Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidermal Growth Factor (EGF) is a 6045 dalton polypeptide which stimulates the proliferation of various cell types in vitro and in vivo. EGF binds to diffusely distributed membrane receptors which rapidly cluster primarily on coated pits areas on the plasma membrane. Subsequently, the EGF-receptor complexes are endocytosed and degraded by lysosomal enzymes. The lateral diffusion coefficient (D) of EGF-receptor complexes on cultured cells increases gradually from D = 2.8 X 10(-10) cm2/sec at 5 degrees C to 8.5 X 10(-10) cm2/sec at 37 degrees C. In the same range of temperature the rotational correlation times change from 25 to 50 microseconds to approximately 350 microseconds. Hence, at 4 degrees C, the occupied EGF receptors translate and rotate rapidly in the plane of the membrane. At 37 degrees C, EGF receptors form microclusters composed of 10 to 50 molecules. Moreover, it is concluded that both at 4 degrees C and 37 degrees C lateral diffusion of the occupied receptors is not the rate determining step for either receptor clustering or internalization. EGF receptor is a 150,000 to 170,000 dalton glycoprotein. The receptor is in close proximity to an EGF-sensitive, cAMP-independent, tyrosine-specific protein kinase which also phosphorylates the receptor molecules itself. The EGF sensitive kinase is similar to the kinase activity which is associated with certain RNA tumor viruses. The fact that the non-mitogenic cyanogen-bromide cleaved EGF is as potent as native EGF in stimulating phosphorylation suggests that EGF-induced, protein phosphorylation is a necessary but insufficient signal for the induction of DNA synthesis by EGF. EGF receptor serves also as the binding site for Transforming Growth Factors (TGF) which compete with EGF and induce anchorage-independent growth of normal cells in soft agar. Tumor promoters such as phorbol ester effect the binding of EGF to its membrane receptors and its ability to stimulate DNA synthesis. EGF itself has also some tumor promoting activity. Hence, the membrane receptor for EGF seems to participate in the regulation of normal and neoplastic growth. Monoclonal antibodies against EGF receptor (IgM) induce various early and delayed effects of EGF, while their monovalent Fab' fragments are devoid of biological activity. These observations support the notions that EGF receptor rather than EGF itself is the active moiety and that the role of the hormone is to perturb the receptor in the appropriate way, probably by inducing the microaggregation of EGF receptors.
CRC Crit Rev Biochem 1983
PMID:Regulation of cell proliferation by epidermal growth factor. 630 52

Most anticancer agents fail to induce clear responses in the treatment of colorectal cancer. This can be explained by involvement of overexpression of the membrane glycoprotein, P-gp 170, which is associated with multidrug resistance (MDR), and/or with involvement of ras. Fluoropyrimidines are amongst the few options in the chemotherapeutic treatment of colorectal cancers. 5'-Deoxy-5-fluorouridine (dFUrd) needs intracellular activation via 5-fluorouracil into 5-fluoro-2'-deoxyuridine-5'-monophosphate and 5-fluorouridine-5'-triphosphate. In the present study, the cytotoxic activity of dFUrd in vitro and dFUrd combined with daunorubicin (DNR) was assessed with the (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium) bromide assay in cells with increased P-gp 170 expression versus controls. Surprisingly, dFUrd was most active in cells with high P-gp 170 expression, a finding which can not be explained by intracellular metabolic activity only. The results also show that dFUrd improves the DNR uptake in MDR-positive cells, and this is related with increased cytotoxicity of the anthracycline.
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PMID:5'-Deoxy-5-fluorouridine increases daunorubicin uptake in multidrug-resistant cells and its activity is related with P-gp 170 expression. 790 63

The effects of glutathione (GSH) and of purified human and rat GSH S-transferases (GSTs) on the covalent DNA binding of 3 putative ultimate food-borne carcinogens, the N-acetoxy derivatives of 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), 2-amino-3-methylimidazo(4,5-f)quinoline (IQ), and 2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline (MeIQx), were studied in vitro. GSH (5 mM) alone slightly inhibited (10%) the DNA binding of N-acetoxy-PhIP (100 microM) at pH 7.5, but the binding could be strongly inhibited in the presence of both GSH and GSTs. Among human GSTs, the isozyme A1-1 (alpha-class) was most effective (90% inhibition) followed by A1-2 (40% inhibition); the effect of adding A2-2 was negligible, suggesting that the activity exists in subunit A1. In addition, human GST P1-1 (pi-class) also had some inhibitory effect (30%). Among the rat GSTs tested, GST 1-2 and GST 12-12 (theta-class), which are the equivalent of human A1-2 and T2-2, respectively, were able to inhibit DNA binding of N-acetoxy-PhIP (75 and 40%, respectively). This activity toward N-acetoxy-PhIP was dependent on enzyme concentration and was subject to inactivation by triethyltin bromide, a known GST inhibitor. In contrast, the binding of N-acetoxy-IQ or N-acetoxy-MeIQx to DNA was unaffected by addition of the human or rat GSTs; however, GSH alone significantly inhibited (40%) their binding to DNA. High-performance liquid chromatographic analyses of incubation mixtures containing N-acetoxy-PhIP, GSH, and GST A1-1 failed to detect GSH conjugates of PhIP. Only oxidized glutathione and the parent amine, PhIP, were detected as reaction products, suggesting a redox mechanism. GST activity in human hepatic and colon mucosal cytosols was subsequently examined using the synthetic or O-acetyltransferase-generated N-acetoxy derivatives of PhIP, IQ, and MeIQx as substrates. GST activity toward N-acetoxy-PhIP was expressed in all 8 livers but not in 6 colons. No activity toward N-acetoxy-IQ or N-acetoxy-MeIQx was detected in human liver cytosols. This study indicates that a GST-dependent detoxification pathway may be an important determinant for the organ specificity of the heterocyclic amine carcinogens. Moreover, the high specificity of the reaction for GST A1-1, which is known to be inducible by cruciferous and yellow-green vegetable consumption, is consistent with the protective effects of such diets against human colorectal cancer.
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PMID:Effects of human and rat glutathione S-transferases on the covalent DNA binding of the N-acetoxy derivatives of heterocyclic amine carcinogens in vitro: a possible mechanism of organ specificity in their carcinogenesis. 806 58

Multidrug resistance to anticancer drugs proved to be related to the MDR1 gene which encodes the P-glycoprotein, an energy-dependent drug-efflux pump for lipophilic drugs. We investigated the expression of the MDR1 gene in clinical samples by RT-PCR. The subjects were all resected cases of 14 colorectal cancers, five gastric cancers, two esophageal cancers, two gallbladder cancers and 20 lung cancers. Adrenal gland was used as a positive control. Total RNA was extracted from a fresh tissue sample. The cDNA was synthesized from 1 microgram of total RNA using reverse transcriptase. With the above cDNA as the template, amplification of the 157-bp fragment of the MDR1 gene was performed using PCR. The PCR product was polyacrylamide gel-electrophoresed and ethidium bromide-stained. In addition, a dot blot analysis was performed to quantify the amount of PCR product. Since PCR was performed simultaneously under the same conditions, the PCR product was quantified at four stages, from (3+) to (-), to indicate the degree of expression of MDR1 mRNA. Adrenal gland showed (3+)-(2+) and colorectal cancer exhibited mostly (2+)-(1+). Both cancerous and non-cancerous areas evidenced a similar degree of expression in the cases of colorectal cancer. The MDR1 gene was expressed at low levels in other digestive tract cancers and in lung cancer. The levels of MDR1 expression revealed no correlation to either histological type or clinical stage. The present method may contribute to designing anti-cancer protocols.
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PMID:[Analysis of MDR1 (multidrug resistance) gene expression by RT-PCR]. 838 54

Instability of microsatellites is a hallmark of the DNA replication error phenotype (RER+) due to the inactivation of mismatch repair genes. In humans, microsatellite instability has first been described in colorectal tumors developing in either hereditary nonpolyposis colorectal cancer or sporadic patients. Colorectal tumorigenesis in RER+ and RER- tumors is probably due to distinct mechanisms, and RER+ tumors have a better prognosis than RER- tumors. The study of the RER status of a tumor may thus be important in the future to determine biological prognosis factors and investigate therapeutical strategies. The RER status of 134 primary tumors and 26 cell lines derived from colorectal cancers was established by PCR amplification and analysis of a minimum of 32 microsatellite loci. This characterization allowed us to unambiguously classify 35 primary tumors and 7 cell lines as RER+. Typing of a single poly(A) tract, BAT-26, was sufficient to confirm the RER status of 159 of these 160 tumors and cell lines. Moreover, in DNA from unaffected individuals, normal tissues of a subset of the RER+ patients, and all RER- tumors or cell lines, BAT-26 was quasi-monomorphic, showing only minor size variations. BAT-26 alleles showing shortening from 4 to 15 bp were observed in all but 1 of the RER+ tumors and cell lines. The size difference between the range of normal large alleles and unstable small alleles was sufficient to be detected by electrophoresis on conventional polyacrylamide gels stained with ethidium bromide. We thus propose a simple, low-cost, and rapid method to screen for the RER status of colorectal cancer primary tumors and cell lines, even in the absence of matching normal DNA and, in most cases, without the need for radioactivity. This method could easily be set up in routine laboratories.
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PMID:BAT-26, an indicator of the replication error phenotype in colorectal cancers and cell lines. 900 May 72

The molecular biology section of the Hereditary Non-Polyposis Colorectal Cancer study group-Germany, instituted a multicenter study to test the reliability and quality of microsatellite instability (MSI) analysis. Eight laboratories compared MSI analyses performed on 10 matched pairs of normal and tumor DNA from patients with colorectal carcinomas. A variety of techniques were applied to the detection of microsatellite changes: (a) silver and ethidium bromide staining of polyacrylamide gels; (b) radioactive labeling; and (c) automated fluorescence detection. The identification of highly unstable tumors and tumors without MSI was achieved in high concordance. However, the interpretation of the band patterns resulted in divergent classifications at several microsatellite marker loci for a large fraction of this tumor/normal panel. The data on more than 30 primers per case suggest that the enlargement of the microsatellite panel to more than 10 loci does not influence the results. In this study, cases with MSI in less than 10% of loci were classified as microsatellite stable, whereas MSI was diagnosed in cases with more than 40% of all markers unstable. We propose that a panel of five microsatellite loci consisting of repeats with different lengths should be analyzed in an initial analysis. When less than two marker loci display shifts in the microsatellite bands from tumor DNA, the panel should be enlarged to include an additional set of five marker loci. The number of marker loci analyzed as well as the number of unstable marker loci found should always be identified. These criteria should result in reports of MSI that are more comparable between studies.
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PMID:Microsatellite instability analysis: a multicenter study for reliability and quality control. 935 34

There is a need for a clinically useful drug-response assay for cancer patients to individualize their chemotherapy. Collagen sponge-gel-supported histoculture has been shown to maintain tissue architecture and function in vitro and has been utilized to develop the histoculture drug-response assay (HDRA) for individualizing chemotherapy. In order to evaluate the HDRA with the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide end point for clinical use, chemosensitivity to mitomycin C, doxorubicin, 5-fluorouracil, and cisplatin of 107 advanced gastric and 109 advanced colorectal cancers was determined in vitro in a correlative clinical trial. Two hundred eight (96.3%) of 216 of the patient specimens were evaluable in the HDRA. Thirty-eight patients with remaining measurable lesions after surgery were evaluable for comparison of the effects of chemotherapy in the HDRA with clinical outcome. Their overall response in the HDRA to all four drugs correlated to published historical data. Twenty-nine patients were treated with drugs shown to be ineffective in the HDRA, and all 29 cases showed clinical chemoresistance. In nine patients treated with drugs shown to be effective in the HDRA, six showed clinical chemoresponse and three showed arrest of disease progression. The correlation rate of the assay to clinical drug-sensitivity response was thus calculated to be 92.1% (35/38), with 100% (29/29) true-negative and 66.7% (6/9) true-positive rates, 100% (6/6) sensitivity, and 90.6% (29/32) specificity. Thirty-two patients with stage III and IV gastric cancer without remaining measurable tumor lesions after surgery were treated with mitomycin C and a fluoropyrimidine adjuvantly. The survival rate of 10 patients whose tumors were sensitive to either mitomycin C and/or 5-fluorouracil in the assay was significantly (P < 0.005) better than that of 22 patients whose tumors were shown to be insensitive to both drugs. Twenty-nine patients with stage III and IV colorectal cancer without remaining measurable tumor lesions after surgery were treated with fluoropyrimidines adjuvantly. The recurrence-free survival rate of 7 patients whose tumors were sensitive to 5-fluorouracil in the assay was significantly (P < 0.05) better than that of 22 patients whose tumors were insensitive. Thus the HDRA with the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide end point should be of clinical value to choose optimal chemotherapy for response as well as for survival.
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PMID:Clinical applications of the histoculture drug response assay. 981 86

Nonsteroidal anti-inflammatory drugs have potential for use in the prevention and/or treatment of colorectal cancer. We have studied the cytotoxic effect of a specific COX-2 inhibitor, celecoxib, against LLC, HCA-7, and HCT-15 cells grown in cell culture and have compared these results with its effect on HCA-7 cells grown as xenografts in nude mice. "High-dose" celecoxib (>20 microM) reduced the viability of all three cell lines in vitro as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometric analysis demonstrated that this loss of viability was attributable to the induction of apoptosis. Significantly, concentrations of the drug <10 microM had no effect on cell viability in vitro. The cytotoxic effects of high-dose celecoxib were independent of COX-2 inhibition because similar effects were observed in cox-2 (+/+), cox-2 (+/-) and cox-2 (-/-) fibroblasts. A plasma concentration of 2.3+/-0.7 microM was achieved when celecoxib (1250 mg/kg of chow) was fed to animals ad libitum. Despite a lack of toxicity at 2-3 microM celecoxib in vitro, there was attenuation of HCA-7 xenograft growth in vivo. Celecoxib had no effect on apoptosis, cell division, or the epithelial architecture of the normal gut in treated mice. These results support the need for additional clinical evaluation of celecoxib for treatment and/or prevention of colorectal cancer in humans.
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PMID:Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models. 1108 26

The folate-dependent enzymes are attractive targets for cancer chemotherapy. Methotrexate (MTX), which inhibits dihydrofolate reductase, has been widely used for the treatment of solid tumors and hematological cancers. Raltitrexed ("Tomudex") ), which inhibits thymidylate synthase, is a novel anticancer agent active against colorectal cancer and some other solid tumors. We studied the optimal schedule of raltitrexed and MTX in combination against four human colon cancer cell lines Colo201, Colo320, LoVo, and WiDr. These cells were simultaneously exposed to raltitrexed and MTX for 24 h, or sequentially exposed to raltitrexed for 24 h followed by MTX for 24 h, or vice versa. Cell growth inhibition after 5 days was determined by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of drug combinations at the concentrations of drug that produced 80% and 50% cell growth inhibition (IC(80) and IC(50)) were analyzed by the isobologram method (Steel and Peckham, 1979). Cytotoxic interactions between raltitrexed and MTX were schedule-dependent. The simultaneous exposure to raltitrexed and MTX showed additive effects in Colo201, LoVo and WiDr cells and antagonistic effects in Colo320 cells. The sequential exposure to raltitrexed followed by MTX produced additive effects in all four cell lines. The sequential exposure to MTX followed by raltitrexed produced synergistic effects in Colo201, LoVo and WiDr cells and additive effects in Colo320 cells. These findings suggest that the sequential administration of MTX followed by raltitrexed produces more than the expected cytotoxicity and may be the optimal schedule at the cellular level. Further in vivo and clinical studies will be necessary to determine the toxicity and to test the antitumor effects of sequential administration of MTX followed by raltitrexed proposed on the basis of the in vitro synergism.
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PMID:Schedule-dependent synergism and antagonism between raltitrexed ("Tomudex") and methotrexate in human colon cancer cell lines in vitro. 1117 47

Raltitrexed (Tomudex) is a novel thymidylate synthase inhibitor with significant activity against advanced colorectal cancer. We studied the cytotoxic interactions of raltitrexed and 5-fluorouracil (5-FU) in four human colon cancer cell lines on various schedules. The cell growth inhibition after 5 days was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The cytotoxic interactions at the IC80 level were evaluated by the isobologram method. Simultaneous exposure to raltitrexed and 5-FU for 5 days produced additive to synergistic effects in Colo201 cells, and produced additive effects in Colo321, LoVo, and WiDr cells. Simultaneous exposure to raltitrexed and 5-FU for 24 h produced additive effects in Colo201, LoVo, and WiDr cells, and produced antagonistic effects in Colo320 cells. Sequential exposure to raltitrexed for 24 h followed by 5-FU for 24 h produced additive effects in Colo201, Colo320, and LoVo cells, and produced antagonistic effects in WiDr cells. The reverse sequence produced additive effects in Colo201 cells, and produced antagonistic effects in Colo320, LoVo, and WiDr cells. Simultaneous exposure to raltitrexed and 5-FU for 4 h and sequential exposure to raltitrexed for 4 h followed by 5-FU for 4 h with a 20-h interval produced additive effects, while the reverse sequence produced antagonistic effects in LoVo and WiDr cells. These findings suggest that the simultaneous administration of raltitrexed and 5-FU or the sequential administration of raltitrexed followed by 5-FU may be the optimal sequence, while the reverse sequence may be inappropriate. Preclinical and clinical studies of the simultaneous administration of raltitrexed and 5-FU and the sequential administration of raltitrexed followed by 5-FU are required to better understand the antitumor, toxic, and pharmacokinetic interactions of this combination in order to develop the combination chemotherapy of raltitrexed and 5-FU.
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PMID:Schedule-dependent interaction between raltitrexed and 5-fluorouracil in human colon cancer cell lines in vitro. 1121 72


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