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Abstract
Owing to their high turnover, the intestinal mucosal cells have a particularly high requirement for polyamines. Therefore, they are an excellent charcol for the study of polyamine function in rapid physiological growth and differentiation. After a cursory introduction to the major aspects of polyamine metabolism, regulation, and mode of action, we discuss the contribution of the polyamines to the maintenance of normal gut function, the maturation of the intestinal mucosa, and its repair after injuries. Repletion of cellular polyamine pools with (D,L)-2-(difluoromethyl)ornithine has considerably improved our understanding of how the polyamines are involved in the regulation of normal and neoplastic growth. Unfortunately, the attempts to exploit polyamine metabolism as a cancer therapeutic target have not yet been successful. However, the selective inactivation of ornithine decarboxylase appears to be a promising chemopreventive method in familial adenomatous polyposis. Presumably, it relies on the fact that ornithine decarboxylase is a critical regulator of the proliferative response of the protooncogene c-myc, but not of its apoptotic response.
| Abbreviations | ||
| AcetylCoA, | = | acetylcoenzyme A; |
| AdoMet, | = | S-adenosyl-L-methionine; |
| AdoMetDC, | = | S-adenosyl-L-methionine decarboxylase; |
| APC, | = | adenomatous polyposis coli tumor suppressor gene; |
| Cdk, | = | cyclin-dependent kinase; |
| COX, | = | cyclooxygenase; |
| dAdoMet, | = | decarboxylation product of AdoMet; |
| c-myc, | = | protooncogene; |
| DAO, | = | diamine oxidase; |
| DFMO, | = | (D, L-)-2-(difluoromethyl)ornithine; |
| EGF, | = | epidermal growth factor; |
| FAD, | = | flavin adenine dinucleotide; |
| FAP, | = | familial adenomatous polyposis; |
| K-ras, | = | oncogene; |
| GI, | = | gastrointestinal; |
| IEC-6 cells, | = | a rat small intestine crypt cell-derived cell line; |
| IL, | = | interleukin; |
| iNOS, | = | inducible nitric oxide synthase; |
| LOH, | = | loss of heterozygosity; |
| MAD1, | = | transcriptional repressor of ODC (c-Myc antagonist); |
| MAPK, | = | mitogen-activated protein kinases; |
| MGBG, | = | methylglyoxal-bis(guanylhydrazone); |
| MMR, | = | DNA mismatch repair genes; |
| MSI, | = | multiple microsatellite loci; |
| MST, | = | multiple microsatellite loci; |
| MTA, | = | methylthioadenosine; |
| NO, | = | nitric oxide (radical); |
| NOS, | = | nitric oxide synthase; |
| NSAID, | = | non-steroidal anti-inflammatory drugs; |
| OAZ, | = | ornithine antizyme; |
| ODC, | = | ornithine decarboxylase; |
| p21, p27, p53, | = | cell-cycle inhibitors (Cdk inhibitors); |
| PAO, | = | polyamine oxidase (FAD dependent); |
| PHA, | = | lectin phytohaemagglutinin; |
| PKC, | = | protein kinase C; |
| PPARγ, | = | peroxisome proliferator-activated (nuclear) receptor-γ; |
| Rb, | = | retinoblastoma protein; |
| SAT, | = | acetylCoA:spermine/spermidine N1-acetyltransferase; |
| Smad, | = | protein transcription activators; |
| SMO, | = | spermine oxidase (FAD-dependent); |
| Spdsyn, | = | spermidine synthase; |
| Spmsyn, | = | spermine synthase; |
| TGF, | = | transforming growth factor; |
| TNF, | = | tumor necrosis factor; |
| TRPV1, | = | a major ion channel expressed in nociceptive sensory afferents. |
| Abbreviations | ||
| AcetylCoA, | = | acetylcoenzyme A; |
| AdoMet, | = | S-adenosyl-L-methionine; |
| AdoMetDC, | = | S-adenosyl-L-methionine decarboxylase; |
| APC, | = | adenomatous polyposis coli tumor suppressor gene; |
| Cdk, | = | cyclin-dependent kinase; |
| COX, | = | cyclooxygenase; |
| dAdoMet, | = | decarboxylation product of AdoMet; |
| c-myc, | = | protooncogene; |
| DAO, | = | diamine oxidase; |
| DFMO, | = | (D, L-)-2-(difluoromethyl)ornithine; |
| EGF, | = | epidermal growth factor; |
| FAD, | = | flavin adenine dinucleotide; |
| FAP, | = | familial adenomatous polyposis; |
| K-ras, | = | oncogene; |
| GI, | = | gastrointestinal; |
| IEC-6 cells, | = | a rat small intestine crypt cell-derived cell line; |
| IL, | = | interleukin; |
| iNOS, | = | inducible nitric oxide synthase; |
| LOH, | = | loss of heterozygosity; |
| MAD1, | = | transcriptional repressor of ODC (c-Myc antagonist); |
| MAPK, | = | mitogen-activated protein kinases; |
| MGBG, | = | methylglyoxal-bis(guanylhydrazone); |
| MMR, | = | DNA mismatch repair genes; |
| MSI, | = | multiple microsatellite loci; |
| MST, | = | multiple microsatellite loci; |
| MTA, | = | methylthioadenosine; |
| NO, | = | nitric oxide (radical); |
| NOS, | = | nitric oxide synthase; |
| NSAID, | = | non-steroidal anti-inflammatory drugs; |
| OAZ, | = | ornithine antizyme; |
| ODC, | = | ornithine decarboxylase; |
| p21, p27, p53, | = | cell-cycle inhibitors (Cdk inhibitors); |
| PAO, | = | polyamine oxidase (FAD dependent); |
| PHA, | = | lectin phytohaemagglutinin; |
| PKC, | = | protein kinase C; |
| PPARγ, | = | peroxisome proliferator-activated (nuclear) receptor-γ; |
| Rb, | = | retinoblastoma protein; |
| SAT, | = | acetylCoA:spermine/spermidine N1-acetyltransferase; |
| Smad, | = | protein transcription activators; |
| SMO, | = | spermine oxidase (FAD-dependent); |
| Spdsyn, | = | spermidine synthase; |
| Spmsyn, | = | spermine synthase; |
| TGF, | = | transforming growth factor; |
| TNF, | = | tumor necrosis factor; |
| TRPV1, | = | a major ion channel expressed in nociceptive sensory afferents. |
