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

alpha-Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, blocks polyamine synthesis and has demonstrated antitumor activity against small cell lung cancer and colon cancer in cell culture and animal tumor models. To evaluate clinical efficacy and further define toxic effects of this new agent, phase II trials of DFMO were performed in previously treated patients with advanced small cell lung cancer and previously untreated patients with metastatic colon cancer. Oral DFMO was administered at a dose of 2.25 g/m2/day every 6 hours continuously to patients with small cell lung cancer. The same dose was given to patients with colon cancer but on a schedule of "3 weeks on, 1 week off" to avoid hearing loss. Evaluation of toxicity indicated that thrombocytopenia was seen only in patients receiving continuous DFMO who had received prior chemotherapy, while reversible hearing loss and gastrointestinal side effects occurred on both intermittent and continuous schedules in previously treated and untreated patients.
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PMID:Phase II trials of alpha-difluoromethylornithine, an inhibitor of polyamine synthesis, in advanced small cell lung cancer and colon cancer. 301

There is as yet no specific chromosomal abnormality or gene marker identified for colorectal polyps and cancer. Thus available markers include only phenotypic markers. Tumor markers that have been studied include tetraploidy and increased colonic mucosal proliferation; and these markers have identified those patients that are at high risk for colon cancer. The current "gold standard" of colorectal cancer markers is the carcinoembryonic antigen (CEA). CEA is best used as a monitor of disease and recurrence, and not as a screening or diagnostic test. Newer carbohydrate markers include CA 19-9, incompatible A and B antigens, and T and Lewis antigens. These markers have not shown increased specificity or sensitivity compared to CEA. An interesting recently described marker is ornithine decarboxylase (ODC), which serves as a simple overall index of colonic mucosal proliferation. Ornithine decarboxylase levels have shown correlation with the progression from normal mucosa to adenoma and carcinoma, especially in hereditary polyposis syndromes. This enzyme may also serve as a potential therapeutic target. Many markers have been found useless in further clinical trials. Ornithine decarboxylase needs to be studied in greater detail to determine its sensitivity and specificity, in patients with hereditary colonic neoplasia and in patients without genetic syndromes.
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PMID:Ornithine decarboxylase as a marker for colorectal polyps and cancer. 305 22

The growth and survival of mouse (MC-26) colon carcinoma in vitro and in vivo are significantly reduced by inhibitors of polyamine biosynthesis. alpha-Difluoromethylornithine (DFMO), is a specific and irreversible inhibitor of ornithine decarboxylase (ODC); the rate-limiting enzyme in polyamine biosynthesis. DFMO treatment inhibits the growth of MC-26 colon cancer cells and decreases MC-26 cell survival both in vitro and in vivo. In the present study, we examined the effects of cyclosporine (CsA) on growth, survival, and polyamine levels in MC-26 colon cancer in vitro. CsA had inhibitory effects on MC-26 colon cancer growth which were similar to DFMO; these effects were blocked by the addition of the polyamine, putrescine. The combination of CsA (8.3 X 10(-4) mM) and DFMO (0.5 mM or 1.0 mM) inhibited MC-26 cell survival to a greater extent than either agent alone. These results suggest that CsA given in combination with other agents which inhibit polyamine synthesis may be useful for the treatment of colon cancer.
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PMID:Effects of cyclosporine and alpha-difluoromethylornithine on the growth of mouse colon cancer in vitro. 310 Aug 97

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.
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PMID:Cyclosporine and alpha-difluoromethylornithine exhibit differential effects on colon and pancreatic cancer in vitro. 311 20

Ornithine decarboxylase (ODC) activity in biopsy specimens of normal-appearing rectal mucosa was measured in 15 control patients, 5 patients with colon adenomas, and 11 patients with colon cancer. While women had significantly higher ODC activity than men, ODC activity was increased regardless of gender in the rectal mucosal biopsies of patients with benign or malignant colonic neoplasia compared with those of controls. The positive predictive value of ODC activity for remote colonic neoplasia was 61% for women and 91% for men. The results provide a rationale for long-term studies of ODC activity in rectal mucosa as a biological marker of high risk for large bowel neoplasia.
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PMID:Ornithine decarboxylase levels in the rectal mucosa of patients with colonic neoplasia. 341 68

Cell proliferation has an important role in carcinogenesis. Increased ornithine decarboxylase (ODC) activity with resulting polyamine synthesis is a phenomenon common to cells undergoing rapid proliferation and to models of tumor promotion. In colon cancer, bile acids are considered to be important tumor promoters. Inferential data suggest that bile acids can increase ODC activity and stimulate or alter cell proliferation in the large bowel. These changes may underlie tumor promotion by bile acids. Confirmation of this relationship will solidify this concept and build a framework for understanding the mechanism of bile acid promotion in colon carcinogenesis.
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PMID:Bile acids, ornithine decarboxylase, and cell proliferation in colon cancer: a review. 354 61

The expression of c-myb, c-myc, histone H3, and ornithine decarboxylase genes was examined by Northern blot analysis in the normal and neoplastic mucosa of ten subjects affected by colon cancer. The mRNA levels of c-myb protooncogene were detected at low levels in all normal samples but were increased in the neoplastic mucosa of six cases in comparison to the normal counterpart. In five of these six cases the mRNA levels of c-myc, histone H3, and ornithine decarboxylase mRNAs were also increased, suggesting that there is a relation between the high expression of c-myb and the fraction of cycling neoplastic cells.
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PMID:Expression of c-myb protooncogene and other cell cycle-related genes in normal and neoplastic human colonic mucosa. 365 34

We have investigated the effect of age, a high-fat diet, sodium deoxycholate, and the ornithine analogue alpha-difluoromethylornithine on ornithine decarboxylase (ODC) activity in the rat colon. The relative levels of ODC activity were also determined in normal mucosa and tumor tissue from rat and human colon. The colonic ODC activity induced by intrarectal instillation of sodium deoxycholate in male Sprague-Dawley rats was highest in young animals, and it decreased with increasing age. A high level of dietary fat caused both an increased in basal colonic ODC activity and enhanced ODC induction by deoxycholate. alpha-Difluoromethylornithine given in drinking water inhibited, in a dose-dependent fashion, deoxycholate-induced ODC activity. The frequency of azoxymethane-induced intestinal tumors was also significantly reduced by alpha-difluoromethylornithine. Since colonic ODC activity is increased in carcinogenesis by known promoting agents and decreased by tumor inhibitors, this short-term assay may provide a useful system for identifying colon tumor promoters and inhibitors. The ODC activity in colon tumors of Sprague-Dawley rats was found to be significantly higher than in normal-appearing mucosa in the same animals. Similarly, ODC activity in human colon cancer was found to be higher than that of the normal-appearing mucosa in the same specimen. These results strengthen the utilization of the rat model for studies, the results of which may apply to the human situation.
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PMID:Ornithine decarboxylase activity in the rat and human colon. 643 May 47

Proliferation of both mouse and human breast cancer cells was inhibited by chlorpheniramine (CPA) in a dose-response manner. At the beginning of the exponential phase of growth (two days after seeding), 250 microM CPA was able to reduce cell proliferation by 75% (in Ehrlich cell cultures) and 30% (in MCF-7 cultures). The antiproliferative effect of CPA was also tested on a poorly-differentiated and hormone-insensitive human breast cancer cell line (MDA-MB231) and on a highly proliferative human colon cancer cell line (clone 3). CPA was cytotoxic for MDA-MB231 cells at concentrations higher than 50 microM, and it was also cytotoxic for the colon cancer cell clone 3 at 250 microM CPA. Nevertheless, colon cancer cells were slightly stimulated at CPA concentrations less than 100 microM. CPA reduced (by 50-70%) the ornithine decarboxylase induction occurring early after culture seeding of experimental mammary tumors (Ehrlich carcinoma cells) and human breast cancer cells (MCF-7). The presented data suggest that in addition to ODC inhibition, CPA presents other still unknown cytotoxic effects.
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PMID:Chlorpheniramine inhibits the synthesis of ornithine decarboxylase and the proliferation of human breast cancer cell lines. 764 40

Many dietary factors have been studied for their potential in the chemoprevention of human colorectal cancer. From an epidemiological standpoint, there have been many studies linking calcium intake to colon cancer risk. Significant reductions in risk have been shown for the consumption of milk, dietary calcium and dairy products in general. Additionally, there have been numerous studies of calcium and cell proliferation in experimental animals. Supplemental calcium in the diet or drinking water has been reported to decrease the colonic epithelial hyperproliferation induced by bile and fatty acids, enteric resection, a nutritional stress diet, and to suppress induction of the tumor-promotion enzyme ornithine decarboxylase. Calcium has also demonstrated an inhibitory effect on experimental colon carcinogenesis. Mechanisms of calcium inhibition are still speculative, but the "calcium soaps" hypothesis, fatty acid destabilization of cellular membranes, modulation of protein kinase C and K-ras mutations are under investigation. Additionally, numerous clinical studies of calcium modulation of human colonic hyperproliferation in high-risk groups as well as chemoprevention trials of calcium supplementation are currently ongoing. Although the question of whether dietary calcium can prevent human colorectal cancer remains to be answered, the data presently available appear promising.
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PMID:Role of calcium in colon cancer prevention: experimental and clinical studies. 769 3


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