Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Differentiation inducers act through polyamine-dependent and independent pathways. Sodium butyrate (NaB) inhibits proliferation and induces terminal differentiation in human and murine cancer cell lines. An effect of this agent on polyamine biosynthesis has not been demonstrated previously. In the present study, we examined the effects of NaB on polyamine biosynthesis in mouse colon cancer (MC-26) cells. All studies were performed on exponentially growing cells, and ODC and polyamine transport measurements were performed as described previously. NaB inhibited the growth of MC-26 cells in a dose-dependent manner. Cell shape was significantly altered by treatment with NaB (development of dendritic-like processes and flattening and spreading out of cells on culture dishes). NaB stimulated ODC activity in a dose-dependent manner. The activity was elevated by 8 h after treatment, and at 48 h there was a ten-fold increase in activity (compared with control activity). The increase in ODC activity led to an increase in polyamine biosynthesis; putrescine, spermidine, and spermine levels in MC-26 cells were significantly elevated by 24 h after treatment with NaB. Polyamine uptake was similar in control cells and cells treated with NaB alone. Our finding of significant stimulation of polyamine uptake by NaB after inhibition of endogenous synthesis (by an ODC-dependent pathway) in DFMO-treated cells suggests that cellular requirements are increased for polyamines in NaB-treated cells. We conclude that polyamine-dependent processes are important in the mechanism of action of NaB in colon cancer cells.
 ...
PMID:Sodium butyrate stimulates polyamine biosynthesis in colon cancer cells. 134 Dec 66

The proliferative activity and polyamine levels of the rectal epithelium in unoperated ulcerative colitis patients and in ulcerative colitis patients after total colectomy and ileorectal anastomosis were determined and compared with control subjects. Cell proliferation was evaluated in rectal biopsies by in vitro 3H thymidine incorporation by measuring the labeling index and the position of labeled cells along the crypt; polyamines were determined with a chromatographic method. In ulcerative colitis patients the labeling index was significantly increased, and labeled cells were shifted toward the upper part of the crypt when compared with controls. Ileorectal anastomosis patients showed a normalization of the labeling index and a distribution of labeled cells similar to controls. Polyamine levels were also increased in ulcerative colitis patients; in ileorectal anastomosis patients, the level of polyamines was decreased in respect to unoperated patients and return to normal values except for spermine. Because the increased proliferation and higher polyamine levels are related to increased colon cancer risk, our results confirm that ulcerative colitis is a risk factor for the development of carcinoma. Ileorectal anastomosis may reduce this risk through a normalization of mucosal cell proliferative activity and of some polyamine levels.
 ...
PMID:Mucosal cell proliferation of the rectal stump in ulcerative colitis patients after ileorectal anastomosis. 202 43

Polyamine biosynthesis is important for cell proliferation and growth. The purpose of this study was to determine the biochemical and pharmacological parameters associated with host toxicity from a continuous infusion of alpha-difluoromethylornithine (DFMO). Twenty-five patients with metastatic carcinoma of the colon or rectum received continuous infusion of DFMO at a median dose of 8 g/m2/day (range, 6-14) for 28 days. DFMO plasma levels, RBC, plasma putrescine, spermidine, and spermine levels, and patient toxicities were evaluated. There was a significant decrease in RBC and plasma levels of putrescine, spermidine, and spermine following DFMO administration compared with the baseline RBC and plasma levels. Pearson correlation coefficient comparing nadir platelet count and steady-state DFMO level was statistically significant (n = 37; P less than 0.01; r = -0.53). Sustained suppression of circulating polyamine levels was also achieved with continuous DFMO infusion. The correlation between steady-state plasma DFMO levels and lowering of platelet count warrants prospective evaluation to determine its clinical usefulness.
 ...
PMID:Alterations in polyamine metabolism during continuous intravenous infusion of alpha-difluoromethylornithine showing correlation of thrombocytopenia with alpha-difluoromethylornithine plasma levels. 250 35

alpha-Difluoromethylornithine (DFMO) is a known irreversible inhibitor of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis. Cyclosporine (CsA) has been reported to inhibit ODC activity in vitro. In the present study, we compared the effects of DFMO and CsA on growth, survival, and polyamine levels in mouse colon cancer (MC-26) and hamster pancreatic cancer (H2T) cells in vitro. The growth and survival of MC-26 and H2T cells were inhibited by both DFMO and CsA. However, H2T cells were observed to be significantly more sensitive than MC-26 cells to both CsA and DFMO. The inhibitory effects of CsA were blocked by the addition of the polyamine, putrescine, in both MC-26 and H2T cells. Polyamine levels were altered significantly in both MC-26 and H2T cells treated with CsA and DFMO. However, the profile of these alterations differed between MC-26 and H2T cell lines. Putrescine and spermidine levels in MC-26 cells were more sensitive to DFMO inhibition than were H2T cells. Spermine levels were consistently elevated in MC-26 cells exposed to CsA or DFMO, while the level of spermine in H2T cells decreased significantly in response to the same drugs. These results suggest that CsA and DFMO exhibit different effects on colon and pancreatic cancer growth in vitro. In addition, the differences in the sensitivity of pancreatic and colon cancer to CsA and DFMO indicate potentially important differences in polyamine metabolism between the two cell lines.
 ...
PMID:Cyclosporine and alpha-difluoromethylornithine exhibit differential effects on colon and pancreatic cancer in vitro. 311 20

Polyamines and gastrin receptors (GR) were studied in samples of colon cancer and mucosa from 40 patients and in control mucosa from 11 patients without cancer. Polyamines (i.e., putrescine, spermidine, spermine) are essential for growth and differentiation. The concentration of polyamines is elevated in rapidly proliferating normal tissues and in some cancers. The presence of GR in human colon cancers has been previously reported. The purpose of the present study was twofold: (1) to determine whether polyamine levels are elevated in colon cancers and in adjacent normal colon mucosa compared to colon mucosa from patients without cancer; and (2) to examine the relationship between polyamine levels and GR in colon cancers. Polyamine levels in colon cancers were significantly higher than in the normal colon mucosa from the same patients. The polyamines, spermidine and spermine, were significantly higher in colon mucosa from patients with cancer compared to patients without cancer. Spermidine and the spermidine:spermine ratio, an index of cell proliferation, were increased in colon cancers with GR compared to cancers without GR. There were no significant correlations between polyamine levels and the following: patient age, CEA level, site of cancer, stage, or differentiation. Because polyamine levels are increased in colon mucosa from patients with cancer, measurement of polyamines may detect patients at risk for subsequent development of colon cancer. Increased levels of polyamines in colon cancers with GR is evidence that gastrin may play a trophic role in human colon cancers.
 ...
PMID:Polyamine levels and gastrin receptors in colon cancers. 338 34

Polyamines are short-chain aliphatic amines required for normal cellular growth that are ubiquitously found in all living tissues. Polyamine content has been shown to correlate with cellular proliferation. Quantitation of polyamines may thus provide a biochemical measure of proliferation in the colorectal mucosa where dysregulated epithelial proliferation is associated with colorectal cancer risk. A case-control study was conducted to validate the hypothesized association between mucosal polyamine measurements and colorectal cancer risk. Polyamines were measured in 4-6 multiple rectal mucosal biopsies from 11 normal control subjects and seven case patients with colon cancer. Compared with the controls, mean polyamine measurements, after adjustment for age and sex, were significantly increased for spermidine (P < 0.003) and spermine (P < 0.017). Subsequent analysis indicated that in controls 1-4 biopsies appeared adequate to characterize an individual. However, mucosal polyamines in the cases exhibited more sampling variability, requiring 4-8 biopsies to achieve an acceptable level of reliability. After adjustment for age and sex, the odds ratios for spermidine and spermine levels, compared to the controls, were 4.8 (95% confidence interval: 1.6-33.7) and 2.3 (1.2-6.3), respectively. The results of this study indicate that increases of mucosal polyamine measurements, after taking the sampling and methodological variability into account, are significantly associated with colorectal cancer risk, and suggest that polyamine measurements in rectal mucosa may play an important role as biomarkers for identifying high-risk individuals and/or for using as intermediate endpoints in prevention trials.
 ...
PMID:Mucosal polyamine measurements and colorectal cancer risk. 891 76

Polyamine synthesis (by the action of ornithine decarboxylase [ODC] and S-adenosylmethionine decarboxylase [SAMDC]) and polyamine content are high in colon cancer. In addition, colonic lumen is rich in polyamines synthesised by colonic microflora; for this reason, polyamine depletion in colon cancer may be a logical approach to impair growth of colon cancer cells. We evaluated highly specific and reportedly non-toxic hydroxylamine-containing inhibitors of ODC (1-aminooxy-3-aminopropane, APA) and SAMDC (S-(5'-deoxy-5'-adenosyl)-methylthioethyl-hydroxylamine, AMA) in human colon cancer cells (Caco-2 and HT-29) in culture. APA depleted ODC activity within 24 hr, more rapidly than did difluoromethylornithine. APA and AMA in combination (100 microM each) reduced ODC and SAMDC activities to undetectable levels within 24 hr and intracellular polyamines to 8-23% of control. The resulting growth arrest could be reversed only by twice as much spermidine as is physiologically present in the colonic lumen. In concentrations sufficient to deplete growth, APA and AMA were not toxic. Simultaneous treatment with APA, AMA, and 5-fluorouracil reduced colon cancer cell survival more potently than treatment with 5-fluorouracil alone. The hydroxylamine-containing ODC and SAMDC inhibitors APA and AMA are potent inhibitors of colon cancer cell proliferation and might be therapeutically promising in colon cancer.
 ...
PMID:Hydroxylamine-containing inhibitors of polyamine biosynthesis and impairment of colon cancer cell growth. 1116 34

Polyamines and their rate-limiting enzyme, ornithine decarboxylase (ODC), are actively involved in cell growth and differentiation. The phytoestrogen genistein has been demonstrated to possess antitumor properties by influencing proliferation, differentiation, and apoptosis. The aim of this study was to investigate the effects of genistein at concentrations ranging from 0.01 to 100 microM on the polyamine biosynthesis, cell proliferation, and apoptosis in the estrogen receptor-positive DLD-1 human colon cancer cell line. Polyamine levels and ODC activity were evaluated by high performance liquid chromatography and radiometric technique, respectively. The proliferative response was estimated by [3H]-thymidine incorporation and the colorimetric 3-(4,5 di-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. Apoptosis was investigated by DNA fragmentation. Bax and Bcl-2 gene expressions were evaluated by multiplex-polymerase chain reaction. At concentration >or=1 microM, genistein decreased significantly the ODC activity and the polyamine levels. At the same concentration, genistein also increased significantly Bax mRNA expression, but not Bcl-2 mRNA expression. Higher concentrations (>or=10 microM) were needed to obtain a significant inhibition of cell proliferation and DNA fragmentation. The results of this study suggest that genistein can affect growth of DLD-1 cells by both decreasing polyamine biosynthesis and inducing apoptosis. However, further studies are required to assess the true ability of a soy rich diet in modifying colon cancer risk.
 ...
PMID:Effects of genistein on the polyamine metabolism and cell growth in DLD-1 human colon cancer cells. 1609 Oct 8

Polyamine metabolic genes are downstream targets of several genes commonly mutated in colon adenomas and cancers. Inhibitors of ornithine decarboxylase, such as difluoromethylornithine (DFMO), and agents that stimulate polyamine acetylation and export, such as non-steroidal anti-inflammatory drugs (NSAIDS), act at least additively to arrest growth in human cell models and suppress intestinal carcinogenesis in mice. These preclinical studies provided the rationale for colon cancer prevention trials in humans. A Phase IIb clinical study comparing the combination of DFMO and the NSAID sulindac versus placebo was conducted. Endpoints were colorectal tissue polyamine and prostaglandin E2 contents and overall toxicity to participants. Participants in the Phase IIb study served as a vanguard for a randomized, placebo-controlled prospective Phase III trial of the combination of DFMO and sulindac with the primary study endpoint the prevention of colon polyps. Seventy percent of participants will have completed the three years of treatment in December 2006.
 ...
PMID:Rationale for, and design of, a clinical trial targeting polyamine metabolism for colon cancer chemoprevention. 1739 14

Polyamine transport plays an important role in the homeostatic regulation of the polyamine levels. In animals, dietary polyamines are absorbed efficiently in the intestinal tract. In the colon, luminal bacterial derived polyamines are important contributors to cellular polyamine contents. Polyamine transport involves unique uptake and export mechanisms. The amino acid transporter SLC3A2 acts as a polyamine exporter in colon cancer-derived cells. Polyamine uptake is mediated by caveolin-1 dependent -endocytosis. The K-RAS oncogene signals increased polyamine uptake and decreased polyamine export. Here, we describe the methods of polyamine transport analysis in the colon and the small intestine using -membrane vesicles, culture cells, and mouse models.
 ...
PMID:Polyamine transport systems in mammalian cells and tissues. 2131 84


1 2 Next >>