Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.1.1.17 (ornithine decarboxylase)
6,351 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both 2-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (EC 4.1.1.17), and methylglyoxal bis(guanylhydrazone) (MGBG), a competitive inhibitor of S-adenosylmethionine decarboxylase (EC 4.1.1.50), strikingly stimulated melanotic expression of murine Cloudman S91 melanoma cells. The stimulation of tyrosinase (EC 1.10.3.1) activity and melanin formation by DFMO was closely associated with intracellular depletion of putrescine and spermidine developed in response to the drug. However, little or no evidence was obtained indicating that enhanced melanogenesis in response to MGBG was mediated through an inhibition of polyamine biosynthesis. Indirect inhibitors of ornithine decarboxylase, such as 1,3-diaminopropane and 1,3-diaminopropan-2-ol, but not putrescine, likewise inhibited the growth of the melanoma cells and stimulated their melanin production. The stimulation of melanogenesis by polyamine antimetabolites was not mediated by cyclic adenosine 3':5'-monophosphate, in contrast to the effect elicited by alpha-melanotropin. It is also unlikely that MGBG or the diamines acted as lysosomotropic agents capable of stimulating tyrosinase activity in situ, since the enzyme activity was stimulated by the drugs irrespective of whether assayed in cultured cells or using cell-free homogenates. None of the agents stimulated tyrosinase activity in vitro. The effect of DFMO and MGBG on melanoma cell proliferation was reversible, but the restoration of normal growth and melanin formation, especially in cells exposed to DFMO, was remarkably slow. The present results represent a further experimental model, in which the inhibition of polyamine accumulation is accompanied by signs of terminal differentiation.
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PMID:Effects of inhibitors of polyamine biosynthesis on the growth and melanogenesis of murine melanoma cells. 391 40

The mitogenic action of prolactin in Nb 2 node lymphoma cells was inhibited by two drugs which interfere with polyamine biosynthesis. At concentrations of 0.5 mM and above alpha-difluoromethyl ornithine (DFMO), which inhibits ornithine decarboxylase and the conversion of ornithine to putrescine, significantly attenuated the mitogenic effect of prolactin. This inhibition was prevented by the addition of putrescine, spermidine, or spermine to the culture medium. At concentrations of 1 microM and above methylglyoxal bis(guanylhydrazone) (MGBG), which inhibits S-adenosylmethionine decarboxylase and hence the conversion of putrescine to spermidine and spermine, abolished the mitogenic action of prolactin. This inhibition was prevented by the addition of spermidine or spermine, but not putrescine, to the culture medium. These studies show that ongoing polyamine biosynthesis is essential for prolactin to express its mitogenic effect in this lymphoma cell line.
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PMID:Prolactin stimulation of Nb 2 node lymphoma cell division is inhibited by polyamine biosynthesis inhibitors. 393 Oct 86

Although ornithine decarboxylase under most conditions is the rate-controlling enzyme of polyamine biosynthesis and thus the most logical target for chemical intervention, the inhibition of the enzyme triggers a series of compensatory reactions all aimed to circumvent the inhibition. These include secondary induction of adenosylmethionine decarboxylase, enhanced accumulation of extracellular polyamines and an overproduction of ornithine decarboxylase resulting from enhanced expression and gene amplification. Thus chemotherapy based on an intervention of polyamine formation has also to be directed to reactions other than the decarboxylation of ornithine. Adenosylmethionine decarboxylase is the second natural target for chemotherapy. Virtually all effective inhibitors of this enzyme are members of the family of bis(guanylhydrazones). Small modifications, such as increased hydrophobicity at the glyoxal portion of the parent compound glyoxal bis(guanylhydrazone), greatly enhance the inhibition of adenosylmethionine decarboxylase and diminish the undesirable inhibition of diamine oxidase. However, although ethylglyoxal and propylglyoxal bis(guanylhydrazone) appear to utilize the putative polyamine carrier for their cellular entry, their cellular accumulation, in contrast to that of glyoxal and methylglyoxal bis(guanylhydrazone), is not stimulated by putrescine and spermidine deprivation produced by inhibitors of ornithine decarboxylase. It is obvious that the cellular accumulation of each of the bis(guanylhydrazones) is determined by their different efflux rates: GBG and MGBG are effectively retained whereas EGBG is rapidly excreted by the tumor cells. GBG and MGBG, but possibly not EGBG, behave as mitochondrial poisons and rapidly produce extensive morphological damage of the mitochondria. The bis(guanylhydrazones) likewise inhibit carnitine-dependent mitochondrial oxidation of long-chain fatty acids, competitively in respect to carnitine. It is possible that this inhibition has something to do with the mitochondrial damage, as carnitine protects tumor cells from the early mitochondrial damage produced by MGBG. Carnitine also protects experimental animals from MGBG-induced acute toxicity and death.
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PMID:S-adenosylmethionine decarboxylase as target of chemotherapy. 393 95

Methylglyoxal-bis(guanylhydrazone) (MGBG), an inhibitor of polyamine synthesis, was administered to 35 patients with hormone-resistant advanced adenocarcinoma of the prostate in doses of 500 or 600 mg/m2 per week intravenously. Of 31 patients with bidimensional measurable soft-tissue lesions, 25 had an adequate trial, defined as four or more doses. Six (24%; 95% confidence limits, 8% to 32%) patients achieved a partial remission (greater than or equal to 50% reduction in tumor size) in soft-tissue disease. Response was noted to start after one to two doses and persisted for a median of three months (range, 1 to 4 months). Toxicity was tolerable, and significant myelosuppression was not observed. The lack of response in osseous metastases may be secondary to the short duration of remission or to the presence or inducibility of the enzyme ornithine decarboxylase in bone. Since some animal prostatic cancer tumor models are sensitive to cytotoxic drugs that produce polyamine inhibition, clinical trials of MGBG combined with other inhibitors of the polyamine pathway should be explored.
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PMID:Methylglyoxal-bis(guanylhydrazone) in hormone-resistant adenocarcinoma of the prostate. 396 52

The actions of prolactin (PRL) on casein and lipid biosynthesis in cultured mouse mammary gland explants require the ongoing synthesis of the polyamines. This is supported by the fact that (MGBG) methylglyoxal bis(guanylhydrazone), a drug that inhibits the conversion of putrescine to spermidine, abolishes the effects of PRL on casein and lipid biosynthesis; the inhibitory effects of MGBG are reversed by the addition of spermidine to the culture medium. alpha-Difluoro methyl ornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase activity, reduces the PRL-stimulated ornithine decarboxylase (ODC) activity by more than 95%, and yet does not suppress the effects of PRL on RNA, casein or lipid synthesis. These observations suggest that PRL's early action on ODC activity is not essential for the subsequent actions of PRL on the synthesis of certain of the components of milk.
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PMID:Early action of prolactin on ornithine decarboxylase activity is not essential for the subsequent actions of prolactin on casein and lipid biosynthesis. 619 64

Treatment of mice with DL-alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (EC 4.1.1.17), produced a significant spermidine depletion in liver, small intestine, and bone marrow among eight tissues studied. The accumulation of methylglyoxal bis(guanylhydrazone) (MGBG) was selectively enhanced in small intestine and in bone marrow cells in response to a prior DFMO treatment. In other tissues studied, i.e., brain, skeletal and cardiac muscle, liver, kidney, and spleen, a preceding treatment with DFMO had no effect on the accumulation of subsequently injected MGBG. When mice, primed with DFMO and then treated with a single injection of MGBG, were given nontoxic doses of spermidine or putrescine through a gastric tube, high concentrations of MGBG in the small intestine and in bone marrow cells were effectively reduced. In spite of the route of administration, bone marrow cells appeared to be more sensitive than intestinal tissue as regards the prevention of the tissue accumulation of MGBG by the polyamines. The different sensitivity of various tissues to the natural polyamines in this respect may offer a means to develop a tissue-specific "polyamine rescue concept" to be used in connection with MGBG treatment.
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PMID:Modulation of the tissue disposition of methylglyoxal bis(guanylhydrazone) in mice by polyamine depletion and by polyamine administration. 640 Nov 67

Difluoromethylornithine (DFMO) and methylglyoxal bis (guanylhydrazone) (MGBG), inhibitors of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AMDC), respectively, were tested for antitumor activity in the BALB/C mouse renal adenocarcinoma model, wherein ODC and AMDC activity are elevated compared to the normal kidney. Additionally, an indirect effector of AMDC synthesis, arabinofuranosyladenine and an inhibitor of AMDC synthesis, cycloleucin (CL), were tested in this model. Simultaneous administration of both DFMO and MGBG affected the growth of renal adenocarcinoma less than did administration of DFMO or MGBG alone. Combinations of inhibitors of polyamine synthesis demonstrated a high toxicity with low therapeutic activity. The most effective tumor suppression was observed with CL alone but associated toxicity was severe. Suramin, an ODC stimulator, may have enhanced tumor growth.
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PMID:Experimental chemotherapy in a transplantable renal adenocarcinoma. I: Effects of some inhibitors of polyamine synthesis. 640 77

Stable variants of the human cell line, VA2-B, have been developed which are 10- to 20-fold less sensitive to the antiproliferative effects of methylglyoxal bis(guanylhydrazone) (MGBG) than the parent cell lines and which are not drug transport deficient. The lines were characterized biochemically giving particular attention to parameters related to the two known sites of MGBG action, mitochondria and polyamine metabolism. Dose-response studies with MGBG (0 to 30 microM for 40 to 48 hr) revealed that, of the parameters related to polyamine metabolism (i.e., polyamine pools, S-adenosylmethionine, and ornithine decarboxylase activities), only spermine pool size reduction seemed to correlate with inhibition of cell growth by MGBG. By contrast, decreases in pyruvate oxidation (used here as a measure of mitochondrial function) closely paralleled growth inhibition in all cell lines. Similarly, MGBG-induced changes in mitochondrial ultrastructure were less conspicuous in the variants than in the parent cell line and also corresponded with growth inhibition. Respiration of isolated mitochondria from one of the variant lines was about 2-fold more resistant to the inhibitory effects of MGBG than mitochondria from the VA2 cells. Finally, treatment with alpha-difluoromethylornithine, a potent inhibitor of polyamine biosynthesis having no known effect on mitochondrial function, resulted in comparable inhibition of growth in variant and parent cell lines. Overall, the data suggest that a phenotypic alteration in mitochondrial function, rather than in polyamine metabolism, may represent the basis for MGBG resistance in these variant cell lines.
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PMID:Biochemical and ultrastructural characterization of human cell variants resistant to the antiproliferative effects of methylglyoxal bis(guanylhydrazone). 641 70

Difluoromethylornithine (DFMO) and methylglyoxal-bis(guanyl-hydrazone) (MGBG), inhibitors of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AMDC), respectively, were tested in two experimental prostatic cancer models. DFMO resulted in a reduction in tumor size in both the rapidly growing R-3327 rat prostatic adenocarcinoma (30.5 +/- 15 versus 61 +/- 9.5 in control animals) and the human DU-145 adenocarcinomas (1.7 ml versus 3.3 ml in control animals) in nude mice. MGBG was tested only in the rat tumor, where it induced a reduction of 22.9 +/- 9.5 ml versus 61 +/- 9.5 in control animals in tumor size but was highly toxic. Flutamide or 9-B-D-arabinofuranosyladenine (Ara-A) proved ineffective per se in reducing tumor growth of the human DU-145 or of the R-3327-G strain, respectively, but increased the efficacy of DFMO against the DU-145 tumor had a high level of ODC which was reduced by DFMO of by Ara-A; the R-3327 tumor had a low level of ODC which was too low to be decreased by DFMO.
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PMID:Some effects of inhibitors of polyamine synthesis on experimental prostatic cancer. 642 51

alpha-Difluoromethylornithine (DFMO) and methylglyoxal bis-(guanylhydrazone) (MGBG) were tested against a murine renal adenocarcinoma, because polyamines are necessary for neoplastic cell growth and because human renal adenocarcinomas contain higher levels of spermidine than do normal renal cells; MGBG inhibits spermidine synthesis and has some activity against human renal tumors; DFMO irreversibly inhibits ornithine decarboxylase, the first rate-limiting enzyme controlling polyamine biosynthesis; and DFMO promotes intracellular accumulation of MGBG in experimental tumor models and human leukemia. DFMO (2%) in drinking water, MGBG (15 mg/kg i.p.), or a combination of DFMO and MGBG was administered daily to BALB/c mice (n = 80) with intrarenal transplants of renal adenocarcinoma cells. At 28 days, renal carcinomas weighed 64 and 73% less, respectively, in DFMO- and DFMO-MGBG-treated mice than in control animals (p less than 0.01). MGBG alone had no antigrowth effect. DFMO-MGBG reduced the total metastatic index (total number of metastases/total number of animals) to 1.2 versus 3.6 in control animals (p less than 0.01) and increased survival by 12.3 +/- 1.5 (S.E.) days, from 30.8 to 42.5 days (p less than 0.05). Compared with control, DFMO-, or MGBG-treated animals, DFMO-MGBG exposure reduced tumor growth and the number of metastases, prevented metastases in some animals (47%), and increased survival of mice bearing renal adenocarcinomas. DFMO also appeared to selectively increase the uptake of [14C]MGBG by tumor tissue, which may help to explain the enhanced synergistic antigrowth effect of DFMO and MGBG against this murine renal adenocarcinoma.
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PMID:Effects of alpha-difluoromethylornithine and methylglyoxal bis(guanylhydrazone) on the growth of experimental renal adenocarcinoma in mice. 643 12


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