Disease relevance of Amd1

• The current study evaluates the therapeutic effects of antisense ODC and AdoMetDC sequences on colorectal cancer in vitro and in vivo [1].
• Polyamine depletion by ODC-AdoMetDC antisense adenovirus impairs human colorectal cancer growth and invasion in vitro and in vivo [1].
• Biological activity of the S-adenosylmethionine decarboxylase inhibitor SAM486A in human breast cancer cells in vitro and in vivo [2].
• SAMDC expression was examined in a H-ras transformed cell capable of metastasis formation [3].
• However, the activity of SAMDC increased up to 30-fold in DFMO-treated melanoma, while only a moderate increase was observed in the renal enzyme [4].

High impact information on Amd1

• BE3333 suppressed ornithine decarboxylase and S-adenosylmethionine decarboxylase, induced spermidine/spermine N1-acetyltransferase, and thus decreased the amount of polyamines [5].
• Inhibitors of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (SAMDC), derived from methylglyoxal-bis(guanylhydrazone) (MGBG), have been shown to have significant antitumor activity in several human solid tumor systems (U. Regenass et al., Cancer Res., 52:4712-4718, 1992) [6].
• Consistent with SAMDC inhibition, putrescine pools increase 10-fold, whereas spermidine and spermine pools fall to < 10% of control [6].
• The new SAMDC inhibitor showed potent antitumor activity against syngeneic tumors (B16 melanoma and Lewis lung carcinoma) and nude mouse human tumor xenografts (T-24 bladder carcinoma, SK MEL-24 melanoma, and MALME-3M melanoma) [6].
• The compound displays potent inhibition of SAMDC (50% inhibitory concentration, 5 nM), modest inhibition of diamine oxidase (50% inhibitory concentration, 4 microM), and no detectable inhibition of ornithine decarboxylase [6].

Chemical compound and disease context of Amd1

• DFMO also significantly affected the other biochemical markers of hyperplasia, namely lowered CB 3717-induced cell proliferation rate and increased S-adenosylmethionine decarboxylase (AdoMetDC) activity [7].
• 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 [8].
• Specific inhibitors of polyamine biosynthesis, such as methylglyoxal bis(guanylhydrazone), an inhibitor of S-adenosylmethionine decarboxylase, and the ornithine analogs, alpha-methylornithine and alpha-hydrazinoornithine, also inhibited the induction of Friend erythroleukemia cell differentiation [9].
• Combined use of alpha-difluoromethylornithine and an inhibitor of S-adenosylmethionine decarboxylase in mice bearing P388 leukemia or Lewis lung carcinoma [10].
• The alphaMHC/AdoMetDC mice did not display an overt cardiac phenotype, but there was an increased cardiac hypertrophy after beta-adrenergic stimulation with isoprenaline ('isoproterenol'), as well as a small increase in spermine content [11].

Biological context of Amd1

• Homozygous (Amd1(-/-)) blastocysts at E3.5 arrested cell proliferation immediately after the onset of cell culture, and this arrest was rescued by the addition of spermidine [12].
• However, homozygous Amd1(-/-) embryos died early in embryonic development, between E3.5 and E6.5 days post-coitus [12].
• RESULTS: Our study demonstrated that adenovirus-mediated ODC and AdoMetDC antisense expression inhibits tumor cell growth through a blockade of the polyamine synthesis pathway [1].
• We have previously identified a mouse AdoMetDC gene that exhibits the hallmarks of a retroposon; that is, it has no introns, is flanked by direct repeats, and has a poly(dA) tract at its 3'-end [13].
• These results were confirmed by transfecting these cells with plasmids containing a luciferase complementary DNA fused to follow the 5'UTR from ODC or AdoMetDC [14].

Anatomical context of Amd1

• Chromosomal DNA breakage did not occur in Amd1(-/-) blastocysts at E3.5, as determined by TUNEL assay [12].
• AdoMetDC activity was not greatly different in the two cell lines, but ODC activity was much greater in the P2 cells [14].
• Growth factor-mediated altered expression and regulation of S-adenosylmethionine decarboxylase in a H-ras transformed cell line capable of malignant progression [3].
• Altered ornithine decarboxylase and S-adenosylmethionine decarboxylase expression and regulation in mouse fibroblasts transformed with oncogenes or constitutively active Mitogen-Activated Protein (MAP) kinase kinase [15].
• The activities of S-adenosylmethionine decarboxylase and spermidine and spermine syntheses were likewise significantly increased in testis of the transgenic animals [16].

Associations of Amd1 with chemical compounds

• To examine the role of polyamines in embryogenesis, we carried out targeted disruption of the mouse Amd1 gene, encoding AdoMetDC, to generate mice that can not synthesize spermidine and spermine [12].
• The induction of ODC activity by TPA was specifically blocked by methylglyoxal bis(butylamidinohydrazone) (MGBB), a competitive inhibitor of ODC and S-adenosylmethionine decarboxylase, but not by the analog methylglyoxal bis(guanylhydrazone) (MGBG) [17].
• The cells were resistant to ethylglyoxal bis(guanylhydrazone), and showed AdoMetDC activity approximately five-times higher than control cells [18].
• EGF and bFGF were able both to cooperate with cycloheximide, an inhibitor of protein synthesis, to augment the expression of SAMDC mRNA [3].
• Evidence is presented to suggest that the PMA-mediated alterations in ODC and in SAMDC gene expression in NR3 cells and in C2 cells involved protein kinase C - mediated events [19].

Regulatory relationships of Amd1

• Treatment of the L1210 cell for 48 h with 3 microM CGP 48664 decreases SAMDC activity to < 10% of control and initiates a compensatory 3-fold rise in ornithine decarboxylase [6].
• There was no significant difference between PRO/Re and C57BL/6J male mice for either putrescine- or spermidine-stimulated S-adenosylmethionine decarboxylase activity [20].
• S-Adenosylmethionine decarboxylase gene expression is regulated by the cAMP signal transduction pathway in H-ras transformed fibrosarcoma cells capable of malignant progression [21].

Other interactions of Amd1

• The level of ODC activity is about 70 fold higher at the time of birth than in the adult mouse, whereas AdoMetDC activity is very low after birth and increases as the brain matures [22].
• Drug-induced elevations in ODC and, to a lesser extent, AdoMetDC activities were reversed by later treatment with exogenous AdoMet [23].
• In these cultures, AdoMetDC activity decreased with a t1/2 of 7 h during transition from long slender to short stumpy-like forms as soon as the stationary phase was reached [24].
• The alphaMHC (alpha-myosin heavy chain) promoter was used to generate transgenic mice with cardiac-specific expression of AdoMetDC [11].
• Catecholamine depletion evoked by reserpine drastically decreases the folate-induced activity of S-adenosylmethionine decarboxylase (AdoMetDC), which limits polyamine biosynthesis, but has no effect on SSAT activity augmented by CB 3717 [25].

Analytical, diagnostic and therapeutic context of Amd1

• Activities of S-adenosylmethionine decarboxylase (AdoMetDC) and spermidine/spermine N1-acetyltransferase (SAT) were not increased by the intraperitoneal injection of MGBC [26].
• Molecular cloning of the mouse S-adenosylmethionine decarboxylase cDNA: specific protein binding to the conserved region of the mRNA 5'-untranslated region [27].
• Maximal effect was obtained 6-8 hr after treatment at which time single dose of chlorpromazine (50 mg/kg) stimulated ornithine decarboxylase activity 7-fold and decreased S-adenosylmethionine decarboxylase activity to 50% from the control level [28].
• S-adenosylmethionine decarboxylase as target of chemotherapy [29].
• Localization of S-adenosylmethionine decarboxylase in murine tissues by immunohistochemistry [30].

References