Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cultured mouse L1210 leukaemia cells treated with DL-2-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase (EC 4.1.1.17), in the presence of micromolar concentrations of cadaverine, started to overproduce ornithine decarboxylase after an exposure of several weeks. The more than 60-fold excess of the enzyme protein in the drug-treated cells apparently resulted from a strikingly enhanced accumulation of mRNA for the enzyme associated with only a modest (about 2-fold) gene amplification.
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PMID:Gene expression of ornithine decarboxylase in L1210 leukaemia cells exposed to DL-2-difluoromethylornithine in the presence of cadaverine. 393 20

Derivatives of glyoxal bis(guanylhydrazone) (GBG), such as methylglyoxal bis(guanylhydrazone) and ethylglyoxal bis(guanylhydrazone), are potent inhibitors of S-adenosylmethionine decarboxylase (EC 4.1.1.50), the key enzyme required for the synthesis of spermidine and spermine. These compounds, but not the parent compound, induce a massive accumulation of putrescine, partly by blocking the conversion of putrescine into spermidine, but also by strikingly stimulating ornithine decarboxylase (ODC; EC 4.1.1.17) activity. The mechanism of the stimulation of ODC activity and enhanced accumulation of the enzyme protein apparently involved a distinct stabilization of the enzyme against intracellular degradation. However, although the parent compound GBG also stabilized ODC, it powerfully inhibited the enzyme activity and the accumulation of immunoreactive protein in cultured L1210 leukaemia cells. Kinetic considerations indicated that, in addition to the stabilization, all three compounds, GBG in particular, inhibited the expression of ODC. It is unlikely that the decreased rate of synthesis of ODC was attributable to almost unaltered amounts of mRNA in drug-treated cells, thus supporting the view that especially GBG apparently depressed the expression of ODC at some post-transcriptional level.
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PMID:Effects of bis(guanylhydrazones) on the activity and expression of ornithine decarboxylase. 406 86

Because alpha-difluoromethylornithine (DFMO) reduces the incidence of experimental colon cancers, inhibits the growth of human lung cancer cells and human leukemia cells in culture, and in combination with methylglyoxal (bis)guanylhydrazone induces remission in children with leukemia, its effectiveness against a human colon adenocarcinoma cell line (Colo 205) was tested alone and in combination with 5-fluorouracil (5-FU). Both DFMO (2 X 10(-4) M) and 5-FU (10(-6) M) inhibited Colo 205 cell proliferation. Above 5 X 10(-4) M DFMO (p less than 0.001) and at 10(-4) M 5-FU (p less than 0.001), Colo 205 growth was completely inhibited. Although DFMO did not sensitize Colo 205 cells to a noninhibitory concentration of 5-FU, the effectiveness of inhibitory concentrations of 5-FU and DFMO in reducing Colo 205 cell growth was additive. DFMO (2 X 10(-4) M) caused 89 to 93% inhibition of ornithine decarboxylase activity (p less than 0.001) and reduced levels of putrescine (93%; p less than 0.01) and spermidine (57%; p less than 0.02). Growth rate and the intracellular putrescine and spermidine contents were restored by 10(-6) M putrescine. DFMO could be an effective chemotherapeutic agent against human colonic cancer because of its effects at such unusually low concentrations in vitro.
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PMID:Effects of alpha-difluoromethylornithine and 5-fluorouracil on the proliferation of a human colon adenocarcinoma cell line. 640 95

Treatment of mice bearing L1210 leukaemia with 2-difluoromethylornithine, a specific inhibitor of ornithine decarboxylase (EC 4.1.1.17), produced a profound depletion of putrescine and spermidine in the tumour cells. Sequential combination of methylglyoxal bis(guanylhydrazone), an inhibitor of adenosylmethionine decarboxylase (EC 4.1.1.50), with difluoromethylornithine largely reversed the polyamine depletion and led to a marked accumulation of cadaverine in the tumour cells. Experiments carried out with the combination of difluoromethylornithine and aminoguanidine, a potent inhibitor of diamine oxidase (EC 1.4.3.6), indicated that the methylglyoxal bis(guanylhydrazone)-induced reversal of polyamine depletion was mediated by the known inhibition of diamine oxidase by the diguanidine. In spite of the normalization of the tumour cell polyamine pattern upon administration of methylglyoxal bis(guanylhydrazone) to difluoromethylornithine-treated animals, the combination of these two drugs produced a growth-inhibitory effect not achievable with either of the compounds alone.
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PMID:Role of diamine oxidase during the treatment of tumour-bearing mice with combinations of polyamine anti-metabolites. 641 Oct 77

Polyamine depletion by pretreatment with alpha-difluoromethylornithine (DFMO), a specific and irreversible inhibitor of ornithine decarboxylase, potentiates the cytotoxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in L1210 leukemia cells grown in a modified soft agar system. The dose enhancement ratio was 1.97 at a control colony formation level of 5%. The basis for this enhancement was investigated at the level of DNA damage using a modified fluorometric assay to quantitate the production of alkaline-labile strand breaks per relative DNA molecular mass. Pretreatment of cultured L1210 cells for 48 hr with 5 mM DFMO depleted intracellular putrescine and spermidine (but not spermine) pools and resulted in a 2.3-fold increase in BCNU-induced (10 micrograms/ml, 2 hr) DNA strand breaks per relative DNA molecular mass. The inclusion of 10 microM spermidine during the DFMO pretreatment fully prevented growth inhibition and enhancement of BCNU-induced DNA damage while maintaining cellular spermidine pools at control levels. The inclusion of 2 microM putrescine or spermidine also prevented growth inhibition and enhancement of DNA damage while maintaining spermidine pools at only 25 to 35% of control. Thus, the portion of spermidine essential for cell growth appears to be associated with DNA. BCNU itself was found to reduce cellular polyamine levels by causing their leakage from cells. In addition, BCNU was found to react directly with spermidine in a cell-free system, resulting in a major reaction product detectable by high-performance liquid chromatography. While decreased interaction of BCNU with polyamines could account, in part, for enhancement effects of DFMO, it is more probable that alterations in DNA structure secondary to polyamine depletion are responsible for these effects.
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PMID:Enhancement of 1,3-bis(2-chloroethyl)-1-nitrosourea-induced cytotoxicity and DNA damage by alpha-difluoromethylornithine in L1210 leukemia cells. 643 May 55

Several lines of evidence have suggested, but not proved, that polyamines are associated with DNA in intact cells. In an attempt to investigate the roles of polyamines in gene-associated functions, we examined the effects of polyamine depletion on the spontaneous mutation rate in a rat basophilic leukemia cell line. The frequency of 6-thioguanine-resistant mutant cells increased by approximately 9-fold as a result of the treatment with alpha-difluoromethylornithine, a potent inhibitor of ornithine decarboxylase (EC 4.1.1.17). This increase was prevented by supplementing the cultures with putrescine, suggesting that polyamine depletion, but not the direct mutagenic action of the enzyme inhibitor, is responsible for the mutant-increasing effect. These results suggest that polyamines may participate in the conservation of genetic information at either the chromosome or gene level.
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PMID:Enhancement of the rate of spontaneous mutation to 6-thioguanine resistance in mammalian cells by polyamine depletion. 643 7

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

(2R,5R)-6-Heptyne-2,5-diamine hydrochloride (MDL 72175) is a new, potent, and selective inhibitor of mammalian ornithine decarboxylase. MDL 72175 given p.o. in drinking fluid reduced by 80% the growth of EMT6 sarcoma in mice and of HTC hepatoma in rats. It prolonged the survival of mice bearing L1210 or P388 leukemias and inhibited the development of Lewis lung carcinoma in mice at doses 10- to 20-fold lower than those of alpha-difluoromethylornithine, the most widely used irreversible inhibitor of ornithine decarboxylase. MDL 72175 depleted putrescine and spermidine levels in the tumors to the same extent as did alpha-difluoromethylornithine. In the EMT6 sarcoma, MDL 72175 achieved at low doses a greater maximal antitumor effect than did alpha-difluoromethylornithine. In combination therapy, MDL 72175 plus Adriamycin gave at least additive antitumor effects on solid tumors and experimental leukemias in animals. The combination MDL 72175 plus methylglyoxal bis(guanylhydrazone) also gave additive antitumor effects on P388 leukemia, associated with an increased uptake of methylglyoxal bis(guanylhydrazone); in contrast, antagonistic effects were observed with this combination on EMT6 tumors in mice. Since MDL 72175 did not present toxicity at effective antitumor doses, this new ornithine decarboxylase inhibitor can be considered as a promising antitumor drug.
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PMID:Antitumor properties of (2R,5R)-6-heptyne-2,5-diamine, a new potent enzyme-activated irreversible inhibitor of ornithine decarboxylase, in rodents. 643 61

Alterations in ornithine decarboxylase (ODC) activity and in the polyamine and nucleic acid (RNA and DNA) concentrations were studied in P388 leukemia cells and in the host liver at different times after intraperitoneal inoculation of 5 X 10(6) tumor cells into BDF1 mice. ODC activity of leukemia cells had a maximum at day 5 after tumor transplantation. Cellular spermidine concentration declined significantly during the first 5 to 6 days. The RNA concentration of tumor cells changed parallel to that of spermidine. In the livers of ascites tumor-bearing mice ODC activity was 5- to 20-fold of control and had a maximum at days 5 to 6 after tumor cell inoculation. Spermidine concentration in the host liver increased, whereas spermine decreased gradually with tumor growth.
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PMID:Polyamine metabolism in P388 leukemia cells and in ascites tumor-bearing mice. 647 29

The activity of ornithine decarboxylase (ODC) was determined in P388 murine leukemia cells treated with adriamycin (ADR) and methotrexate (MTX). Some of the cell lines were resistant to ADR, MTX or their combinations. A similar pattern was found between the cytotoxicity and the suppression of ODC activity in these cell lines in terms of drug concentrations. In a cell line resistant to one drug, a relatively high concentration of that drug was required to inhibit ODC activity. This effect was independent of the sensitivity of the cells to the other drug. A similar correlation between arrest of growth and the inhibition in the induction of ODC was also observed in human epithelial carcinoma cells. In this case too, the growth of multidrug resistant cells was not affected by vinblastine, neither was the induction of ODC. On the other hand, both the growth and the induction of ODC were inhibited by vinblastine in drug-sensitive cells. These findings suggest that ODC measurements might be used for predicting the chemosensitivity of tumor cells.
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PMID:Ornithine decarboxylase--a predictor for tumor chemosensitivity. 784 62


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