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)

During the differentiation of human enterocytes, the secretion of apolipoprotein B is switched from the apoB-100 form seen almost exclusively in fetal cells to the apoB-48 form seen almost exclusively in adult cells. This switch is accomplished by the post-transcriptional editing of the messenger RNA for apoB-100. We report that a similar switch occurs during the differentiation of the human colonic carcinoma cell line, Caco-2, and that this is accomplished by the same mRNA editing mechanism. Caco-2 cells cultured on Millipore filters developed confluent electrically resistant monolayers, and on Western blot analysis, using a monoclonal antibody directed against the amino terminal region of human apoB-100 (Mab C1.4), secreted greater than 50% apoB-48 (of total apoB-100) into culture media, while Caco-2 cells grown on plastic secreted greater than 95% apoB-100. To assess whether mRNA editing was responsible for the switchover from apoB-100 to apoB-48, apoB cDNA fragments spanning nucleotides 6504-6784 of apoB mRNA were synthesized using RNA isolated from Caco-2 cells grown on filters and Caco-2 cells grown on plastic. The appropriate oligonucleotide primers and Moloney murine leukemia virus reverse transcriptase were used. The resulting cDNA fragments were amplified by the polymerase chain reaction (PCR), and PCR products were subcloned and sequenced. A single cytosine/thymine base change occurred in 8/20 clones of cDNA derived from Caco-2 cells grown on filters (corresponding to a cytosine/uridine change in mRNA) and in 1/25 clones of cDNA derived from Caco-2 cells grown on plastic. PCR products of genomic sequences from Caco-2 cells did not contain the stop codon.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Editing of apolipoprotein B messenger RNA in differentiated Caco-2 cells. 235 74

Utilizing the P388 murine leukemia cells sensitive (P388/S) and resistant (P388/ADR) to Adriamycin (ADR), we evaluated the effect of quinidine, an anti-arrhythmic agent, on the cytotoxic activity of ADR and Mitoxantrone (MITO), both in vitro as well as in vivo. Quinidine enhanced the cytotoxicity of both ADR and MITO in P388/S and P388/ADR cells, as assessed by the decrease in color intensity of formazan crystal in the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. A dose dependent inhibition of 3H-thymidine and 3H-uridine incorporation was observed when the P388/S and P388/ADR cells were exposed to quinidine alone. A non-toxic concentration of quinidine (5 microM) enhanced the DNA biosynthesis inhibition induced by ADR (55 to 65%) and MITO (37 to 44%) in P388/ADR cells, indicating reversal of resistance, while in P388/S cells only a minimal increase in DNA biosynthesis inhibition was observed. The combination of quinidine at doses of 50 to 100 mg/kg significantly potentiated the antitumor activity of ADR and MITO in P388/ADR bearing mice, whereas the potentiation of ADR and MITO antitumor response was lower in P388/S bearing mice. Quinidine increased the cellular levels of ADR by 53 to 126% in P388/ADR cells in vitro, but failed to indicate such elevated levels of cellular ADR in P388/S cells. This enhanced intracellular accumulation of ADR in P388/ADR cells, explains the therapeutic efficacy of ADR and MITO in P388/ADR, both in vitro as well as in vivo. Results suggest the efficacy of quinidine to ameliorate the antitumor effects of ADR and MITO in drug resistant tumor cells.
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PMID:Evaluation of quinidine effect on the antitumor activity of adriamycin and mitoxantrone in adriamycin-sensitive and -resistant P388 leukemia cells. 236 55

A study was made of the in vivo effects of equitoxic doses of AT-125 and 5-FU combination, being administered either simultaneously (% ILS 152) or with a 6-h pretreatment with AT-125 (% ILS 184). To examine the biochemical basis for the scheduled synergism, measurements were made of the concentration of PRPP, the specific activities of CPS II, cytidine, thymidine, uridine, deoxyuridine kinases, and fluorinated nucleotide formation in P388 tumors and the small intestine. Two hours after in vivo simultaneous treatment of mice bearing tumors the concentration of PRPP increased 9- and 6-fold above baseline in the tumor and the small intestine, respectively. In the AT-125 pretreatment arm the concentration of PRPP increased 18- and 7-fold above baseline in the tumor and the small intestine, respectively. CPS II activity was reduced to 28%-18% of control in the tumors in the simultaneous and pretreatment groups, respectively, whereas it remained unchanged in the small intestine. Specific activities of cytidine kinase (5.5 +/- 1), thymidine kinase (4.0 +/- 1.6), uridine kinase (35.6 +/- 6.5), and deoxyuridine kinase (2.4 +/- 1.1) nmol/mg protein/h remained unchanged with treatment. In concert with the increased intratumor concentration of PRPP, fluorinated nucleotide formation was proportionally increased in the treatment arms. These results indicate the importance of drug scheduling of the above two agents in treating P388 leukemia.
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PMID:Biochemical mechanisms for the scheduled synergism of (alpha S, 5S)-2 amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid and 5-fluorouracil in P388 leukemia. 240 73

The thymic leukemia cell line EL4 has been shown to produce the lymphokine Interleukin-2 (IL-2) following stimulation with phorbol ester (PMA). We investigated intracellular enzyme pathways triggered by phorbol stimulation using an EL4 cell line which responds to PMA with IL-2 synthesis (EL4r) and one which does not produce IL-2 following stimulation (EL4nr). By comparing these two cell lines we hoped to establish which enzyme activities were associated with IL-2 synthesis. The enzyme pathways studied included calcium/phospholipid dependent protein kinase (C-kinase) activity, the induction of polyamine synthesis, RNA, DNA and protein synthesis and finally IL-2 production. Our results indicate that both EL4 cell lines have a receptor for PMA, which can activate the C-kinase enzyme. Further, in both cell lines PMA activates the nuclear synthesis of polyamines as demonstrated by ornithine decarboxylase induction. Both RNA and protein synthesis measured by 3H-uridine and 3H-leucine uptake respectively appear comparable between EL4r and EL4nr. The only difference in cellular responsiveness between EL4r and EL4nr was in the 3H-thymidine uptake, and IL-2 production. IL-2 production or lack of production was established by 3H-uridine and 3H-thymidine incorporation as well as viable cell count using the IL-2 dependent cell line CTLL-2. We, therefore, conclude that EL4r and EL4nr cells show similar intracellular responses to phorbol ester except for 3H-thymidine uptake and detectable IL-2 production. Our results suggest that failure of PMA-stimulated EL4nr cells to produce IL-2 is either due to inability of this cell line to synthesize IL-2 or the production of defective IL-2. It is not due to failure of PMA to activate C-kinase or the subsequent nuclear events.
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PMID:The activation of calcium/phospholipid dependent protein kinase and the association with interleukin-2 production. 242 45

A novel anticancer drug, 1-phenyl-3-phenylamino-4-(p-toluenesulfinyl-trans-1,5-hexadiene has been synthesized and found to have in-vitro cytotoxicity against P388 (LD50 = 15 micrograms/ml) and L1210 (LD50 = 19 micrograms/ml) murine leukemia cells in culture. The LD50 compared favorably with that for doxorubicin. The compound was more cytotoxic to P388 tumor cells than to normal mouse splenocytes. The compound inhibited the uptake of both tritiated thymidine (42% inhibition) and tritiated uridine (24% inhibition) after 3 h of incubation when used at 5 micrograms/ml. No effect on uptake of tritiated leucine was observed during this time period. The compound was cytotoxic to normal mouse splenocytes which had been stimulated to divide by the mitogen concanavalin A. No effect was found on normal, non-dividing splenocytes. These results suggest that this novel compound is cytotoxic to leukemic cells or other rapidly dividing cells through inhibition of DNA and/or RNA synthesis.
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PMID:Synthesis and in-vitro cytotoxic activity of phenyl-amino-4-(p-toluenesulfinyl)-trans-1,5-hexadiene. 245 63

Effects of human recombinant G- and GM-CSF upon HL-60 myeloid leukemic cell differentiation and proliferation have been studied. Minimal morphologically apparent differentiation was noted with treatment up to 7 days and concentrations up to 1000 units/ml. Cell surface marker analysis disclosed modest increases of MO1 and HLA-Dr expression following treatment with G-CSF/GM-CSF, for 2-4 days. Macromolecular synthesis rates following 24-hr exposures to CSF disclosed stimulation of [3H]uridine greater than [3H]thymidine greater than [3H]leucine by GM-CSF only. Proliferation was also assessed by flow cytometric DNA histogram analysis which also disclosed greater increases in the percentage of S + G2/M cells following GM-rather than G-CSF treatment. This study documents subtle early effects of G- and GM-CSF upon HL-60 proliferation and differentiation. Differentiative effects were relatively more marked with G-CSF while proliferative effects were more marked with GM-CSF.
Leukemia 1988 Nov
PMID:Early effects of G- and GM-CSF upon HL-60 proliferation and differentiation. 246 Jul 7

Some 3'-blocked pyrimidine analogs were synthesized and tested as inhibitors of replication of human immunodeficiency virus (HIV) and Moloney-murine leukemia virus (MuLV). The analogs were of 3 kinds: (1) analogs of 3'-azido-3'-deoxythymidine (AZT) in which the C-5 CH3 of the base was exchanged for H (AZU) or C2H5 (AZEU); (2) 3'-fluoro-3'-deoxythymidine (FLT) and analogs thereof, in which the C-5 CH3 of the base was exchanged for H (FLU), C2H5 (FLEU) or nC3H7 (FLPU); (3) the threo analogs of AZT (AZT increases) and AZU (AZU increases). All analogs were less active inhibitors of HIV replication than AZT, except FLT, which was as active as AZT. The 3'-fluoro analogs and AZEU did not inhibit MuLV replication at non-cytotoxic concentrations. Oral administration of FLT to MuLV-infected mice result in antiviral effects only at toxic drug levels. AZU and FLU were less potent inhibitors of HIV replication than AZT or FLT, but the 2'-deoxy uridine analogs were less cytotoxic to human embryonic fibroblasts than the thymidine analogs. The 5'-triphosphates of AZU, AZT, AZEU, FLT and FLEU were tested as inhibitors of the HIV- and MuLV-reverse transcriptases. Ranking of the Ki/Km values for HIV-RT resulted in the following order of potency of the 5'-triphosphates AZT = FLT greater than AZU greater than AZEU greater than FLEU. The 5'-triphosphates of AZEU, FLT and FLEU did not inhibit the MuLV-RT, which explains, in part, the lack of effect of these analogs against MuLV replication. The threo forms (azido "up") of AZU and AZT were less active inhibitors of HIV replication than the erythro forms (azido "down"). A 15N-NMR and 1H-NMR study showed that the furanose moieties of analogs with the azido function "up" assume a conformation distinct from that of the analogs with azido "down". This is due to intramolecular stabilisation of the "N" conformer in the threo ("up") diastereomer, due to interaction of the azido functions with the nucleobase and possibly the OH group of C-5' of the furanose. As discussed, this conformation might explain the decreased biological activity of threo forms compared with the erythro forms.
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PMID:An analysis of the inhibition of replication of HIV and MuLV by some 3'-blocked pyrimidine analogs. 246 76

N-Trifluoroacetyladriamycin-14-O-hemiadipate (AD 143), a DNA nonbinding derivative of Adriamycin, was studied for its effect on the uptake of labeled nucleosides into human leukemia (ML-1) and lymphoma (P3HR-1) cells in culture. After preincubation with AD 143 at concentrations as low as 5.2 microM (ML-1) or 13 microM (P3HR-1), the ability of the cells to take up extracellular labeled nucleosides was decreased by more than 50%. Similar experiments with Escherichia coli cells showed that AD 143 at the same concentrations did not have any effect. Influx of [3H]thymidine or [3H]uridine was studied by centrifugation of the cells through phthalate oil mixture, and it was found that the influx of the labeled nucleosides was decreased after treatment of the cells with AD 143. An increase in the membrane fluidity was observed after treatment of the cells with AD 143, as revealed by electron paramagnetic resonance spectroscopy studies. These observations suggest that the decreased incorporation of [3H]thymidine and [3H]uridine into acid-precipitable material that we observed earlier in the AD 143-treated cells may in part be the result of the AD 143-induced alteration of cell membrane activities, which in turn causes an inhibition of nucleoside uptake.
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PMID:Nucleoside uptake and membrane fluidity studies on N-trifluoroacetyladriamycin-14-O-hemiadipate-treated human leukemia and lymphoma cells. 254 96

A new cytotoxic acridine alkaloid that exhibited antitumor activity in vivo was isolated from a marine Dercitus species sponge collected at a depth of 160 m in the Bahamas. This violet alkaloid, designated dercitin, inhibited the proliferation of cultured murine and human leukemia, lung, and colon tumor cells at nM concentrations (IC50 values of 63-150 nM) and prolonged the life of mice bearing ascitic P388 tumors (%T/C = 170, 5 mg/kg, i.p., QD1-9). Dercitin was also active against i.p. B16 melanoma and modestly inhibited the growth of s.c. Lewis lung carcinoma on the same schedule. DNA blocked the antiproliferative effects of the agent in culture, and incorporation studies indicated that dercitin disrupted DNA and RNA synthesis with less effects on protein synthesis, similar to the effects of known DNA intercalators. After 1-h exposure to 400 nM dercitin, the rates of incorporation of [3H]uridine, [3H]thymidine, and [3H]leucine by cultured P388 cells were inhibited 83, 61, and 23%, respectively. Equilibrium dialysis indicated that dercitin bound calf thymus DNA with an affinity of 3.1 microM and maximal binding of 0.20 mol dercitin/mol base pair. Binding involved intercalation as evidenced by ability to relax supercoiled phi X174 DNA (half maximal concentration for dercitin relaxation was 36 nM). The effects of dercitin on DNA mobility were reversible, and complete relaxation of DNA with topoisomerase I in the presence of dercitin followed by phenol extraction resulted in the appearance of supercoiled DNA. Dercitin, at microM concentrations, had a small effect in the K+-sodium dodecyl sulfate assay using cultured P388 cells, suggesting minimal inhibition of topoisomerase activity. But, dercitin completely inhibited DNA polymerase I/DNase nick translation of DNA at 1 microM. Relaxation of DNA at a given concentration was greater than inhibition of nick translation suggesting that the effects of dercitin on enzyme activity were secondary to changes in DNA conformation. Results indicate that dercitin is a new marine natural product that probably exerts its biological effects through intercalation into nucleic acids.
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PMID:Antitumor activity and nucleic acid binding properties of dercitin, a new acridine alkaloid isolated from a marine Dercitus species sponge. 254 17

Cytotoxicity and mechanisms of action of 2 metabolites of benfluron (BF), namely 7-dihydrobenfluron (DBF) and benfluron N-oxide (NOBF) were tested. Cytotoxicity in the primary biochemical screening was measured by the inhibition of 14C-adenine and 14C-valine incorporation into the TCA-insoluble fraction of Ehrlich ascites carcinoma (EAC) cells under defined in vitro conditions. Both metabolites were found to have cytotoxic effects, with NOBF being more active than DBF. Further we investigated the kinetics of incorporation not only of adenine and valine, but also of 14C-thymidine and 14C-uridine both into Ehrlich carcinoma cells and into P388 leukemia cells.
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PMID:Primary screening and inhibition of macromolecular biosynthesis by benfluron metabolites in vitro. 270 27


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