Tumor Suppression with a Combination of α-Difluoromethyl Ornithine and Interferon

Sunkara, Prasad S.; Prakash, Nellikunja J.; Mayer, Gerald D.; Sjoerdsma, Albert

doi:10.1126/science.6186025

Cited by 69 publications

(17 citation statements)

References 19 publications

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“…DL-a-Difluoromethylomithine (DFMO), an irreversible inhibitor of ornithine decar boxylase (ODC, EC 4.1.1.17), the first ratelimiting enzyme in polyamine biosynthesis, was reported to have antitumor activity in different transplanted or chemically induced tumors [4][5][6][11][12][13][14][15], and/or to potentiate the cytotoxicity of various chemotherapeutic agents [6,7,[16][17][18],…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…Because DFMO appears to be synergistic with a number of other cytotoxic agents [17][18][19]32,33], it may be in combination chemotherapy that DFMO will be most useful. The initial study of the combined use of two polyamine biosynthesis inhibitors, DFMO and methylglyoxal-bis(guanylhydrazone) (MGBG), administered to children was promising [25].…”

Section: Discussionmentioning

confidence: 99%

“…These have included both transplanted tumor cell lines [18,33,37,38] and chemically-induced mammary [40], colon [39], and epidermal [41] tumors. The decline in tumor putrescine level achieved after DFMO administration ranged from 50 to 99~ in the different tumor types.…”

Section: Discussionmentioning

confidence: 99%

Alterations in human circulating and bone marrow mononuclear cell polyamine levels in hematologic malignancies as a consequence of difluoromethylornithine administration

Maddox¹,

Freireich²,

Keating

et al. 1988

Invest New Drugs

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The effect of administering increasing intravenous doses of difluoromethylornithine on human tumor cell polyamine levels was determined in patients with hematologic malignancies. Difluoromethylornithine from 5.5. to 64 gm/m2 per day was administered to nine patients with refractory acute leukemia or multiple myeloma. Putrescine, spermidine, and spermine levels were determined on a daily basis in the circulating mononuclear cells and on a weekly basis in the mononuclear cells of the bone marrow. Tumor cell putrescine levels declined in 5 patients, spermidine levels declined in 4 patients, and spermine levels declined in 3 patients. Alterations in the polyamine levels of the bone marrow mononuclear cells paralleled those occurring in the peripheral blood mononuclear cells in the patients with leukemia. Seven to ten days of DFMO treatment were required for mononuclear cell polyamine levels to decrease. The higher drug doses were not significantly more effective than the lower doses in bringing about a decline in tumor cell polyamine levels, either with respect to treatment time required for onset of response or with respect to the ultimate extent of response.

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“…DFMO is a potent inhibitor of murine melanoma growth in vitro and in vivo (Kapyaho, 1985;Sunkara et al, 1983;Sunkara et al, 1985). DEX, a-IFN, and RA in combination synergistically enhanced human melanoma cell sensitivity to growth inhibition by continuous DFMO exposure.…”

Section: Discussionmentioning

confidence: 99%

Median Effect and Long Term Recovery Analysis of Biological Modifier Interactions With Difluoromethylornithine on the Proliferation of Human Melanoma Cells

Bregman

Buckmeier

Funk

et al. 1987

Pigment Cell Research

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The ability of difluoromethylornithine (DFMO), a specific polyamine synthesis inhibitor, to interact with various biological modifiers to inhibit the colony‐forming growth of human melanoma cells was determined by using the median effect principle to computer model the strength of two agent interactions. Either alpha‐ or gamma‐IFN (interferon) in combination with DFMO resulted in a synergistic inhibition on human melanoma colony formation. For human melanoma cells which were not resistant to 13‐cis RA (retinoic acid), an additive suppression on colony formation was obtained with the retinoid‐DFMO combination. Dexamethasone (DEX) interacted with DFMO to yield a synergistic reduction in melanoma colony number on glucocorticoid sensitive cells and no growth enhancement with DFMO on glucocorticoid resistant melanoma lines. Human melanoma cells displayed differential long‐term growth sensitivity to DFMO treatment. C8146C human melanoma cells were terminally growth‐inhibited by a 96 h exposure to DFMO, in a manner which was concentration and time dependent. The proliferation of C82‐7A melanoma cells was inhibited by 95% in presence of DFMO, but upon removal of DFMO the cells regained their ability to proliferate and form colonies. The simultaneous addition of DEX plus alpha‐IFN plus 13‐cis‐RA with DFMO caused most of the human melanoma cells in these lines to become permanently growth arrested. Pre‐treatment with DEX plus alpha‐IFN plus 13‐cis RA, but without DFMO, did not have any long term effect on the ability of melanoma cells to recover and proliferate in soft agar. Since human melanoma cells are heterogeneous with respect to sensitivity to these hormones, it may be advantageous to use DFMO with several of these agents in combination.

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Tumor Suppression with a Combination of α-Difluoromethyl Ornithine and Interferon

Cited by 69 publications

References 19 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

Alterations in human circulating and bone marrow mononuclear cell polyamine levels in hematologic malignancies as a consequence of difluoromethylornithine administration

Median Effect and Long Term Recovery Analysis of Biological Modifier Interactions With Difluoromethylornithine on the Proliferation of Human Melanoma Cells

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