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)

In addition to being regulated by a complex array of cis- and trans-acting factors, c-myc protooncogene expression may be modulated by antisense RNA transcripts. Our previous studies have determined that depletion of intracellular polyamines by alpha-difluoromethylornithine results in a marked decrease in the transcription of the human c-myc gene. Because of reports that antisense transcription occurs in the 5' and 3' regions of this gene, we used a genomic clone of the human c-myc gene to ascertain whether polyamine depletion might induce an antisense RNA transcript. These studies demonstrate that polyamine depletion of the human colon cancer cell line COLO 320 results in induction of an endogenous RNA transcript with high homology to the antisense strand of the second intervening sequence (PvuII-RsaI) of the c-myc gene. Furthermore, during such depletion, steady state levels of this transcript vary inversely to the sense direction c-myc RNA. RNase protection studies suggest that the antisense transcript may arise from a different gene locus than the c-myc gene. To further identify the origins of this RNA, a cDNA library was generated from size-selected RNA and screened with c-myc sequences. A 438-base pair cDNA was isolated with approximately 85% homology, to a 285-base region in the second intron of the c-myc gene. Computer homology analysis further reveals that a 120-base region within this cDNA also has approximately 85% homology to the antisense strands of a number of genes, including the growth-related genes, N-myc, p53, and thymidine kinase. These studies provide the initial characterization of an endogenous antisense RNA transcript which could influence cell growth by modulating the expression of c-myc and other genes.
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PMID:Characterization of an endogenous RNA transcript with homology to the antisense strand of the human c-myc gene. 137 45

The fluoropyrimidines fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd) have shown activity in a variety of malignancies. Nevertheless, even in initially responsive tumors, the development of resistance is a frequent problem. To understand the biochemical basis for acquired resistance, two pairs of cell lines were investigated. MCF7/Adr cells were obtained from the breast cancer cell line MCF7 by incubation with increasing concentrations of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH). These cells are resistant to Adriamycin (200- to 600-fold) and cross-resistant to 5-FU (25-fold) and FdUrd (67-fold). The resistant cells showed significantly increased levels of thymidylate synthase, the target enzyme of the fluoropyrimidines' active metabolite, 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP). Other biochemical characteristics, including folate pools, drug uptake, metabolism, and retention, were unchanged. Fd9XR cells have been selected from a human colon cancer cell line (HCT-8) by exposure to FdUrd. These cells are resistant to FdUrd (1,000-fold) but not 5-FU. Biochemical evaluations show that the resistant cells are deficient of thymidine kinase and are thus unable to convert FdUrd to FdUMP. This understanding of the various biochemical mechanisms is essential for the design of specific modulations to overcome resistance to fluoropyrimidines.
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PMID:Mechanisms of resistance to fluoropyrimidines. 153 73

An important question in the management of patients with cancer is early identification of the individual who following 'curative' primary therapy will develop recurrence. Another question is which of several alternative treatments is most appropriate. If the patient at risk can be identified early more aggressive and appropriate adjuvant chemotherapy can be initiated to insure remission or longer periods of disease free survival. In this review the role of tissue and/or serum enzyme activities in this regard is considered. Enzymes alone or in combination with tumor markers or other factors may be used. Lactic dehydrogenase (LDH) is perhaps the most common clinical enzyme used in cancer patients for prognostic purposes. It has an important role in germ cell tumors and in association with chorionic gonadotropin and can predict response to therapy and the prospects of remission. LDH is a valuable prognostic marker in lymphoma, leukemia and in colon cancer. Patients can be stratified into treatment protocols based on LDH activity. The stage of cellular proliferation can be evaluated by assay of thymidine kinase in the serum of patients with Hodgkins Disease and in Lymphoma. An important new marker, Cathepsin D in breast tissue may be useful in predicting women with breast cancer who are at risk for early recurrence.
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PMID:Enzymes as prognostic markers and therapeutic indicators in patients with cancer. 157 80

Azidothymidine (AZT), inhibiting thymidine kinase (EC 2.7.1.21) (Weber, G. et al., Cancer Commun. 2:129-133, 1990) and dipyridamole, inhibiting nucleoside transport (Zhen, Y.-s. et al., Cancer Res. 43:1616-1619, 1983) exert blocking action on the activities of salvage pathways of nucleotide biosynthesis. Determined by clonogenic assay in human colon cancer HT-29 cells, the cell survivals for AZT, 10 microM, dipyridamole, 5 microM, and methotrexate (MTX), 0.025 microM, were 90, 82, and 62%, respectively; while the combinations of AZT + MTX, dipyridamole + MTX and AZT + dipyridamole + MTX, reduced survivals to 36, 4.3, and 0.7%. AZT or dipyridamole was synergistic with MTX, whereas AZT plus dipyridamole showed an even more marked potentiation of MTX activity. The survivals for 5-fluorouracil (5-FU), 0.5 microM, alone, AZT + 5-FU, dipyridamole + 5-FU, and AZT + dipyridamole + 5-FU were 86, 47, 29 and 5.1%, respectively. Similar results were observed in human pancreatic carcinoma BxPC-3 and PANC-1 cells. AZT markedly enhanced the inhibitory effect of dipyridamole in reversing the thymidine-hypoxanthine rescue from MTX cytotoxicity. AZT inhibited [14C]thymidine incorporation into DNA in HT-29 cells and strongly enhanced the effect of dipyridamole. The results indicate that combinations composed of AZT, dipyridamole, and antimetabolites, such as MTX and 5-FU, are potentially effective in the chemotherapy of human neoplasias.
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PMID:Azidothymidine and dipyridamole as biochemical response modifiers: synergism with methotrexate and 5-fluorouracil in human colon and pancreatic carcinoma cells. 159 84

Attempts have been made to use enzyme assays primarily in tissue, to predict risk of colon cancer in high risk colon cancer families, and in patients with polyposis. Efforts have also been made to predict recurrence in surgically "cured" cancer patients. The use of thymidine kinase, ornithine decarboxylase, LDH isoenzymes, and other enzymes for these purposes will be reviewed.
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PMID:Enzymes used in predicting high risk to colon cancer. 217 52

As zinc status may influence susceptibility to colon cancer, we examined the effect of dietary zinc deficiency on the proliferation of epithelial cells (colonocytes) in the large bowel of rats. When compared to feed-restricted rats, those with zinc deficiency showed a significant reduction in proliferation in the distal colon as assessed by accumulated metaphase arrest and crypt cell production rates in vivo. Zinc deficiency had no apparent effect on thymidine kinase activity in colonocytes but was accompanied by minor changes in fecal mass and fecal pH. In rats, zinc deficiency is associated with a reduction in the rate of proliferation of colonocytes in the distal colon.
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PMID:Zinc deficiency is associated with suppression of colonocyte proliferation in the distal large bowel of rats. 248 56

Male Fischer 344 rats were fed either fiber-free (FF), continuous 10% wheat bran (CWB) or intermittent 50% wheat bran (IWB) diets for 6 wk to investigate possible alterations in physiological effects associated with colon cancer (fecal bulk, transit time, colonic cell proliferation) induced by meal distribution of the bran. The FF and CWB groups consumed unvaried diets throughout the day. The IWB group consumed two consecutive meals of a 50% bran diet for a total of 4 hr each day followed by a fiber-free diet for the remaining hours of the day. Similar daily quantities of bran were consumed in the CWB and IWB groups. Dry fecal weights rose significantly and transit times declined in both bran-fed groups independent of the meal distribution of bran. Colonic cell proliferation (estimated by thymidine kinase activity) was similar in all groups. The results suggest that these physiological effects of wheat bran are independent of the meal distribution of the bran.
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PMID:Influence of meal distribution of wheat bran on fecal bulk, gastrointestinal transit time and colonic thymidine kinase activity in the rat. 253 47

Dietary fibers may tend to enhance or inhibit chemically induced experimental colon cancer, depending on the particular fiber consumed. This study examined the relationship between colonic thymidine kinase enzyme activity and mucin histochemistry and the reported effects of various dietary fibers on chemically induced colon carcinogenesis. Fiber-supplemented diets containing fibers reported to inhibit (wheat bran) or enhance (guar gum, carrageenan) chemically induced colon carcinogenesis in the rat were selected. Four groups of male Fischer 344 rats consumed 10% wheat bran, 5% guar gum, 5% carrageenan, or fiber-free diets ad libitum for 4 weeks. At the completion of the treatment period, the distal 12 cm of colonic mucosa was scraped off and homogenized for determination of thymidine kinase activity, and a 0.5-cm section of midcolon was processed by the high-iron diamine/Alcian blue method for mucin histochemistry. Final animal weights did not differ significantly among groups. Thymidine kinase enzyme specific activity (mumole thymidine phosphate formed x 10(6)/min/mg protein, means +/- SEMs) was not significantly different in the fiber-free, wheat bran, and guar gum groups (10.98 +/- 1.50, 7.41 +/- 1.09, and 9.11 +/- 2.04, respectively) but was markedly elevated at 41.84 +/- 4.65 in the carrageenan group (alpha less than 0.001). Mucin histochemistry failed to reveal any significant differences among dietary groups.
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PMID:Alterations in colonic thymidine kinase enzyme activity induced by consumption of various dietary fibers. 284 79

We have analysed cell cycle variations in thymidylate synthase (TS) protein in asynchronously growing NCl H630 and HT 29 colon cancer and MCF-7 breast cancer cell lines. Western immunoblot analysis using the TS 106 monoclonal antibody revealed a 14- to 24-fold variation in TS levels between the peak exponential and confluent growth phase in the three cell lines. Similar variations in TS levels and TS activity were detected using the 5-fluorodeoxyuridine monophosphate and deoxyuridine monophosphate biochemical assays. The percentage of cells in S-phase, which paralleled changes in TS levels, reached a maximum of 38-60% in asynchronous exponentially growing cells compared with 5-10% in confluent cells. In asynchronous exponential cells, analysis of TS levels in each cell cycle phase using two-parameter flow cytometric analysis revealed that TS protein levels were 1.3- to 1.5-fold higher in S than in G0/G1 phase cells, and 1.5- to 1.8-fold higher in G2/M than G0/G1 cells. Similar differences of 1.1- to 1.5-fold between G0/G1 and S-phase and 1.6- to 1.9-fold between G0/G1 and G2/M-phase were detected by Western immunoblot and biochemical assays. TS protein was not detectable by Western blot analysis, flow cytometry or biochemical analysis in the G0/G1 population of confluent cells. Twenty-six per cent of cells in this population were G0 cells compared with 2% in exponentially growing cells. In contrast to TS, a 4-fold difference in thymidine kinase (TK) was detected between G0/G1 and S-phase cells in exponentially growing MCF-7 cells. The level of TS enzyme is associated with cellular proliferation and the percentage of cells in S-phase; however, TS protein is not exclusively associated with S-phase in asynchronously growing cells. The variation in TS levels between exponentially growing and confluent cell population appears to be due to differences in TS levels between G0 and G1 cells.
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PMID:Increased thymidylate synthase protein levels are principally associated with proliferation but not cell cycle phase in asynchronous human cancer cells. 777 4

Interferon-alpha (IFN-alpha) exhibits synergistic antitumor activity when combined with tumor necrosis factor-alpha (TNF-alpha) in vitro and in vivo and increases the cytotoxicity of 5-fluorouracil (5-FU) in vitro. Using a colon cancer cell line transplanted into nude mice, we examined the effects of pretreatment for 3 days with IFN-alpha (10(6) IU) and/or TNF-alpha (2.9 x 10(3) JRU) on 5-FU metabolism. 5-FU 30 mg/kg was administered after the pretreatment. IFN-alpha increased the tumor level of 5-fluorodeoxuridine monophosphate (FdUMP), and decreased the free level of thymidylate synthetase. Pretreatment with TNT-alpha alone decreased HUMP whereas TNF-alpha plus IFN-alpha abolished the enhancement of FdUMP production by IFN-alpha. TNF-alpha also suppressed thymidine kinase activity. Neither IFN-alpha nor TNF-alpha altered the incorporation of 5-FU into RNA.
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PMID:Suppressive effect of TNF-alpha on increased production of FdUMP by IFN-alpha. 868 Jul 97


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