UMLS:C0023418 - FACTA Search

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Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of alpha-difluoromethylornithine (DFMO), an ornithine analogue which is an ornithine decarboxylase inhibitor, on the actions of the topoisomerase II-reactive agents 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and etoposide (VP-16) were investigated in 2 murine L1210 leukemia lines and 2 human HL-60 leukemia lines. One of the human lines was resistant to the cytotoxic and DNA cleaving effects of m-AMSA (HL-60/AMSA). In all 4 lines, alpha-DFMO depleted cellular putrescine and spermidine to nondetectable levels. VP-16-induced DNA cleavage (quantified using alkaline elution) was decreased in all lines following alpha-DFMO treatment. The m-AMSA-induced DNA cleavage was decreased in one of the L1210 lines and in the HL-60 line sensitive to m-AMSA; m-AMSA-induced DNA cleavage was increased in the other L1210 line. The low frequency of m-AMSA-induced DNA cleavage produced in HL-60/AMSA was unaffected by alpha-DFMO treatment. Alterations in drug-mediated DNA effects induced by alpha-DFMO could not be uniformly explained by alpha-DFMO-induced alterations in m-AMSA or VP-16 cellular uptake, as indicated by direct measurements of cell-associated drug or results of DNA cleavage assays in nuclei isolated from alpha-DFMO-treated cells. Exogenous putrescine prevented the effects of alpha-DFMO on drug-induced DNA cleavage, substantiating polyamine depletion as the cause of the altered frequency of DNA cleavage. Cytotoxicity assays in 2 of the lines demonstrated that drug-induced reductions in colony-forming ability paralleled drug-induced DNA cleavage. (2R,5R)-6-heptyne-2,5-diamine, a putrescine analogue which is also an ornithine decarboxylase inhibitor, was also used to deplete polyamine levels in HL-60. (2R,5R)-6-heptyne-2,5-diamine was more potent than alpha-DFMO and produced effects on m-AMSA- and VP-16-induced DNA cleavage and cytotoxicity identical to those produced by alpha-DFMO.
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PMID:Effect of polyamine depletion by alpha-difluoromethylornithine or (2R,5R)-6-heptyne-2,5-diamine on drug-induced topoisomerase II-mediated DNA cleavage and cytotoxicity in human and murine leukemia cells. 282 33

Difluoromethylornithine (DFMO), a specific, irreversible, enzyme-activated inhibitor of ornithine decarboxylase activity, the first and rate-limiting step in polyamine biosynthesis, has been shown to inhibit neoplastic cell proliferation in culture. In most cases, such inhibition is not accompanied by cell loss, with the exception of multiple cell lines of human small cell lung carcinoma (SCC), a human leukemia cell line (HL-60), and possibly the B16 melanoma cell line. The first two cell types grow as anchorage-independent suspension cultures, the HL-60 as single cells and the SCC as multicellular spheroid aggregates. Moreover, in the spectrum of human lung carcinoma cells in culture, the SCC cells respond in a cytotoxic manner to DFMO, whereas the non-small cell lung carcinoma (non-SCC) cells, which are anchorage dependent, show only growth inhibition, without actual cell loss. In the present study, we have investigated relationships between anchorage-dependent and -independent growth patterns of cells in culture and their response to DFMO treatment. Two non-SCC lung cancer cell lines, which normally grow as anchorage-dependent monolayers, show growth inhibition but no cell loss with the addition of DFMO. When these anchorage-dependent cells were forced to grow as multicellular aggregates, by coating the culture flask with Teflon, the cells developed an increased sensitivity to DFMO. They showed not only inhibition of cell proliferation but also cell death. Two SCC cell lines, which normally grow as anchorage-independent spheroids, developed adherence to the culture dishes coated with fibronectin. These cells, which show a cytotoxic response to DFMO during normal anchorage-independent growth, developed a decreased sensitivity to DFMO, showing only cell growth inhibition, but no cell death when treated during anchorage-dependent growth. Our data thus suggest that the state of anchorage dependence of lung cancer cells in culture is a critical factor in determining their response to polyamine depletion during treatment with DFMO.
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PMID:Anchorage dependency effects on difluoromethylornithine cytotoxicity in human lung carcinoma cells. 300 7

The anticancer agent etoposide (VP-16) produces DNA strand scission in intact tumor cells or isolated nuclei. This activity may be mediated by topoisomerase II, an enzyme capable of producing double strand breaks in mammalian cells. Two established tumor cell lines were examined to see whether polyamines, which alter DNA conformation and topoisomerase II activities, affected the cytotoxicity, strand scission, and antitumor efficacy of VP-16. L1210 murine leukemia and 8226 human myeloma cells were treated with alpha-difluoromethylornithine (DFMO) to reduce intracellular polyamine levels via inhibition of ornithine decarboxylase. The polyamines putrescine and spermidine were markedly reduced by a 48-h incubation with 50 microM DFMO. This DFMO concentration did not inhibit colony formation in either cell line, but did reduce the growth rate of both cultures. In contrast, VP-16 produced a dose-dependent inhibition of colony formation. This was especially marked in the 8226 cell line. This correlated with DNA single strand breaks (SSBs) detected by the alkaline elution technique. When cells previously treated with DFMO were exposed to VP-16, a synergistic inhibition of colony formation (determined by isobologram analysis) was observed. However, VP-16-induced SSBs were only marginally increased by the DFMO pretreatment. When putrescine was combined concurrently with VP-16, both the in vitro cytotoxic effects and the number of DNA SSBs in L1210 cells were significantly reduced. These results demonstrate that putrescine inhibits VP-16-induced SSBs and commensurate cytotoxic effects, while DFMO, which depletes intracellular putrescine and partially reduces intracellular spermidine, acts to produce synergistic cytotoxic effects when combined with VP-16.
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PMID:Modulation of etoposide cytotoxicity and DNA strand scission in L1210 and 8226 cells by polyamines. 301 79

With the use of the isoschizomeric restriction endonucleases HpaII and MspI, we found that mouse tumour ornithine decarboxylase (ODC; EC 4.1.1.17) genes are extensively methylated. ODC genes in L1210 mouse leukaemia cells were apparently more methylated than in Ehrlich ascites carcinoma, as revealed by the use of HpaII endonuclease, yet the digestion of genomic DNA isolated from these two murine tumour cell lines with MspI, which cleaves at a CCGG sequence, also with internally methylated cytosine, resulted in an apparently identical restriction pattern. It is possible that the amplification of ODC genes in Ehrlich ascites-carcinoma cells in response to 2-difluoromethylornithine (DFMO) was associated with hypomethylation, or that less-methylated genes were amplified. A human myeloma (Sultan) cell line only revealed three separate hybridization signals when cleaved with HpaII. One of these signals was amplified under the pressure of DFMO. When cleaved with MspI, these three HpaII fragments disappeared and were replaced by a double signal of 2.3-2.4 kilobase-pairs (kbp) in size. The amplified ODC sequences in the Sultan myeloma cell line apparently originated from chromosome 2, as indicated by a unique hybridization signal in a 5.8 kbp HindIII fragment specific for the human ODC locus on chromosome 2. A comparison of different human cells, the Sultan myeloma, a lymphocytic B-cell leukaemia (Ball), normal mononuclear leucocytes and leucocytes obtained from leukaemia patients, revealed interesting differences in the methylation of ODC genes. The use of two restriction endonucleases (HpaII and CfoI), the cleavage site for both of which contains a CG sequence and which only cleave when cytosine is unmethylated, indicated that ODC genes in the lymphocytic leukaemia cells were much less methylated than those in the normal leucocytes or in the Sultan cells.
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PMID:Mouse and human ornithine decarboxylase genes. Methylation polymorphism and amplification. 303 86

alpha-Difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase, was used alone and in combination with multiple doses of methylglyoxal-bis(guanylhydrazone) (MGBG) to treat mice with systemic L1210 leukemia. Used as a single agent (administered p.o. as a 3% solution in tap water), DFMO exerted a weak therapeutic effect against this tumor. The therapeutic effect of MGBG (administered i.p. at 50 mg/kg/day) was only slightly better. However, 1-3 days of pretreatment with DFMO strongly potentiated the effect of MGBG treatment. Thus, mice treated with the combination exhibited an increase in life span of up to 138%. The prolonged survival of leukemic mice treated with a combination of DFMO and MGBG was associated with inhibition of polyamine synthesis and a marked decrease in the spermidine and spermine content of the tumor cells as compared to untreated controls. As a consequence, there was a continuous decrease in the S- and G2-phase fractions with a concomitant increase in G1. Used singly, DFMO and MGBG had no significant effect on the cell-cycle distribution. The effects of the combination of DFMO and MGBG on the cell-cycle distribution are consistent with the contention that polyamine deficiency primarily interferes with initiation of DNA synthesis. However, the possibility that selective S-phase kill partly contributes to this change in cell-cycle distribution cannot be excluded.
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PMID:Synergistic antileukemic effect of two polyamine synthesis inhibitors. Host survival and cell-cycle kinetic analysis. 308 54

In vivo effects of DL-alpha-difluoromethylornithine (DFMO) on the metabolism of polyamines and nucleotide phosphates were monitored in P388/S leukemia cells grown intraperitoneally in BDF1 inbred male mice. Inhibiting the ornithine decarboxylase (ODC) activity DFMO depleted putrescine and spermidine to 30-50 and 50-60%, respectively, and increased spermine to 25-60% compared with the controls, when given as 2% solution in drinking water of the tumor-bearing animals. DFMO treatment caused a parallel 56% elevation of total nucleotide content in tumor cells with distinct and significant increase of some nucleotide phosphates. The most pronounced alterations were shown in the intracellular UTP (202%), CTP (103%), ADP (92%) and ATP (71%) concentrations. Changes in polyamine and nucleotide phosphate metabolisms were dependent on tumor progression. A possible explanation of the metabolic events induced by DFMO is discussed.
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PMID:In vivo effects of DL-alpha-difluoromethylornithine on the polyamine and nucleotide phosphate metabolism in P388/S leukemia cells. 308 89

We recently selected a variant mouse L1210 leukaemia-cell line overproducing ornithine decarboxylase (ODC) (EC 4.1.1.17) as a result of chronic exposure to 2-difluoromethylornithine (DFMO) in the presence of micromolar concentrations of cadaverine. These cells, now grown for more than 2 years in the presence of DFMO and cadaverine, continued to accumulate ODC-specific mRNA in an amount 30-50 times higher than that in the parental cells, yet showing practically no changes in the gene dosage for the enzyme. However, analysis of the genomic DNA with the isoschizomeric restriction enzymes HpaII and MspI revealed that the ODC sequences in the overproducer cells were hypomethylated in comparison with the parental cells. The natural polyamines (putrescine, spermidine and spermine) were almost totally replaced by cadaverine and aminopropylcadaverine. Omission of cadaverine from the culture medium, but leaving 10 mM-DFMO, resulted in an about 10-fold ODC gene amplification within a few weeks. The accumulation of ODC mRNA was enhanced by the same factor. Concomitantly, the content of the natural polyamines was almost normalized, representing about 65% of that found in the parental cells. The present results suggest that, under a given selection pressure, an overproduction of the target gene product may be primarily based on an enhanced transcriptional activity, possibly associated with hypomethylation and, if not sufficient, a secondary amplification of the active gene occurs.
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PMID:Cadaverine supplementation during a chronic exposure to difluoromethylornithine allows an overexpression, but prevents gene amplification, of ornithine decarboxylase in L1210 mouse leukaemia cells. 312 32

The antitumor and antimetastatic effects of alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, combined with an inhibitor of S-adenosylmethionine decarboxylase, either methylglyoxal bis(guanylhydrazone) (MGBG) or ethylglyoxal bis(guanylhydrazone) (EGBG), were studied in mice bearing P388 leukemia or Lewis lung carcinoma. Although EGBG is a more specific inhibitor of polyamine biosynthesis than the widely used MGBG, the antitumor effect of the DFMO-EGBG combination on P388 leukemia-bearing mice was less than that of the DFMO-MGBG combination. The prolongation of survival time by the DFMO(1000 mg/kg)-MGBG(25 mg/kg) combination was 2.65-fold, while that of the DFMO(1000 mg/kg)-EGBG(50 mg/kg) combination was 1.34-fold. When mice were fed a polyamine-deficient diet, stronger antitumor effects were exerted; the prolongation of survival time by the DFMO-MGBG and the DFMO-EGBG combinations was 2.89-fold and 2.03-fold, respectively. The antitumor effect of combined use of the two polyamine antimetabolites with mice on normal and polyamine-deficient diets correlated with a decrease of polyamine charge contents in the tumor cells. The above in vivo results were confirmed clearly in the KB cell culture system. The antimetastatic activity of DFMO on Lewis lung carcinoma-bearing mice was strengthened by the addition of MGBG or EGBG. The antimetastatic activity of the DFMO-MGBG or DFMO-EGBG combination did not parallel the polyamine charge contents in the primary tumor and blood.
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PMID:Combined use of alpha-difluoromethylornithine and an inhibitor of S-adenosylmethionine decarboxylase in mice bearing P388 leukemia or Lewis lung carcinoma. 313 38

Diethylglyoxal bis(guanylhydrazone) (DEGBG), a novel analog of the antileukemic agent methylglyoxal bis(guanylhydrazone) (MGBG) was synthesized. It was found to be the most powerful inhibitor of yeast S-adenosylmethionine decarboxylase (AdoMetDC) so far studied (Ki approx. 9 nM). This property, together with the finding that the compound is a weaker inhibitor of intestinal diamine oxidase than are MGBG and its glyoxal, ethylglyoxal and ethylmethylglyoxal analogs, makes the compound a promising candidate as a polyamine antimetabolite for chemotherapy studies. DEGBG was also found to potentiate the antiproliferative effect of the ornithine decarboxylase inhibitor alpha-difluoromethyl ornithine against mouse L1210 leukemia cells in vitro. DEGBG increased several-fold the intracellular putrescine concentration of cultured L1210 cells, just as MGBG and its ethylglyoxal analog are known to do. The results strongly suggest that DEGBG is worth further studies. Combined with previous studies, they also made possible the construction of some empirical rules concerning the structure-activity relationships of bis(guanylhydrazone) type inhibitors of AdoMetDC. The identity of DEGBG was confirmed by a single-crystal X-ray analysis and by 1H- and 13C-NMR spectroscopy. It consisted of the same isomer as MGBG and several of its analogs are known to consist of.
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PMID:Diethylglyoxal bis(guanylhydrazone): a novel highly potent inhibitor of S-adenosylmethionine decarboxylase with promising properties for potential chemotherapeutic use. 313 21

We have selected mouse myeloma and leukemia cell lines overproducing ornithine decarboxylase (ODC) under the pressure of alpha-difluoromethylornithine (DFMO), a mechanism-based inhibitor of the enzyme. Two of the tumor cell variants overproduced ODC by virtue of an amplification of transcriptionally active ODC genes. In one case the overproduction of the enzyme was based on an enhanced transcription of the enzyme's message at normal gene copy number. The DFMO-resistant cells exhibited ODC activity that was 8 to 25 times higher than the enzyme activity in the parental cells. When plated into soft agar, the parental mouse myeloma cells failed to form any colonies, whereas the ODC overproducing variant cells grew soft agar at a plating efficiency of about 16%. The difference between parental and ODC overproducing cells was even more striking in case of mouse leukemia L1210 cells. The parental L1210 cell formed colonies in soft agar at an efficiency of 1.9% while two overproducer variant cell lines formed colonies at up to 60% plating efficiency. These results clearly indicate that an overproduction of ODC offers a distinct growth advantage to tumor cells.
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PMID:Overproduction of ornithine decarboxylase confers an apparent growth advantage to mouse tumor cells. 313 35

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