Irreversible inhibition of the early increase in ornithine decarboxylase activity following growth stimulation is required to block Ehrlich ascites tumor cell proliferation in culture

Oredsson, Stina; Anehus, Siw; Heby, Olle

doi:10.1016/s0006-291x(80)80200-2

Cited by 38 publications

(15 citation statements)

References 14 publications

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“…Orally administered DMFO re sulted in a stimulation ofSAMDC activity in metastatic Lewis lung carcinoma but without elevating spermine content [4], Again, Kingsnorth et al [5] observed a 18-22% increase of spermine content of dimethylhydrazine-induced colon tumors in mice after postopera tive treatment with DFMO. Similarly, a slight increase in spermine content was found in mouse embryonal carcinoma and other mammalian cells as a consequence of druginduced polyamine deficiency [6,7,14,24,25].…”

Section: Resultsmentioning

confidence: 90%

In vivo Effects of <i>DL</i>-α-Difluoromethylornithine on the Polyamine and Nucleotide Phosphate Metabolism in P388/S Leukemia Cells

Kremmer¹,

Boldizsár²,

Holczinger³

1986

Pathobiology

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In vivo effects of DL-α-difluoromethylornithine (DFMO) on the metabolism of polyamines and nucleotide phosphates were monitored in P388/S leukemia cells grown intra-peritoneally 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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Section: Resultsmentioning

confidence: 90%

In vivo Effects of <i>DL</i>-α-Difluoromethylornithine on the Polyamine and Nucleotide Phosphate Metabolism in P388/S Leukemia Cells

Kremmer¹,

Boldizsár²,

Holczinger³

1986

Pathobiology

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“…Inhibition of putrescine synthesis by DFMO treatment alone also causes an increase in SAMDC activity (14). Even though the CHO-A7 cells were starved for substrates of the polyamine biosynthetic pathway, there was an initial accumulation of spermine, corresponding to that seen in DFMO-treated Ehrlich ascites tumor cells (17). This increase in spermine content may be explained by the fact that putrescine normally inhibits spermine synthase by competing with spermidine.…”

Section: Discussionmentioning

confidence: 99%

Polyamine starvation prolongs the S and G2 phases of polyamine-dependent (arginase-deficient) CHO cells.

Anehus¹,

Pohjanpelto²,

Baldetorp³

et al. 1984

Mol. Cell. Biol.

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This study analyzes the effects of polyamine starvation on cell cycle traverse of an arginase-deficient CHO cell variant (CHO-A7). These cells grow well in serum-free medium, provided that it contains ornithine or polyamines or both. In the absence of ornithine or polyamines or both, the CHO-A7 cells develop severe polyamine deficiency and, as a consequence, grow more slowly. When grown to a stationary phase in the presence of ornithine or putrescine or both, the CHO-A7 cells became arrested in GO/early G1. However, when starved for ornithine and polyamines, they accumulated in the S and G2 phases. Ornithine and polyamine starvation of CHO-A7 cells causes an increase in ornithine decarboxylase activity. When this increase was prevented by treatment with DL-a-difluoromethylornithine, an enzyme-activated irreversible inhibitor of ornithine decarboxylase, growth was further suppressed, and a greater fraction of cells were found in the S and G2 phases of the cell cycle.A high rate of synthesis of the polyamines putrescine, spermidine, and spermine is associated with cell growth and division (6,18,27). In eucaryotes, putrescine is formed solely by decarboxylation of ornithine in a reaction catalyzed by ornithine decarboxylase (ODC) (18). Ornithine is either taken up from the plasma or synthesized intracellularly by the action of arginase (18). In fact, arginase may be considered the initial enzyme ih the polyamine biosynthetic pathway, at least in cells that do not have a complete set of urea cycle enzymes (11,18).An obvious means of determining the physiological function of the polyamines is to use mutants with specific defects in the various steps of polyamine biosynthesis. The first successful isolation of polyamine-dependent mammalian cells was recently reported. Thus, arginase-deficient (8,21) and ODC-deficient (25) Chinese hamster ovary (CHO) cell lines are presently being characterized. In the absence of polyamines in the medium, these cells develop severe polyamine deficiency, and their proliferation gradually decreases and eventually ceases (21,25). These findings clearly demonstrate the requirement of polyamines for growth.Our present conception of cell cycle kinetics of polyamine-deficient cells is entirely based on experiments with inhibitors of polyamine biosynthetic enzymes (6). It is irrefutably important to compare these results with results of experiments in which polyamine deficiency has been achieved by other means. Therefore, we have studied the effects of polyamine starvation on the cell cycle kinetics of the arginase-deficient CHO cell variant CHO-A7. Because these cells cannot make their own ornithine and are maintained in the absence of serum (a normal source of arginase) (8, 24), they are dependent on the addition of ornithine for polyamine synthesis.Flow cytometric analysis revealed a progressive lengthening of the S and G2 phases, relative to G1, during the course of starvation for ornithine and polyamines. Since the polyamine-starved cells exhibited a compensatory increase in * Correspondi...

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“…Initial studies in HTC cells, L1210 leukemia cells, human prostatic adenoma cells (Mamont et al, 1978), human embryo fibroblasts (H61tta et al, 1979), HeLa cells (Oredsson et al, 1980;Sunkara et al, 1983) and rat 9L gliosarcoma cells in culture (Seidenfeld et al, 1980) indicated that DFMO had antiproliferative properties in a broad range of systems. Cytotoxicity has also been shown in small-cell lung carcinoma cells (Luk et al, 1981(Luk et al, , 1982b and in HL-60 human promylocytic leukemia cells (Luk et al, 1982a).…”

Section: Activitymentioning

confidence: 99%

Metabolism and action of amino acid analog anti-cancer agents

Ahluwalia

Grem

Zhang

et al. 1990

Pharmacology & Therapeutics

218

173

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Abstract--The preclinical pharmacology, antitumor activity and toxicity of seven of the more important amino acid analogs, with antineoplastic activity, is discussed in this review. Three of these compounds are antagonists of L-glutamine: acivicin, DON and azaserine; and two are analogs of L-aspartic acid: PALA and L-alanosine. All five of these antimetabolites interrupt cellular nucleotide synthesis and thereby halt the formation of DNA and/or RNA in the tumor cell. The remaining two compounds, buthionine sulfoximine and difluoromethylornithine, are inhibitors of glutathione and polyamine synthesis, respectively, with limited intrinsic antitumor activity; however, because of their powerful biochemical actions and their low systemic toxicities, they are being evaluated as chemotherapeutic adjuncts to or modulators of other more toxic antineoplastic agents. CONTENTS

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Irreversible inhibition of the early increase in ornithine decarboxylase activity following growth stimulation is required to block Ehrlich ascites tumor cell proliferation in culture

Cited by 38 publications

References 14 publications

In vivo Effects of <i>DL</i>-α-Difluoromethylornithine on the Polyamine and Nucleotide Phosphate Metabolism in P388/S Leukemia Cells

In vivo Effects of <i>DL</i>-α-Difluoromethylornithine on the Polyamine and Nucleotide Phosphate Metabolism in P388/S Leukemia Cells

Polyamine starvation prolongs the S and G2 phases of polyamine-dependent (arginase-deficient) CHO cells.

Metabolism and action of amino acid analog anti-cancer agents

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