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)

The expression of the plasminogen activator, urokinase, and the display of its receptor in response to growth factors were examined in a serum-free adapted colon cancer cell line, CBSsf. Cells propagated in protein-free medium secreted 6.5 +/- 1.0 ng/ml of urokinase/10(6) cells in a 3-day period as determined by enzyme-linked immunosorbent assay. Inclusion of insulin or transferrin into the protein-free medium was without effect on this parameter. However, addition of epidermal growth factor (EGF) to the protein-free medium resulted in a 50% reduction in this parameter. This change was also reflected in the plasminogen-dependent solubilization of immobilized radioactive laminin. Plasminogen-supplemented conditioned medium derived from CBSsf cells grown in protein-free medium solubilized 135,000 +/- 25,000 dpm/10(6) cells of radioactive substrate. This value was decreased to 59,000 +/- 6,000 when conditioned medium was collected in the presence of EGF. Dose-response curves indicated that, while 0.5 ng/ml of EGF were suboptimal for the suppression of urokinase secretion, a concentration of 5.0 ng/ml had a maximum effect on this measurement. Northern hybridization studies indicated that the reduced plasminogen activator reflected, at least in part, translation of a less abundant transcript. Examination of the colon carcinoma cell line for altered urokinase receptor display revealed that EGF caused a dose-dependent increase in the amount of radioactive urokinase bound. This did not reflect reduced occupation of binding sites with endogenous ligand. Scatchard manipulation of the binding data indicated that the increased amount of radioactive plasminogen activator bound to cells cultured with EGF reflected an increase in receptor number from 7,500 to 13,000 sites/cell. Time course studies revealed that the decrease in urokinase secretion precedes changes in receptor display by 5 h. A 60% reduction in assayable urokinase was demonstrated in the conditioned medium from cells treated with the growth peptide for 10 h. However, a 24-h period was required to observe an increase (80%) in the amount of radioligand bound to EGF-treated cells. These data suggest EGF to be a regulator of both urokinase production and urokinase receptor display in a colon cancer cell line.
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PMID:Examination of the effects of epidermal growth factor on the production of urokinase and the expression of the plasminogen activator receptor in a human colon cancer cell line. 253 3

Human colorectal carcinomas frequently express elevated levels of c-myc mRNA in the absence of a gross genetic change at the c-myc locus. To test the hypothesis that these tumors are defective in a gene function necessary for the regulation of c-myc expression, we fused an osteosarcoma cell line that exhibits normal c-myc regulation with two colon carcinoma cell lines that express deregulated levels of c-myc mRNA. The levels of c-myc transcripts in all of the hybrid clones examined were normal and were induced normally by a mitogenic stimulus. Since rates of c-myc mRNA turnover in the colon carcinoma cells were found to be comparable to those in normal cells, increased message stability cannot account for the increased steady-state levels of transcripts. Our findings suggest that loss of function of a trans-acting regulator is responsible for the deregulation of c-myc expression in a major fraction of colorectal carcinomas. Analysis of restriction fragment length polymorphisms in tumor/normal tissue pairs from patients with primary colorectal lesions indicated that deregulation of c-myc expression in the tumors is correlated with frequent loss of alleles of syntenic markers on chromosome 5q; allele loss on 5q could be detected in 9 of 19 tumors expressing deregulated levels of c-myc mRNA, but not in any of 8 tumors expressing normal levels of c-myc RNA. Chromosome 5q is the region known to contain the gene for familial adenomatous polyposis, an inherited predisposition to colon cancer. These findings, together with the earlier finding that the colonic distribution of tumors exhibiting deregulated c-myc expression is similar to that reported for familial polyposis, provide evidence that loss of function of the familial adenomatous polyposis gene is involved in a subset of colorectal cancers in which c-myc expression is deregulated.
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PMID:Evidence that the familial adenomatous polyposis gene is involved in a subset of colon cancers with a complementable defect in c-myc regulation. 254 67

The effects of vasoactive intestinal polypeptide (VIP) and dibutyryl cyclic adenosine 3':5'monophosphate (dbcAMP) on two human colon carcinoma cell lines, HCT 116 and GEO, were investigated. VIP and dbcAMP inhibited the growth of both cell lines in monolayer culture in a dose-dependent manner. Within 6 h of treatment with 1 mM dbcAMP or 0.3 microM VIP, numerous mucin-like droplets were secreted by GEO cells. VIP and dbcAMP also increased carcinoembryonic antigen (CEA) secretion. In both cell lines, a 9-fold increase in conditioned medium CEA levels was observed at 1 mM dbcAMP and a 2.6-fold increase at 1.5 microM VIP. Time- and concentration-dependent evaluation in cAMP levels were elicited by VIP in the two cell lines. Immunocytochemical studies for cell-surface glycoprotein detection in GEO cells showed that VIP induced a morphological and functional organization of mucin-secreting cells. These results indicate that VIP and dbcAMP have antiproliferative and strong differentiation-promoting effects in colon cancer cells. This is the first report of VIP-induced mucin secretion in colon tumor cells.
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PMID:Promotion of differentiation in human colon carcinoma cells by vasoactive intestinal polypeptide. 254 28

Drug development is needed to improve chemotherapy of patients with locally advanced or metastatic colon carcinoma, who otherwise have an unfavorable prognosis. DNA topoisomerase I, a nuclear enzyme important for solving topological problems arising during DNA replication and for other cellular functions, has been identified as a principal target of a plant alkaloid 20(S)-camptothecin. Significantly increased concentrations of this enzyme, compared to that in normal colonic mucosa, were found in advanced stages of human colon adenocarcinoma and in xenografts of colon cancer carried by immunodeficient mice. Several synthetic analogs of camptothecin, selected by tests with the purified enzyme and tissue-culture screens, were evaluated in the xenograft model. Unlike other anticancer drugs tested, 20(RS)-9-amino-camptothecin (9-AC) induced disease-free remissions. The overall drug toxicity was low and allowed for repeated courses of treatment.
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PMID:DNA topoisomerase I--targeted chemotherapy of human colon cancer in xenografts. 255 20

Colon cancer is one of the tumors most refractory to treatment by chemotherapy, and this may be due to inherent phenotypic instability of such tumor cells with respect to the biochemical determinants of drug sensitivity. To test this hypothesis, a clonal human colon carcinoma cell line, clone A, was passaged in culture in the absence of selection conditions or mutagens. During this time, sensitivity to several drugs was examined, and was found to decrease 4-fold during 30 weeks of culture. Five randomly selected subclones, having never been exposed to drug or mutagen, displayed a range of sensitivities to etoposide (50% inhibitory concentrations ranging from 1.5 to 4.9 microM) and to vincristine (9-fold range), but all had the same sensitivity to methotrexate. With time these sensitivities also changed, and subsequent subclones were chosen from the lines with highest and lowest drug sensitivity. Again a wide range of phenotypes was observed. Sensitivity to vincristine ranged 14-fold and to doxorubicin 3-fold. Several biochemical determinants of drug sensitivity had a broad range of expression between cell lines. Cellular accumulation of [3H]vincristine, as well as expression of multidrug resistance protein P170 and glutathione transferase activity all varied significantly between subclonal lines. This suggests that some human colon tumors may be phenotypically unstable with respect to drug sensitivity, and this could contribute to clinical resistance to chemotherapeutic compounds.
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PMID:Phenotypic instability of drug sensitivity in a human colon carcinoma cell line. 256 72

Using a murine monoclonal antibody MAb 1A3, which binds to a lipid antigen found enriched in human colon cancer, and MOPC-21 antibody, as a non-specific control, we examined the effect of increasing doses of 125I-labelled MAbs (5 micrograms to 2,000 micrograms) on tumor localization. Biodistribution studies in hamsters with small GW-39 human colon carcinoma tumors [0.44 g +/- 0.014 (SEM)] demonstrated functional saturation of antigen binding sites in tumors when large doses of MAb 1A3 were used. The percentage injected dose bound per gram of tumor (ID/g tumor) remained constant for doses of intact MAb 1A3 less than or equal to 100 micrograms but decreased with doses greater than 100 micrograms, suggesting that a population of antigen binding sites had been saturated. While the percentage ID/g tumor decreased for doses of MAb 1A3 greater than 100 micrograms, the absolute amount specifically bound/g turnover increased (up to the 1,000 micrograms dose), suggesting that another population of less accessible 1A3 antigen could continue to bind MAb 1A3. In contrast, MOPC demonstrated a relatively constant percentage ID/g of tumor (2.26% +/- 0.11) throughout the dose range which was 2-3 times lower than MAb 1A3 (6.8% +/- 0.14) at plateau doses (5-100 micrograms). These data suggest that specific saturation of tumor binding sites was a biphasic phenomenon. Blood and normal tissues did not show binding kinetics suggesting saturation. Results of dose response experiments using MAb 1A3 F(ab')2 fragments (5 micrograms to 1,000 micrograms) closely paralleled those obtained with intact MAb 1A3, but with lower percentages of ID/g tumor, blood and non-tumor tissues as in previous studies with MAb 1A3 and other MAb F(ab')2 fragments. Histological examinations demonstrated that non-specific binding of MOPC or MAb 1A3 to tumor or normal tissues was of such low affinity as to be largely undetected after histological procedures. In contrast, MAb 1A3 (but not MOPC) showed specific cell-binding patterns to tumor but not normal tissues at all doses.
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PMID:Biodistribution and histological localization of anti-human colon cancer monoclonal antibody (MAb) 1A3: the influence of administered MAb dose on tumor uptake. 269 5

We previously reported that the combination of cis-diamminedichloroplatinum (CDDP) and 1-beta-D-arabinofuranosylcytosine (ara-C) induced a remarkable synergistic killing effect on an established human colon carcinoma cell line, LoVo. The current study investigated whether this effect was LoVo specific or could be extended to other colon cancer cell lines as well as to cell lines of different histological origins, including an estrogen receptor-positive breast cancer cell line (MCF7), an ovarian cancer cell line (OV1225), and an esophageal cancer cell line (Hcu18). The six human colorectal cancer cell lines included in this study represent three biological groups with distinct phenotypic properties. Group 1 (well-differentiated) consisted of LoVo and SW48; group 2 (intermediately differentiated) comprised SW480 and SW620; and group 3 (undifferentiated) was represented by SW403 and SW1116. No significant synergistic cytotoxicity was noted after the breast and ovarian cancer cells were treated. However, synergistic lethal effects were observed in all of the six colon cancer cell lines as well as the esophageal cancer cell line. The synergistic effect on the gastrointestinal cancer cell lines was related to the concentration of ara-C and CDDP during treatment. Our results suggest that the cytotoxic synergism between ara-C and CDDP may be tissue-type specific and that synergism may depend on the histological origin of the cancer.
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PMID:Synergism of 1-beta-D-arabinofuranosylcytosine and cis-diamminedichloroplatinum in their lethal efficacies against seven established cancer cell lines of gastrointestinal origin. 270 47

Human colonic tissue is exposed to a variety of toxic chemicals and potential carcinogens in the diet and the intestinal microenvironment. Colonic adenocarcinoma is commonly resistant to the cytotoxic effects of most chemotherapeutic drugs. We have examined drug metabolic and detoxification pathways in clinical specimens of colon carcinoma and normal adjacent mucosa from 17 patients. All elements of xenobiotic metabolism examined are present in these tissues, including cytochrome P-450-dependent enzymes, glutathione, and glutathione-utilizing enzymes. In comparison of tumor tissue to its respective normal mucosa specific alterations in the pathways affecting a number of chemotherapeutic agents were detected, including significantly higher glutathione, glutathione peroxidase, and anionic glutathione-S-transferase activity. These and other alterations found here could be the target of therapeutic maneuvers to enhance the efficacy of antineoplastic treatment of human colon cancer.
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PMID:Implications for therapy of drug-metabolizing enzymes in human colon cancer. 275 17

The effect of leucovorin (LV) given in various doses and schedules on the in vivo antitumor activity and toxicity of 5-fluorouracil (5FU) was studied in two murine colon cancer lines, i.e., Colon 26 (relatively resistant to 5FU) and Colon 38 (5FU sensitive), maintained in Balb-c and C57B1/6 mice, respectively. Mice were treated weekly with 5FU at the maximum tolerated dose, alone and in combination with LV. In Colon 26, neither simultaneous administration of 5FU and LV nor 5FU combined with delayed administration of LV potentiated the antitumor activity of 5FU. LV given twice - 1 hr before (50 mg/kg) and then together (50 mg/kg) with 5FU (100 mg/kg) - gave significantly better delay of tumor growth of both tumor lines than 5FU did alone (100 mg/kg). No differences were found after a total LV dose of 100 or 200 mg/kg. Delayed administration of uridine (3500 mg/kg) allowed the use of higher 5FU doses, which improved the antitumor effect on Colon 26. Systemic toxicity led to moderate weight loss in treated mice, but was comparable for mice treated with 5FU alone or combined with LV. Hematological toxicity consisted of moderate leukopenia (nadir 40%), which was observed with the most active schedule and was less severe than with 5FU alone. This schedule did not cause thrombocytopenia, but after discontinuation the thrombocyte count showed an overshoot. Addition of uridine to this schedule reduced hematological toxicity only slightly. It is concluded that LV potentiated the antitumor activity of 5FU against two solid tumor lines, i.e., a relatively resistant and a sensitive murine colon carcinoma, and that toxicity was moderate.
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PMID:Schedule-dependency of in vivo modulation of 5-fluorouracil by leucovorin and uridine in murine colon carcinoma. 279 68

The follow-up of colon cancer patients by monitoring serum carcinoembryonic antigen has advantages (better survival after early detection of recurrence by CEA rise) as well as disadvantages (false-positive rise of CEA, and early detection of incurable recurrences in asymptomatic patients). The effects of CEA follow-up on quality-adjusted life expectancy (QUALE) of patients with curatively resected colon carcinoma have been simulated by a Markov analysis using literature data. The value of CEA seems insignificant and varies, depending on the literature data used, from a mean increase of QUALE by 6 days (+0.4%) to a mean decrease by 2 days (-0.07%). This value depends on patient-related variables; the negative effects of CEA especially predominate in older patients with favourable Dukes' stages of primary tumour.
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PMID:[Carcinoembryonal antigen and the follow up of patients after resection of colon carcinoma with curative intent: a Markov process in decision analysis]. 281 76


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