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)

We recently reported the presence of an organ-specific 40 kD colonic protein which acts as an autoantigen(s) in patients with ulcerative colitis. Using a specific monoclonal antibody directed against 40 kD protein (7E12H12, IgM isotype), in conjunction with immunocytochemistry and flow cytometry, we examined the presence of the 40 kD protein on human colon cancer cells, DLD-1, and also characterized the ability of cytokines, IFN-gamma and tumour necrosis factor, to modulate the expression of this protein on these tumour cells. The presence of the 40 kD protein was localized to the plasma membrane; less was present within the cytoplasm. Following exposure to IFN-gamma (10-1000 U/ml), DLD-1 colon tumour cells showed a dose- and time-dependent increase in 7E12H12 antibody associated immunofluorescence, with the maximum 7E12H12 antibody binding observed with 100 U/ml IFN-gamma at 48 h. In contrast, tumour necrosis factor did not alter the levels of anti-40 kD antibody binding over that of control cells. Since IFN-gamma is also known to induce class II major histocompatibility antigens, we examined the possibility of cross-reactivity of HLA class II antigens and Mr 40 kD epitope. Neither pre-incubation of DLD-1 colon tumour cells with anti-HLA class II antibodies followed by 7E12H12 nor co-incubation of both antibodies altered the amount of 7E12H12 antibody binding. Using a direct ELISA, a highly enriched preparation of Mr 40 kD protein reactive to anti-40 kD antibody did not react with HLA class II antibodies. The present results suggest that 40 kD protein is present on DLD-1 human colon tumour cells and that although the 40 kD protein epitope expression is increased by the lymphocyte-derived cytokine, IFN-gamma, the epitope is separate and distinct from the class II HLA antigens. Further studies on the 40 KD protein may elucidate its autoantigenic role in the pathogenesis of inflammatory bowel disease.
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PMID:Expression of the 40 kD protein in DLD-1 colon cancer cells and the effect of cytokines. 137 49

Four human colon cancer cell lines (SW620, LS 180, DLD-I, and HCT-15) and sub-lines isolated in vitro by selection with Adriamycin were studied for reversal of intrinsic and acquired Adriamycin resistance, using buthionine sulfoximine (BSO) to deplete cellular glutathione alone and in combination with the P-glycoprotein antagonist verapamil. GSH levels varied among the parental cell lines but did not increase with resistance. In the parental SW620, DLD-I and HCT-15 and their drug-resistant derivatives, there was no relation between the effect of the glutathione-depleting agent BSO, the mRNA expression of both selenium-dependent glutathione peroxidase (GPx) and glutathione S-transferase pi (GST pi), bulk glutathione S-transferase (GST) activity, and the degree of resistance. However, in LS 180 and its derivative sub-lines, which do not principally rely on P-glycoprotein (Pgp) for Adriamycin resistance, treatment with BSO demonstrated a relatively diminished GSH depletion and enhanced recovery. In comparison with the other acquired cell lines, BSO specifically reversed acquired resistance in the LS 180 Adriamycin-resistant subline (LS 180 Ad150) after short-term drug exposure. Furthermore, the LS 180 Ad150 cells demonstrated an increase in both GPx and GST pi mRNA expression. These observations suggest that glutathione-mediated detoxification of Adriamycin may play a role in the resistance of this sub-line. Verapamil enhanced Adriamycin cytotoxicity 1.2- to 12-fold in the intrinsically resistant cells and as much as 15-fold in cell lines with acquired resistance. Combination of BSO with verapamil resulted in additive, but not synergistic, reversal of resistance. The results underscore the complex nature of Adriamycin resistance, and suggest a role for drug-resistance-modulating agents in the treatment of colon carcinoma.
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PMID:Contribution of glutathione and glutathione-dependent enzymes in the reversal of adriamycin resistance in colon carcinoma cell lines. 168 79

Four human colon cancer cell lines (SW620, LS 180, DLD-I, and HCT-15) and Adriamycin-resistant sub-lines with varying degrees of P-glycoprotein expression were studied to evaluate the reversibility of Adriamycin resistance in human colon cancer. Two groups of cell lines were studied. In the first, including a series of Adriamycin-resistant SW620 and DLD-I sub-lines, and in parental HCT-15 cells, P-glycoprotein has a major role in Adriamycin resistance, as evidenced by a correlation between Adriamycin resistance, expression of the multidrug-resistance gene mdr-I and its product, P-glycoprotein (Pgp), decreased drug accumulation and reversibility by verapamil. In these cell lines, increasing doses of verapamil are required to fully reverse increasing levels of resistance. In the second group, including parental SW620, DLD-I and LS 180 cells and Adriamycin-selected LS 180 sub-lines, P-glycoprotein does not have a major role in Adriamycin resistance. There was correlation between the schedule dependence of Adriamycin cytotoxicity and the role of P-glycoprotein in modulating resistance. In the cell lines in which P-glycoprotein was a major determinant of Adriamycin resistance, the drug exposure (defined as the product of the concentration and the time of treatment) needed to achieve a given percent cell kill was reduced as much as 9-fold when cells were treated for 7 days as compared with 3 hr. By comparison, in cell lines in which P-glycoprotein played a lesser role, the drug exposure necessary to achieve a given percent kill increased under conditions of continuous treatment. In some human colon carcinoma cell lines Pgp appears to play a significant role in resistance to Adriamycin, and this can be overcome by the use of competitive inhibitors of Pgp. The increased sensitivity with continuous treatment observed in cell lines with P-glycoprotein-mediated resistance suggests that administration of drugs by continuous infusion may be valuable in reversing clinical drug resistance mediated predominantly by P-glycoprotein.
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PMID:P-glycoprotein expression and schedule dependence of adriamycin cytotoxicity in human colon carcinoma cell lines. 168 80

A series of Adriamycin-resistant human breast MCF-7 and human colon DLD-1 cancer cell lines were established by stepwise selection. The concentration of Adriamycin required to inhibit cell proliferation by 50% (IC50) in the parent breast line (MCF-7), Adriamycin-resistant lines (MCF-Ad5 and MCF-Ad10), and a 5-fluorouracil (5-FU)-revertant line (MCF-R) was 0.005, 3.3, 6, and 4.9 microM, respectively. The Adriamycin IC50 value for the resistant colon line (DLD-Ad) was 8.2 microM, 68-fold higher than that for its parent line (DLD-1) (IC50 = 0.12 microM). The MCF-Ad5 and MCF-Ad10 cells were cross-resistant to 5-FU, with respective 5-FU IC50 values of 11.7 and 22.5 microM, or 7.3- and 14-fold less sensitive than their parent MCF-7 (IC50 = 1.6 microM) line. The MCF-R line completely reverted in sensitivity to 5-FU, with an IC50 of 1.7 microM. The resistant DLD-Ad line was 3.5-fold more resistant to 5-FU than was the parent DLD-1 line. Using both the 5-fluoro-2'-deoxyuridine-5'-monophosphate binding and catalytic assays for measurement of thymidylate synthase (TS) activity, there was significantly increased TS activity in the resistant MCF-Ad5 (2.4- and 2.5-fold), MCF-Ad10 (11.5- and 6.8-fold), and DLD-Ad (4.8- and 10.7-fold) lines, for binding and catalytic assays, respectively, compared with their parent MCF-7 and DLD-1 lines. The level of TS in cytosolic extracts, as determined by Western immunoblot analysis, was markedly increased for the resistant MCF-Ad5 (31-fold), MCF-Ad10 (46-fold), and DLD-Ad (52-fold) cells. Measurement of TS mRNA levels by Northern analysis revealed elevation of TS mRNA in the resistant MCF-AD5 (16.7-fold), MCF-Ad10 (31-fold), and DLD-Ad (55-fold) cells. Southern analysis showed that this increase in TS mRNA was not accompanied by any major rearrangements or amplification of the TS gene. Incorporation of 5-FU into the RNA and DNA of the resistant MCF-Ad10 cells was not significantly different, compared with that for parent MCF-7 cells. These studies suggest that exposure of human breast and human colon cancer cells to Adriamycin leads to overexpression of TS, with concomitant development of resistance to 5-FU.
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PMID:Induction of thymidylate synthase associated with multidrug resistance in human breast and colon cancer cell lines. 170 99

The African tree Combretum caffrum (Combretacae) has been found to contain a powerful inhibitor of tubulin polymerization (IC50 2-3 microM), the growth of murine lymphocytic leukemia (L 1210 and P 388 with ED50 approximately 0.003 microM and human colon cancer cell lines [(e.g. LoVo (ED50 = 0.005 microgram/ml), HT 29 (ED50 0.02 microgram/ml, Colo 205 (ED50 = 0.07 microgram/ml), DLD-1 (ED50 = 0.005 microgram/ml) and HCT-15 (ED50 = 0.0009 microgram/ml] designated combretastatin A-4 (1c). The structure assigned by spectral techniques was confirmed by synthesis.
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PMID:Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4. 292 Aug 9

The effect of sodium butyrate and retinoic acid added singly or in combination on substrate-dependent growth, colonization efficiency in soft agar, and carcino-embryonic antigen (CEA) production in three human colorectal carcinoma cell lines differing in their degree of differentiation was studied. All three colon cancer cell lines regardless of their state of differentiation had their growth markedly slowed by sodium butyrate, and to a lesser extent by retinoic acid. When both agents were added together, a small synergistic inhibition of growth was noted in all the cell lines. Butyrate eliminated colony formation in soft agar in all three cell lines, however, retinoic acid only reduced colony formation in the well differentiated cell line DLD-2. Sodium butyrate was able to induce CEA production in the undifferentiated cell (MIP-101) and the moderately differentiated cells (clone D) which were previously negative for this marker. It also enhanced the baseline production of CEA in the well differentiated cells (DLD-2). Retinoic acid did not induce CEA production in clone D or MIP-101 cells, but did enhance the production of CEA in DLD-2 cells. When both retinoic acid and sodium butyrate were added together, CEA production was either additive (DLD-2) or was inhibited (clone D and MIP-101). One explanation of these results is that only well differentiated cells have functional cellular retinoic acid-binding protein (cRABP), and that certain actions of retinoic acid (inhibition of anchorage-dependent growth) are independent of the presence of cRABP.
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PMID:The effect of sodium butyrate and retinoic acid on growth and CEA production in a series of human colorectal tumor cell lines representing different states of differentiation. 336 71

Polar organic solvents, such as N-methylformamide (NMF), N,N-dimethylformamide, and dimethyl sulfoxide, have been demonstrated to induce differentiation in a number of neoplastic cell lines, including human colon cancer cells. Although the mechanism of action of these agents is yet unknown, one possibility is that polar solvents induce a change in lateral mobility of membrane lipids, important to the maturational process. To determine the relationship between polar solvent treatment and changes in membranes, we examined the effects of exposure to NMF on membrane fluidity in human colon cancer cells (DLD-1; clone A). Membrane viscosity was assessed by determining lipid lateral diffusion following photobleaching of a fluorescent lipid probe in individual intact cells. Exposure of cells to NMF led to a significant increase in membrane viscosity following 2 days of treatment, with maximal changes occurring after 11 days. NMF induced these effects over a limited concentration range with 1.0% NMF in the medium having the maximal effect, and 0.5% or 1.5% having less or no effect. Growth of cells with N,N-dimethylformamide (0.8%) also led to increases in membrane viscosity. The observed membrane changes correlated well with the effect of NMF on differentiation in these cells as previously reported, as well as with cell growth rate and morphology in the present study. The increase in viscosity caused by prolonged NMF treatment was reversible, with a return to untreated levels by 9-11 days after removal of NMF. Thus, there is a strong correlation between the attainment of more benign, better differentiated phenotype in polar solvent-treated clone A cells and increases in membrane viscosity.
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PMID:Polar solvent-induced changes in membrane lipid lateral diffusion in human colon cancer cells. 402 82

A novel, substituted 4-quinolinecarboxylic acid (NSC 339768) demonstrated antitumor activity against L1210 leukemia and B16 melanoma in the National Cancer Institute's Developmental Therapeutics Program. An extensive analogue synthesis program was initiated; over 200 derivatives were synthesized and tested for anticancer activity. One of these compounds, 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid sodium salt, NSC 368390 (DuP-785), was selected for further investigation because of its efficacy against a spectrum of human solid tumors and its water solubility. In initial studies with L1210 leukemia, the compound caused an increase in life span of greater than 80%. The activity was schedule dependent, and the compound was equally efficacious when administered i.p., i.v., s.c., or p.o. In tests against human tumors xenografted under the renal capsule of nude mice, NSC 368390 when injected i.p. in doses of 20-40 mg/kg daily for 9 days inhibited the growth of the MX-1 breast, LX-1 lung, BL/STX-1 stomach, and CX-1 colon carcinomas by greater than 90%. NSC 368390 also inhibited the growth of three distinct human colon carcinomas, the HCT-15, clone A, and DLD-2 tumors, growing s.c. in nude mice. An i.p. dose of 25 mg/kg given daily for 9 days inhibited the growth of the DLD-2 colon cancer by 98%. 1-beta-D-Arabinofuranosylcytosine and Adriamycin were ineffective, and fluorouracil was only moderately effective against these colon tumors. Because of its good activity against human colon tumors and other human carcinomas and its water solubility, NSC 368390 (DuP-785) is being developed as a Phase 1 anticancer agent.
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PMID:Activity of a novel 4-quinolinecarboxylic acid, NSC 368390 [6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarb oxylic acid sodium salt], against experimental tumors. 405 30

We have studied the thermotolerance (TTR) responses of three tumor cell populations obtained from a heterogeneous human colon cancer after exposure to 44 degrees C water bath hyperthermia given in a split dose regimen. The cell populations studied consist of the original tumor line (DLD-1) obtained from surgical biopsy, and two subcloned populations termed clones A and D. All tumor lines were treated with initial heat doses at 44 degrees C which reduced the initial survival level to about 30, 10, or 1%, after which cultures were returned to 37 degrees C. Complete survival curves were then determined for all three lines as a function of time after the initial treatment (0, 2, 4, 8, 12, 14, 20, and 24 h), and the magnitude and kinetics of thermotolerance development and its decay were determined. It was found that the DLD-1 line was more heat sensitive and exhibited a lesser degree of induced thermotolerance than did the A and D subpopulations, indicating intraclonal heterogeneity. Also, the rate of thermotolerance induction, the maximal thermotolerance reached (TTRmax), and the rate of thermotolerance decay were strongly dependent upon the survival level produced by the initial heat exposure. The importance of these findings to the treatment of heterogeneous cancers by heat is discussed.
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PMID:Similarity of thermotolerance characteristics in heterogeneous human colon tumor subpopulations after exposure to fractionated heat doses (44 degrees C). 408 Sep 71

Polar solvents, which induce differentiation in murine and human tumor cells, enhance the effect of ionizing radiation on cultured mouse mammary and human colon cancer cells. To determine whether this enhancement occurs in vivo, DLD-2 human colon carcinoma xenografts in nude mice were treated with combinations of 6 MV photon irradiation, the polar solvent N-methylformamide (NMF), or combinations of the two agents. Nude mice bearing 300-mg s.c. implants of DLD-2 tumors were treated i.p. with 150 mg NMF/kg daily for 19 days. Local tumor irradiations were administered as graded single doses or as fractionated doses, daily for 4 days, following the third NMF injection. The growth-inhibiting effect of the radiation treatment for both single dose and fractionation protocols was enhanced by the polar solvent. NMF alone increased the time required for a doubling of initial tumor volume by 1.7 days, compared to control tumors. Initial tumor volume doubling times compared to untreated controls were increased by 3.6 and 7.6 days by photon doses of 10.0 and 13.75 Gy, respectively, whereas NMF plus 10.0 or 13.75 Gy increased the DLD-2 regrowth delay time by 7.5 or 12.9 days. NMF caused essentially equivalent enhancements, whether split-dose schedules of 2.5 Gy daily for 4 days, and 3.44 Gy daily for 4 days, or single doses of 10.0 and 13.75 Gy were used; therefore, radiation enhancement was not due to effects on sublethal damage repair. The results support the use of NMF, currently in Phase 1-Phase 2 clinical trials, with radiation in the therapy of selected human neoplasms.
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PMID:Enhancement by N-methylformamide of the effect of ionizing radiation on a human colon tumor xenografted in nude mice. 648 57


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