred by the attachment of a lipophilic group to position 14 of the anthracycline molecule. The entrapment efficiency of 14-O-palmitoyl-hydroxyrubicin in multilamellar vesicles composed of dimyristoylphosphatidyl choline and dimyristoylphosphatidyl glycerol was greater than 99%. In addition, the stability of liposomes containing 14-O-palmitoyl-hydroxyrubicin was greater than 99% at 14 days as assessed by the amount of drug leaking out of the liposomes and the absence of crystals of free drug in the liposome pellet. Esterification at position 14 did not significantly decrease the potency of the parent compound 3'-hydroxydoxorubicin. Liposome-entrapped 14-O-palmitoyl-hydroxyrubicin was significantly more active than doxorubicin against two murine tumor models. Against ip L-1210 leukemia, liposome-entrapped 14-O-palmitoyl-hydroxyrubicin injected i.p. into mice at doses of 60 and 80 mg/kg resulted in a %T/C value (median survival of treated/control animals x 100) of greater than 600, with 3-4 of 6 animals being cured, whereas in the same experiments, doxorubicin injected at the optimal dose (10 mg/kg) resulted in a %T/C value of 340, with 1 of 6 animals being cured. In animals bearing liver metastases of M-5076 reticulosarcoma, liposome-entrapped 14-O-palmitoyl-hydroxyrubicin showed significant antitumor activity when given on a three-i.v.-injection schedule of 20 mg/kg on days 4, 8, and 12 (%T/C, 175), whereas doxorubicin injected at optimal doses of 6-8 mg/kg on the same days was devoid of antitumor activity (%T/C, 129-133). These results indicate that esterification at position 14 enhances the affinity of this type of compounds for lipid bilayers without negatively affecting their biological activity.
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PMID:Liposomal formulation and antitumor activity of 14-O-palmitoyl-hydroxyrubicin. 164 93

The metabolism of phosphatidylinositol was studied in normal quiescent hepatocytes, hepatocellular carcinomas induced by single dose of diethylnitrosamine, followed by 2-acetylaminofluorene and partial hepatectomy (Solt-Farber model), and in an established hepatoma cell line, JB1. The JB1 hepatoma cell line and hepatocellular carcinomas demonstrated a 4- to 5-fold higher rate of turnover of [3H]-inositol and [3H]-glycerol than the control hepatocytes. Significantly, elevated levels of second messengers inositol 1,4,5-trisphosphate and sn-1,2-diacylglycerol were noted in hepatic tumor cells within 4 hr of labeling with precursor molecules, whereas no detectable level of 3H-labeled inositol trisphosphate was noted in quiescent hepatocytes, even after incubation with 10 mM LiCl for 30 min. Approximately 2.5-fold higher specific activities of a guanine nucleotide and Ca+2 dependent phosphatidylinositol 4,5-bisphosphate specific phospholipase C were detected in the hepatocellular carcinoma cells. The cellular location of the phospholipase C activity was also different, being membrane bound in hepatocytes and equally distributed between cytosolic and membrane factions in the hepatomas. These data are consistent with the hypothesis that the enhanced production of diacylglycerol and inositol 1,4,5-trisphosphate in hepatocellular carcinomas may be due to the activation of a guanine nucleotide dependent phosphatidylinositol 4,5-bisphosphate specific phospholipase C. These data are the first to compare phosphoinositide turnover in normal liver and hepatic tumor cells and suggest that the sustained levels of second messengers is closely associated with the transformation and enhanced growth rate in hepatic tumor cells.
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PMID:Altered levels of phosphoinositide metabolites and activation of guanine-nucleotide dependent phospholipase C in rat hepatic tumors. 164 43

We report here the complete synthesis of the spin-labeled derivative of an antitumor ether phospholipid, 1-O-octadecyl-2-O-(4'-doxylpentyl)-rac-glycerol-3-phosphocholine. This also represents the first time that the synthesis of a nitroxide spin-labeled diether phospholipid is described. In vitro experiments showed that at micromolar concentrations, this new analog is readily incorporated into the plasma membranes of human HL60 and mouse E8/AK.D1 leukemic cells, and subsequently kills the cells. The availability of this new probe should permit the electron spin resonance spectroscopic approach to investigate ways by which anti-tumor ether phospholipids selectively destroy the tumor cells.
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PMID:Synthesis of the spin-labeled derivative of an ether-linked phospholipid possessing high antineoplastic activity. 165 23


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