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)

Purification of RNA polymerase II from chicken myeloblastosis (leukemia) cells to homogeneity and subsequent structural analysis of the purified enzyme revealed that the enzyme contained seven polypeptides with molecular masses ranging from 27 KDa to 220 KDa. Inclusion of protease inhibitors in the buffer system during purification significantly increased the molar ratio of the largest (220 KDa) polypeptide to the second largest (180 KDa) polypeptide. However, proteolytic conversion of the 220 KDa to 180 KDa polypeptide did not inhibit the DNA binding activity of the enzyme. The enzyme, after dissociation into subunits in a SDS-polyacrylamide gel containing urea was blotted onto a nitrocellulose filter. The filter was incubated with 32P-labeled calf thymus DNA and both the 220 KDa and 180 KDa polypeptides of the enzyme bind DNA, suggesting that the DNA-binding site of the enzyme resides on the 180 KDa polypeptide of the largest subunit.
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PMID:The 180 KDa polypeptide contains the DNA-binding domain of RNA polymerase II. 359 59

A series of water-soluble N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes (IDP) were synthesized and tested for chemical stability, antitumor activity, and toxicity. The results obtained suggest that these complexes are relatively stable for more than 48 h when dissolved in water or phosphate buffer. All complexes had good in vitro cytotoxicity and were not cross-resistant with cis-dichloro-diammineplatinum(II) (DDP) in a DDP-resistant cell line in vitro. When the complexes were administered as a single i.p. injection to C57BL/6 X DBA/2F1 (hereafter called B6D2F1) mice inoculated with L1210 leukemia cells, a significant increase in mean survival time was observed, but there were few long-term survivors. When the complexes were administered on Days 1, 5, and 9 after tumor inoculation, however, cure rates of 50 to 85% were obtained. The oncolytic activity of the IDP complexes against L1210 ascites appeared much greater than that of DDP. The IDP complexes also had good antitumor activity when administered i.p. on Days 1, 5, and 9 following i.p. inoculation of B16 melanoma to B6D2F1 mice. Five of the six IDP complexes had no significant nephrotoxicity (as evidenced by lack of elevated blood urea nitrogen levels). N-Benzyl-iminodiacetato(1,2-diaminocyclohexane)-platinum(II) resolved into three distinct peaks of UV-absorbing material that corresponded with three distinct peaks of platinum-containing material. The exact chemical identity of the active component of this mixture is currently under investigation. The results obtained to date, however, suggest that the N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes are good candidates for further developmental studies.
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PMID:Water-soluble N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes as potential antitumor agents. 377 45

The potential of multilamellar vesicles (MLVs) as carriers of cis-bis-cyclopentenecarboxylato-1,2-diaminocyclohexane platinum(II) (CPDP), a lipophilic cisplatin derivative, was assessed. MLVs composed of dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), and cholesterol at different molar ratios were tested. The MLV-CPDP preparation with the highest antitumor activity against L1210 leukemia in vivo was DMPC:DMPG 7:3-CPDP. The encapsulation efficiency of this preparation was 66 +/- 4% (SD); the stability in 0.9% NaCl solution at 4 degrees C was 89% at 14 days and 93% 18 h after incubation in human AB serum at 37 degrees C. The toxicities of DMPC:DMPG 7:3-CPDP and free CPDP (suspended in hydroxypropyl cellulose) administered i.p. were similar (50% lethal dose = 75 versus 91 mg/kg; blood urea nitrogen values 96 h after the administration of the 50% lethal dose = 32.0 versus 34.4 mg/dl). The mean %T/C [(median survival time of treated mice divided by median survival time of control mice) X 100] obtained after a single i.p. injection of the optimal dose of each preparation tested was 215 (range 200 to 232) for DMPC:DMPG 7:3-CPDP, 175 (range 158 to 209) for DMPG-CPDP, 162 (range 136 to 179) for free CPDP, and 178 (range 169 to 189) for cisplatin. Using a multiple i.p. injection schedule (injections on Days 1, 5, and 9), DMPC:DMPG 7:3-CPDP was more active than free CPDP and cisplatin (%T/C: 403, 284, and 253% respectively). DMPC:DMPG 7:3-CPDP is less toxic and more active against L1210 leukemia in vivo than is cisplatin. The encapsulation of CPDP in MLVs composed of DMPC:DMPG 7:3 provides an adequate vehicle for the administration of this lipophilic compound and enhances its antitumor activity against L1210 leukemia.
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PMID:Toxicity and antitumor activity of cis-bis-cyclopentenecarboxylato-1,2-diaminocyclohexane platinum(II) encapsulated in multilamellar vesicles. 377 46

Dihydrofolate reductase, purified to homogeneity from a subline of L1210 murine leukemia cells resistant to 10(-6) M Methotrexate, was resolved into two principal forms (1 and 2) by isoelectric focusing. These forms had pI values of 7.4 and 8.2, respectively; both stained for protein and catalytic activity. Form 1 was a single component, comprising ca. 10% of the total protein, but multiple components of 2 were observed by narrowing the pH range in the electrophoretic procedure. Urea-denatured enzyme exhibited two bands of approximately equal intensity upon isoelectric focusing. These results were interpreted to mean that the enzyme consists of a set of conformationally different forms, arising from two primary structures. Inhibition of the native enzyme by Methotrexate was polyphasic, and appreciable activity remained when the drug was present at an equimolar concentration. Various agents (KCl, H+, urea, and SH-modifiers), known to "activate" dihydrofolate reductases, produced a monophasic, stoichiometric inhibition. Activating agents appear to induce a more open (and labile) conformation of the enzyme. This leads to increased affinity for MTX accompanied, in some instances, by increased catalytic activity.
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PMID:L1210 dihydrofolate reductase: activation and enhancement of methotrexate sensitivity. 383 18

Dihydrofolate reductase, purified to homogeneity (as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis), from a subline of L1210 murine leukemia cells resistant to 10(-6) M methotrexate, was resolved into two principal forms (1 and 2) by polyacrylamide gel electrophoresis at pH 8.3 or isoelectric focusing. In the latter procedure, these forms had pI values of 7.4 and 8.2, respectively; both stained for protein and catalytic activity. Form 1 appears to be a single component, comprising ca. 10% of the total protein and at least 20% of the total catalytic activity. It is also more sensitive to inhibition by MTX, more heat-stable, and less susceptible to activation than form 2. Multiple components of 2 were observed by narrowing the pH range in isoelectric focusing, and further resolution was achieved by urea denaturation. Substrate and inhibitor complexes of 1 and 2, differentiated by polyacrylamide gel electrophoresis or isoelectric focusing, provided information about the ability of the enzyme to undergo conformational changes. Interconversion of 1 with one of the components of 2 may also involve conformational isomerism. These conclusions are consistent with the well-known ability of eukaryotic dihydrofolate reductases to exhibit increased catalytic activity (attributed to transformations to more open conformations) when treated with salts, chaotropes, or cysteine-modifying agents. Treatment of the L1210/R6 enzyme preparation with one of these activating agents, 5,5'-dithiobis(2-nitrobenzoic acid), derivatized both 1 and 2 (changing their pI values to 7.3 and 6.9, respectively) and altered the enzyme such that stoichiometric inhibition for MTX was observed.
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PMID:Polymorphism of dihydrofolate reductase from a methotrexate-resistant subline of L1210 cells. 407 99

Cells producing the Rauscher strain of murine leukemia virus (MLV) were exposed to (3)H-uridine, and labeled virus was collected at hourly intervals. Ribonucleic acid (RNA) extracted from virions (vRNA) had a characteristic single peak when analyzed by electrophoresis in polyacrylamide-agarose composite gels. Exposure of vRNA to dimethyl sulfoxide, urea, formaldehyde, or heat altered the mobility to a faster moving form (vRNA'). This vRNA' sedimented more slowly than native vRNA in sucrose gradients. Incubation of labeled virions at 37 C resulted in fragmentation of viral RNA which was detectable only after denaturation. Also, large differences in the temperature required for the change from vRNA to vRNA' were seen with alterations in NaCl concentration. These experiments demonstrate that the vRNA of MLV is held in a specific conformation by hydrogen bonds distributed over a large part of the molecule. The possibility that an undefined factor is associated with viral RNA is discussed.
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PMID:Analysis of the ribonucleic acid of murine leukemia virus. 430 79

The ribonucleic acid (RNA) of murine leukemia virus (MLV) Rauscher strain was observed by the aid of electron microscopy with the use of the protein monolayer technique. RNA was observed directly after release from virus particles or after isolation by sedimentation in sucrose density gradients. Molecules were found in an extended linear form. Many of the RNA filaments released by detergent treatment contained curled regions, suggesting the linear filaments were originally coiled within the virus particle. The relationship of the curled areas to the containment of the RNA within the virus particle is discussed, and a mechanism for the inclusion of RNA in the budding virion is proposed. Treatment of the extended MLV-RNA with dimethyl sulfoxide resulted in the collapse of the molecule forming a tangled complex. Treatment with urea or heating at 50 C in 3 mm NaCl also produced this effect. Also under the conditions in which MLV-RNA was linear, RNA from Rous sarcoma virus also was linear, but Newcastle disease virus RNA and ribosomal RNA of rat liver had collapsed structures. The results indicated that the RNA of MLV, and perhaps other RNA-containing tumor viruses, has a specific unique conformation dependent upon hydrogen bonds.
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PMID:Electron microscopic observations on the ribonucleic acid of murine leukemia virus. 430 80

The mechanism of action of the ribonuclease H (RNase H) activity associated with Moloney murine leukemia virus RNA-directed DNA polymerase (RNase H I) and the two-subunit (alpha beta) form of avian myeloblastosis virus DNA polymerase were compared by utilizing the model substrate (A)n.(dT)n and polyacrylamide gel electrophoresis in 7 M urea to analyze digestion products. Examination on 25% polyacrylamide gels revealed that a larger proportion of the RNase H I oligonucleotide products generated by limited digestion of [3H](A)(1100).(dT)n were acid insoluble (15-26 nucleotides long) than acid soluble (less than 15 nucleotides long), while the opposite was true for products generated by alpha beta RNase H. RNase H I was capable of attacking RNA in RNA.DNA in the 5' to 3' and 3' to 5' directions, as demonstrated by the use of [3H,3'- or 5'-32P](A)(380).(dT)n and cellulose--[3H](A)n.(dT)n. Both RNase H I and alpha beta RNase H degraded [3H]-(A)n.(dT)n with a partially processive mechanism, based upon classical substrate competition experiments and analyses of the kinetics of degradation of [3H,3'- or 5'-32P](A)(380).(dT)n. That is, both enzymes remain bound to a RNA.DNA substrate through a finite number of hydrolytic events but dissociate before the RNA is completely degraded. Both RNase H I and alpha beta RNase H were capable of degrading [14C](A)n in [3H](C)n-[14C](A)n-[32P](dA)n.(dT)n, suggesting that retroviral RNase H is capable of removing the tRNA primer at the 5' terminus of minus strand DNA at the appropriate time during retroviral DNA synthesis in vitro.
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PMID:Mechanism of action of Moloney murine leukemia virus RNA-directed DNA polymerase associated RNase H (RNase H I). 616 82

The mechanism of action of Moloney murine leukemia virus RNase H III was studied, utilizing the model substrate (A)n. (dT)n and polyacrylamide gel electrophoresis to assay enzyme activity. Examination by electrophoresis on 15% polyacrylamide gels in 7 M urea and on DEAE-cellulose paper in 7 M urea revealed that, early in a reaction with [3H](A)n. (dT)n as substrate, RNase H III generated products ranging in length from 80 to 90 nucleotides to less than 10 nucleotides and that after extended incubation the limit digest products generated were 3 to 15 nucleotides long. Product oligomers were of the following configuration: [5'-P, 3'-OH](A)n. RNase H III was shown to be an exonuclease requiring free ends in its substrate for activity by the inability to degrade RNA inserted in Escherichia coli ColE1 plasmid DNA. The enzyme was capable of attacking RNA in RNA-DNA hybrids in the 5' to 3' and 3' to 5' directions as demonstrated by the use of [3H, 5'-32P](A)600. (dT)n and cellulose-[3H](A)n. (dT)n. Rnase H III was random in its mode of action because addition of excess unlabeled (A)n. (dT)n to an ongoing reaction with [3H](A)n. (dT)n as substrate resulted in immediate inhibition of enzyme activity.
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PMID:Mechanism of action of Moloney murine leukemia virus RNase H III. 616 72

An RNA-directed DNA polymerase was purified from mouse spleen infected with leukaemia virus activated during N-methyl-N-nitroso urea- (MNU-) induced leukaemogenesis. The enzyme was isolated from the microsomal fraction and purified by successive chromatography of Sephadex G-200 and phosphocellulose. Estimation of molecular weight from the sedimentation rate of the purified enzyme in a sucrose gradient gave a value of 70,000. The enzyme had a pH optimum of 7.4, a KC1 optimum of 50 mmol/l, an Mn2+ optimum of 0.2 mmol/l, and a temperature optimum of 25 degrees C, when (rA)n . (dT) 10 was used as the template-primer. It preferred (rA)n . (dT)10 as the template-primer and transcribed (rC)n . (dG) 12 and (OMeC)n . (dG)12. A comparison of the properties of this DNA polymerase with the enzyme purified from murine type C retroviruses showed that the MNU-activated virus enzyme was both biochemically and biophysically indistinguishable from murine leukaemia virus DNA polymerases.
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PMID:Characterization of an RNA-directed DNA polymerase from mouse spleen infected with leukaemia virus activated during N-methyl-N-nitroso urea-induced leukaemogenesis. 617 78


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