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

The structural specificities of the natural polyamines putrescine (Put), spermidine (Spd) and spermine (Spm) for cell growth are rather stringent, suggesting that appropriate structural analogues of these polycations could serve as potential antineoplastic agents via polyamine antagonism. Norspermidine (Nspd), a homologue of spermidine, had significant antitumor activity against L1210 leukemia, 3LL carcinoma and EL4 lymphoma in mice. The observed antitumor activity of the compound was potentiated by administration of a - difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase. DFMO treatment alone, or in combination with Nspd reduced tumoral Put and Spd levels by greater than 50% in all three tumor models. In animals receiving both Nspd and DFMO, Nspd accumulation in the tumor cells was increased by 50% or more compared to cells from animals receiving Nspd only. Co-administration of Spd, but not Put, abolished the antitumor activity of L1210 observed with DFMO and Nspd treatment, and also reduced the tumoral accumulation of Nspd. These results indicate that appropriate structural analogues of the natural polyamines may be useful as antineoplastic agents.
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PMID:Antitumor activity of norspermidine, a structural homologue of the natural polyamine spermidine. 314 Jul 10

Influence of DL-alpha-difluoromethylornithine (DFMO) treatment on the growth kinetics, labelling index, extra- and intracellular polyamine and nucleotide concentrations was monitored in cultured P388 leukemia cells. A substantial decrease of cell proliferation was observed when the cells were continuously treated with 1-5 mM DFMO. Depletion of cellular polyamines, mostly of putrescine and spermidine, was seen with a concomitant but delayed increase of spermidine and spermine levels in the culture medium. Changes of DNA content and of labelling index of untreated and treated cells seem to indicate that DFMO arrested cells in G1/S transition. The results presented here provide additional in vitro evidence on the characteristic changes in the metabolic imbalance of ornithine in tumor cells induced by DFMO via inhibition of ornithine decarboxylase and ornithine carbamoyl transferase activities.
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PMID:Changes in the polyamine and nucleotide metabolism of P388 leukemia cells treated with DL-alpha-difluoromethylornithine in culture. 314 16

The authors have assayed the level of expression of several cell-cycle related genes in several populations of circulating myeloid leukemic blast cells. The genes explored included oncogenes such as c-myc, c-myb, p53, and cell-cycle-related genes such as vimentin, calcyclin, ornithine decarboxylase (ODC) and histone H3. Particular attention was given to analysis of the relationship existing between the mRNA levels of the histone H3 gene, which is expressed specifically in the S phase of the cell cycle, and the levels of other genes that are expressed in different stages of the G1 phase. Remarkable differences were observed among the different cases indicating that a differential expression of cell-cycle-related genes characterizes many acute leukemias. This differential expression is reflected in an altered ratio among G1-related genes and the H3 histone gene. The large fraction of leukemic cells which does not express histone H3 and therefore is functionally noncycling, shows a heterogeneous pattern of G1-related gene expression. This reflects the inability of most leukemic cells to progress through the G1 phase into the S phase of the cell cycle. This inability represents an abnormality of the cell cycle. It is concluded that the study of the expression of cell-cycle genes and protooncogenes in in understanding how leukemic cells enter a state of proliferation arrest, which appears to occur in a large fraction of leukemic cells.
Leukemia 1988 Dec
PMID:Expression of oncogenes and cell cycle related genes in acute and chronic leukemias. 319 78

The possible roles in experimental colon carcinogenesis of two protooncogenes (c-myc and c-H-ras), two endogenous retrovirus-related DNA sequences [rat leukemia virus (RaLV) and the 30S sequence], and two cell cycle related genes (beta-actin and ornithine decarboxylase) were studied by analyzing the levels of their corresponding RNAs during the course of azoxymethane induced and high fat promoted colon carcinogenesis. F-344 male rats received three s.c. injections of azoxymethane (15 mg/kg) or normal saline and were then subdivided into high or low fat diet groups. During subsequent serial sacrifices normal colon mucosa, adenomas, and carcinomas were harvested for histology and RNA extraction. Seventy-one RNA samples were analyzed by the Northern blot hybridization procedure using the appropriate 32P-labeled DNA probes. A marked increase in the abundance of c-myc, RaLV, and 30S RNAs were seen in all of the colon tumors, including adenomas and invasive carcinomas. No or a very low level of expression of RaLV and c-myc RNA was found in the flat grossly normal mucosa adjacent to the tumors and in the mucosa of the control rats. Some of the colon tumors also displayed increased levels of c-H-ras, ornithine decarboxylase and beta-actin RNAs but these findings were less striking and more variable than those seen with c-myc, RaLV, and 30S RNAs. These results suggest that increased expression of the c-myc protooncogene and of the endogenous retrovirus-like sequences (RaLV) and 30S are hallmarks of colon carcinogenesis in this model system.
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PMID:Changes in expression of oncogenes and endogenous retroviral-like sequences during colon carcinogenesis. 338 91

Methylglyoxal bis(3-aminopropylamidinohydrazone (MGBA) inhibited S-adenosylmethionine decarboxylase (AdoMetDC) activity competitively with S-adenosylmethionine (AdoMet), showing a Ki value of 2.60 x 10(-5) M. It also inhibited ornithine decarboxylase competitively with ornithine, showing a Ki value of 3.80 x 10(-5) M. MGBA inhibited the growth of human erythroid leukemia K562 cells. Putrescine, spermidine, and spermine concentrations in MGBA-treated cells were depressed to 19%, 36%, and 66% of the values of control cells, respectively.
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PMID:Antitumor effect of methylglyoxal bis(3-aminopropylamidinohydrazone), a new inhibitor of S-adenosylmethionine and ornithine decarboxylases, on human erythroid leukemia K562 cells. 340 53

It has been shown previously (Porter et al., Cancer Res., 45: 2050-2057, 1985) that the N1,N8-bis(ethyl) derivative of spermidine has significant antiproliferative activity which appears to derive from its regulatory effects on the polyamine biosynthetic pathway, particularly on ornithine decarboxylase activity. In the present study, N1,N4-bis(ethyl)putrescine (BEP) and N1,N12-bis(ethyl)spermine (BESm) were compared with N1,N8-bis(ethyl)spermidine (BES) in their ability to inhibit cell growth and regulate polyamine biosynthesis. With cultured L1210 murine leukemia cells, the IC50 values at 48 h were approximately 2 mM for BEP, 30 microM for BES, and 1 microM for BESm making the latter the most effective polyamine inhibitor or analogue thus far identified. At concentrations which approximated IC50 values and yielded similar intracellular concentrations at 48 h (1500-2000 pmol/10(6) cells), the effects of the analogues on polyamine biosynthesis generally correlated with their antiproliferative activity. BEP, at 1 mM, exerted relatively minor effects on polyamine biosynthesis. By contrast, 100 microM BES totally eliminated ornithine decarboxylase activity, depleted putrescine and spermidine pools, and decreased spermine pools by 40%. AdoMet decarboxylase activity was lowered slightly. The most impressive effects were obtained with 10 microM BESm which decreased ornithine and AdoMet decarboxylase activities by 99 and 84%, respectively; depleted putrescine and spermidine pools; and decreased spermine pools by 73%. None of the analogues, at 1 or 3 mM, had significant direct inhibitory effects on the decarboxylase activities from untreated cells with the exception of BESm which inhibited ornithine but not AdoMet decarboxylase activity. Thus, the effects of the analogues on these enzymes in treated cells are presumed to be mainly mediated by regulatory mechanisms. In this regard, BESm was superior to BES since both ornithine and AdoMet decarboxylase activities were suppressed. Given its unique activities, BESm would seem to have potential as both an antiproliferative agent and also as an experimental probe for studying regulation of the polyamine pathway, particularly AdoMet decarboxylase.
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PMID:Relative abilities of bis(ethyl) derivatives of putrescine, spermidine, and spermine to regulate polyamine biosynthesis and inhibit L1210 leukemia cell growth. 356 5

The content of polyamines, rate of their biosynthesis, and activity of ornithine decarboxylase (ODK), the key regulatory enzyme in the polyamine biosynthetic pathway, have been studied in the leukocytes of healthy persons and of patients with various forms of leukemia. The polyamine levels and the rate of their biosynthesis were considerably higher in lymphocytes than in granulocytes. In leukemias, as the cell population rejuvenated, both the polyamine content and the spermidine/spermine ratio were found to be markedly elevated approaching the maximal values in human blast cells of K-562 line. The leukemic transformation of myeloid cells was associated with the increase in the ornithine decarboxylase activity and in the rate of polyamine synthesis, whereas these items were significantly lowered in lymphoid leukemic cells. The changes observed in polyamine metabolism in leukemias are considered to be related to the proliferative and biosynthetic activity of the cells.
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PMID:[Polyamine levels and biosynthesis in leukocytes during leukemic transformation]. 358 35

The activities of ornithine decarboxylase (ODC) and spermidine/spermine N1-acetyltransferase (SAT) were increased by the addition of S-adenosylmethionine decarboxylase (AdoMetDC) inhibitor methylglyoxal bis(guanylhydrazone) (MGBG) in cultured human erythroid leukemia K 562 cells. ODC activity began to increase 4 hr after the addition of the drug and attained a maximum at 12 hr. The increase of SAT activity lagged behind that of ODC activity. The increases of both ODC and SAT activities produced by MGBG were blocked by treatment with cycloheximide, suggesting that the increase of enzyme activity resulted from the synthesis of new enzyme proteins. The putrescine content in cells treated with MGBG increased markedly, whereas the levels of spermidine and spermine were depressed lower. On the other hand, methylglyoxal bis(butylamidinohydrazone) (MGBB), a derivative of MGBG inhibiting AdoMetDC effectively, did not induce ODC or SAT activities.
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PMID:Ornithine decarboxylase and spermidine/spermine N1-acetyltransferase are induced in K562 cells by S-adenosylmethionine decarboxylase inhibitor methylglyoxal bis(guanylhydrazone) but not by analogous methylglyoxal bis(butylamidinohydrazone). 377 24

Eleven novel spermidine (SPD) derivatives were synthesized as potential anticancer agents and evaluated for their ability to compete with [3H]SPD for cellular uptake, to inhibit cell growth, to affect polyamine biosynthesis, to suppress enzyme activity, and to substitute for SPD in supporting growth of cultured L1210 leukemia cells. The compounds included a series of N4-SPD derivatives (N4-methyl-SPD, N4-ethyl-SPD, N4-acetyl-SPD, N4-hexyl-SPD, N4-hexanoyl-SPD, N4-benzyl-SPD, and N4-benzoyl-SPD) and a series of N1,N8-SPD derivatives [N1,N8-bis(ethyl)-SPD, N1,N8-bis(acetyl)-SPD, N1,N8-bis(propyl)-SPD, and N1,N8-bis(propionyl)-SPD]. Uptake studies revealed N4-alkyl derivatives to be the most effective competitive inhibitors of [3H]SPD uptake (Ki, 26 to 43 microM) followed by N1,N8-alkyl derivatives (Ki, 71 to 115 microM), then N4-acyl derivatives (Ki, 115 to greater than 500 microM), and N1,N8-acyl derivatives (Ki, greater than 500 microM). The data indicate the relative importance of the terminal amines and of charge as determinants of cellular uptake. Of the 11 derivatives, only N4-hexyl-SPD, N1,N8-bis(ethyl)-SPD, and N1,N8-bis(propyl)-SPD demonstrated antiproliferative activity at 0.1 mM with 50%-inhibitory concentration values at 48 h of 30, 40, and 50 microM, respectively. In the case of the N1,N8-SPD derivatives, recovery from growth inhibition was enhanced considerably by exogenous SPD, suggesting involvement of polyamine depletion. At 10 to 30 microM, both N1,N8-bis(ethyl)-SPD and N1,N8-bis(propyl)-SPD (but not N4-hexyl-SPD) inhibited polyamine biosynthesis as indicated by significant reductions in polyamine pools and in biosynthetic enzyme activities. The more effective of the two, N1,N8-bis(ethyl)-SPD, depleted intracellular putrescine and SPD and reduced spermine by approximately 50% at 96 h and decreased ornithine and S-adenosylmethionine decarboxylase activities by 98 and 62%, respectively. Since neither derivative (at 5 mM) directly inhibited these enzymes from untreated cell extracts by significantly more than SPD itself, it is suspected that they act by regulating enzyme levels. As a measure of regulatory potential of the derivatives, ornithine decarboxylase was assayed in cells treated for 24 h and compared to the effects of 10 microM SPD which reduced the enzyme activity by 80%. None of the N4-SPD derivatives affected ornithine decarboxylase activity, while N1,N8-bis(ethyl)- and (propyl)-SPD were nearly as effective as SPD. Apparently, the central amine of the molecule is critical for regulatory function.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biological properties of N4- and N1,N8-spermidine derivatives in cultured L1210 leukemia cells. 392 Dec 35

Difluoromethylornithine (DFMO), a non-competitive inhibitor of ornithine decarboxylase (ODC), the rate limiting enzyme of the polyamine synthetic pathway was evaluated in a Phase I trial. Intravenous DFMO was given to twenty patients with refractory leukemia by continuous infusion in doses from 5.5 to 64 g/m2. Toxicity clearly attributable to the drug was not severe and other than nausea and vomiting did not increase with dose. The previously reported ototoxicity which occurred with the oral form appeared to be less frequent. Loss of hearing which improved when the drug was stopped was seen in four patients, three of whom were simultaneously receiving aminoglycosides. Anorexia occurred in some patients at all doses. Vomiting, necessitating dosage reduction, was a significant problem at the highest dose administered. No patient achieved a remission but there was stabilization or decrease in circulating blast cells in several patients. This growth inhibition did not appear to be dosage related.
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PMID:Phase I evaluation of intravenous difluoromethylornithine--a polyamine inhibitor. 393 6


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