Disease relevance of alpha-Difluoromethylornithine

• Depletion of polyamines in 9L rat brain tumor cells by treatment with alpha-difluoromethylornithine dramatically altered DNA conformation as measured by viscoelastometry [1].
• Inhibition of cardiac ornithine decarboxylase (ODC) by alpha-difluoromethylornithine (DFMO) did not prevent normal cardiac growth in mature rats but attenuated isoproterenol-induced hypertrophy [2].
• Treatment of hamster pancreatic cancer with alpha-difluoromethylornithine, an inhibitor of polyamine biosynthesis [3].
• Effect of alpha-difluoromethylornithine on rectal mucosal levels of polyamines in a randomized, double-blinded trial for colon cancer prevention [4].
• Dose de-escalation chemoprevention trial of alpha-difluoromethylornithine in patients with colon polyps [5].

Psychiatry related information on alpha-Difluoromethylornithine

• The period of increased polyamine synthesis coincides with the critical period for ototoxicity induced by alpha-difluoromethylornithine, a specific ODC inhibitor, and the period of rapid cochlear development [6].

High impact information on alpha-Difluoromethylornithine

• alpha-Difluoromethylornithine is an enzyme-activated irreversible inhibitor of ornithine decarboxylase that forms a covalent bond with the enzyme [7].
• Furthermore, oral administration of the suicidal ODC inhibitor alpha-difluoromethylornithine reduced UVB-induced BCCs in Ptch1+/- mice [8].
• In a short-term phase IIa trial, we determined that low doses of alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (an enzyme involved in polyamine synthesis), reduced the polyamine content of normal-appearing rectal mucosa of subjects with a prior history of resected colon polyps [4].
• RESULTS: alpha-Difluoromethylornithine inhibited hepatocyte growth factor-induced DNA synthesis by only 21% [9].
• Immature enterocytes from sucklings, pretreated with alpha-difluoromethylornithine, remained sensitive to insulin and expressed enzyme activities at levels equal to controls [10].

Chemical compound and disease context of alpha-Difluoromethylornithine

• Recent evidence indicates that hormone-responsive but not -resistant human breast cancer cells in culture are sensitive to the antiproliferative effect of the polyamine (PA) biosynthetic inhibitor alpha-difluoromethylornithine (DFMO) [11].
• Treatment of 9L rat brain tumor cells with 1.0 mM alpha-difluoromethylornithine (DFMO) produced a time-dependent depletion of cellular putrescine and spermidine [12].
• Time dependence of the potentiation of 1,3-bis(2-chloroethyl)-1-nitrosourea cytotoxicity caused by alpha-difluoromethylornithine-induced polyamine depletion in 9L rat brain tumor cells [12].
• Decreased cytotoxicity of cis-diamminedichloroplatinum(II) by alpha-difluoromethylornithine depletion of polyamines in 9L rat brain tumor cells in vitro [13].
• Combination chemotherapy involving alpha-difluoromethylornithine and 1-beta-D-arabinofuranosylcytosine in murine L1210 leukemia [14].

Biological context of alpha-Difluoromethylornithine

• Rearrangement between ornithine decarboxylase and the switch region of the gamma 1 immunoglobulin gene in alpha-difluoromethylornithine resistant mouse myeloma cells [15].
• NO, like alpha-difluoromethylornithine (DFMO), interferes with cell proliferation by inhibiting ornithine decarboxylase (ODC) and, therefore, polyamine synthesis [16].
• In normal rats, alpha-difluoromethylornithine resulted in a reduction of the leukocyte count to 73% of control, erythrocyte count to 61% of control, and platelet count to 24% of control [17].
• Inhibiting ODC activity with alpha-difluoromethylornithine delayed DCVC-induced cell death [18].
• The specific, irreversible ODC inhibitor alpha-difluoromethylornithine (DFMO, 5-10 mM) blocked the testosterone-evoked increase in ODC activity and polyamine levels and the stimulation of Ca2+ fluxes, endocytosis, hexose transport, and amino acid transport [19].

Anatomical context of alpha-Difluoromethylornithine

• METHODS: Polyamines were depleted in intestinal epithelial cell (IEC)-6 cells by incubating them for 4 days with 5 mmol/L alpha-difluoromethylornithine (DFMO), which inhibits ornithine decarboxylase, the first rate-limiting enzyme in the synthesis of polyamines [20].
• Further, an irreversible inhibitor of OrnDCase, alpha-difluoromethylornithine (CHF2-Orn), rapidly inhibited the endogenous activity of OrnDCase when added to the buffered Hepes solution bathing the oocytes and also inhibited the incorporation of [32P]guanosine into rRNA [21].
• The specific ornithine decarboxylase inhibitor alpha-difluoromethylornithine, when given to adult rats in vivo for 5 wk, resulted in a decrease in peripheral blood cell elements in normal rats and a marked suppression of marrow recovery in rats with chemotherapy-induced marrow hypoplasia [17].
• We describe the first example of unstable gene amplification consisting of linear extrachromosomal DNAs in drug-resistant eukaryotic cells. alpha-Difluoromethylornithine (DFMO)-resistant Leishmania donovani with an amplified ornithine decarboxylase (ODC) gene copy number contained two new extrachromosomal DNAs, both present in 10 to 20 copies [22].
• 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 [23].

Associations of alpha-Difluoromethylornithine with other chemical compounds

• Addition of ornithine or alpha-difluoromethylornithine, a specific inhibitor of ornithine decarboxylase, has no effect on these cells [24].
• The ornithine decarboxylase inhibitor alpha-difluoromethylornithine blocked the MTA-triggered accumulation of putrescine but not decarboxylated SAM [25].
• Treatment of 9L cells with the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO) depletes cells of putrescine and spermidine and sensitizes cells to the cytotoxic effects of the alkylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea [26].
• Cell cycle age response of 9L cells to 1,3-bis(2-chloroethyl)-1-nitrosourea and modification by alpha-difluoromethylornithine [27].
• Growth sensitivity of the sublines to the ornithine decarboxylase inhibitor, alpha-difluoromethylornithine, or the S-adenosylmethionine decarboxylase inhibitor, CGP-48664, was found to be similar to parent cells [28].

Gene context of alpha-Difluoromethylornithine

• ODC induced cell death in a dose-dependent fashion, and alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC enzyme activity, effectively blocked ODC-induced cell death [29].
• Polyamine depletion with alpha-difluoromethylornithine inhibited the activities of RhoA, Rac1, and Cdc42 [30].
• Myc-induced apoptosis operates through ODC and can be prevented with the ODC inhibitor, alpha-difluoromethylornithine (DFMO) [31].
• Depletion of cellular polyamines by alpha-difluoromethylornithine, the specific inhibitor of polyamine biosynthesis, stimulated expression of the NPM gene and induced nuclear translocation of NPM protein [32].
• Depletion of cellular polyamines by alpha-difluoromethylornithine (DFMO) increased basal levels of Smad3 and Smad4 proteins, induced their nuclear translocation, and stimulated Smad sequence-specific DNA-binding activity [33].

Analytical, diagnostic and therapeutic context of alpha-Difluoromethylornithine

• Randomized phase I chemoprevention dose-seeking study of alpha-difluoromethylornithine [34].
• BACKGROUND: alpha-Difluoromethylornithine (DFMO) is a potent inhibitor of carcinogenesis in experimental animal models [5].
• Inhibition of human gastric adenocarcinoma xenograft growth in nude mice by alpha-difluoromethylornithine [35].
• After a 48-hr treatment with 1 mM alpha-difluoromethylornithine, the number of mitotic cells in asynchronously growing 9L cell cultures was reduced markedly [36].
• Although the mechanisms by which this effect occurs are unknown, these studies provide a rationale for combination clinical trials of alpha-difluoromethylornithine with leukocyte interferon [37].

References