Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

2,3-Dihydro-1H-imidazo[1,2-b]pyrazole (IMPY) is an inhibitor of ribonucleotide reductase and of DNA synthesis selected for clinical trials because of its activity against L1210 leukemia variants resistant to other inhibitors of this enzyme. A phase I trial designated to allow in-depth pharmacologic evaluation has recently been completed and the clinical results and preliminary pharmacokinetic data are reported here. Each patient received IMPY by three different schedules. A single iv bolus, intermittent 5-day bolus, and 5-day continuous infusion were given at 3-week intervals. The major dose-limiting toxic effects were vomiting, rbc hemolysis, confusion, and somnolence. All toxic effects seemed to be dose- and schedule-dependent and were readily reversible. IMPY enters the cerebrospinal fluid and is highly concentrated in gastric secretions. Clearance of IMPY is impaired in the presence of hepatic insufficiency. Eighteen of 26 patients entered are evaluable for response, including one patient with colon cancer with minimal response and three patients with stable disease.
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PMID:Clinical toxic effects of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole (IMPY) with relevant pharmacokinetic parameters. 740 59

The success of chemotherapy of colon tumours is currently limited. We have therefore used the human colon tumour cell line HT-29 to evaluate the cytotoxic effects of various drug combinations. Trimidox (3,4,5-trihydroxybenzamidoxime), a recently patented inhibitor of ribonucleotide reductase was combined with cytosinearabinoside (Ara-C) or 2',2'-difluorodeoxycytidine (DFDC) in order to inhibit both pyrimidine de novo and salvage pathways. Synergistic cytotoxic effects were observed. When HT-29 cells were sequentially treated with trimidox (20 microM for 24 h) and Ara-C (2 microM for 2 h), colony numbers decreased to 71% of the value calculated for additive cytotoxicity. When cells were simultaneously treated with trimidox (10 microM and 15 microM) and DFDC (0.2 nM), synergistic inhibition of colony formation was likewise noted (colony numbers decreased to values as low as 73% or 71% of the values calculated for additive cytotoxicity). On the other hand, we combined tiazofurin, an inhibitor of the guanylate de novo pathway, with allopurinol, which inhibits the guanylate salvage pathway by increasing intracellular hypoxanthine concentrations, leading to inhibition of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Synergistic cytotoxic effects were observed under these conditions too. When cells were treated with 10 microM tiazofurin and 400 microM or 800 microM allopurinol the number of colonies decreased to 69% and 27%, respectively, of the values calculated for additive effects. Our data suggest these drug combinations to be promising options in the treatment of human colon cancer.
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PMID:[Synergistic cytotoxic effects of chemotherapy in colon tumor cells by simultaneous inhibition of de novo and salvage energy metabolism pathways]. 794 93

The effects of prolonged exposure to the ribonucleotide reductase (RR) inhibitor, hydroxyurea (HU), were assessed in the presence or absence of recombinant interferon alfa-2a (IFN) in wild-type human colon cancer cells (HT-29) and variants expressing low-level resistance to HU (R200). IFN at nontoxic concentrations decreased the IC50 of HU from 368 microM to 215 microM (P < 0.01) in wild-type cells, but not in the resistant variants. Potential cellular targets for the HU/IFN interaction were examined. In wild-type, but not resistant cells, treatment with HU at clinically achievable concentrations (1000 microM) resulted in rapid early inhibition of RR activity between 4 and 24 h after treatment with a maximal decrease of 65% at 12 h, decreases in cellular levels of dATP, dCTP and dGTP by 50-90% over the same time course, and a two- to fourfold increase in the level of mRNA for both the M1 and M2 subunits of RR, at 24, but not between 1 and 4 h, which probably represents a response to the earlier decrease in RR activity. IFN at a clinically achievable concentration (500 U/ml) failed to augment the effects of HU on RR protein, RR mRNA levels or RR enzyme activity in either the wild-type or resistant cells, suggesting that the mechanism by which IFN augments the effects of HU in the wild-type cells is independent of the effects of HU on M2.
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PMID:Interferon augments the cytotoxicity of hydroxyurea without enhancing its activity against the M2 subunit of ribonucleotide reductase: effects in wild-type and resistant human colon cancer cells. 882 93

Effects of drug treatment with antimetabolites on a human colon cancer cell line, SW480, were studied. Cells were treated with 10 microM of 5-fluorouracil (5FU), an inhibitor of pyrimidine synthesis, or 1000 microM of hydroxyurea (HU), an inhibitor of both purine and pyrimidine syntheses, or the combination. Recombinant alpha-2a-interferon (IFN), 500 U/mL, also was employed, as this augments the effects of both antimetabolites in vitro and in vivo. The predominant effect of this combination was to block cells in early S phase as measured by 5-bromo-2'-deoxyuridine (BrdUrd) incorporation. By 24 hr, 86% of the cells had accumulated in S phase, but failed to progress to G2/M. This was accompanied by an early, rapid decline in all four deoxyribonucleoside triphosphates (dNTPs) by 38-86% at 4-24 hr. Despite these effects, expression of the G1/S transition state enzyme, ribonucleotide reductase (RR), increased at 24 hr as measured by a 3 to 5-fold increase in mRNA levels for the M2 subunit, in the absence of a measurable effect on protein levels. The rise in levels of RR mRNA and the continued progression of cells into S phase were associated with a synergistic inhibition of cell cycle proliferation resulting from treatment with the three-drug combination. This suggests that in the presence of antimetabolite-induced depletion of dNTPs, SW480 cells, which lack a normal p53 gene, will proceed into S phase, and that this is associated with a rise in expression of the G1/S transition state enzyme, RR. Cells arrested in S phase by a p53-independent mechanism will undergo a synergistic enhancement of cell death.
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PMID:Effects of perturbations of pools of deoxyribonucleoside triphosphates on expression of ribonucleotide reductase, a G1/S transition state enzyme, in p53-mutated cells. 1007 25

Using reverse transcriptase-polymerase chain reaction (RT-PCR), we have recently described a bona fide deletion within the coding sequence of the large subunit of ribonucleotide reductase (R1) mRNA in colon cancer. Consecutive studies have raised questions about the nature of this phenomenon, because the corresponding genomic alteration at the DNA level or an aberrant protein could not be detected. Thus we considered an in vitro artifact during RT-PCR as a possible explanation for this observation. In contrast to reverse transcriptase, Taq DNA polymerase or C. therm DNA polymerase did not generate the aberrant product, suggesting the demand for the template switching activity intrinsic to retroviral reverse transcriptases. In fact, virtually the same deletion was observed in RT-PCR experiments when in vitro transcribed R1 mRNA was used. Considering structural prerequisites for template switching within R1 mRNA, we show that two direct repeats adjacent to a strong stem-loop secondary structure flank the deleted region of 1851 base pairs. Because several mRNAs encoding proteins of clinical and diagnostic importance fulfill these criteria, template switching enhances the potential risk of observing artifacts when interpreting results from RT-PCR studies. As shown in the present example, this may involve the artificial generation and the misinterpretation of PCR fragments amplified from targets relevant to tumor biology or cancer pharmacology. As a possible solution, one-step PCR with C. therm polymerase should be considered. This polymerase eliminates the artificial generation of aberrant mRNA signals observed during cDNA synthesis.
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PMID:Reverse transcriptase template switching during reverse transcriptase-polymerase chain reaction: artificial generation of deletions in ribonucleotide reductase mRNA. 1138 63

Here we describe the effects of novel benzoxazol-2-yl and benzimidazol-2-yl hydrazones derived from 2-pyridinecarbaldehyde and 2-acetylpyridine. The IC(50) values for inhibition of cell proliferation in KB-3-1, CCRF-CEM, Burkitt's lymphoma, HT-29, HeLa, ZR-75 and MEXF276L by most of the novel compounds are in the nanomolar range. In colony-forming assays with human tumor xenografts the compounds 2-actylpyridine benzoxazol-2-ylhydrazone (EPH52), 2-acetylpyridine benzoimidazol-2-ylhydrazone (EPH61) and 2-acetylpyridine 1-methylbenzoimidazol-2-ylhydrazone (EPH116) exhibited above-average inhibition of colon carcinoma (IC(50) = 1.3-4.56 nM); EPH52 and EPH116 also exhibited above-average inhibition of melanoma cells. As shown with human liver microsomes, EPH116 is only moderately metabolized. The compound inhibited the growth of human colon cancer xenografts in nude mice in a dose-dependent manner. Thiosemicarbazones derived from 2-formylpyridines have been shown to be inhibitors of ribonucleotide reductase (RR). The following results show that RR is not the target of the novel compounds: cells overexpressing the M2 subunit of RR and resistant to the RR inhibitor hydroxyurea are not cross-resistant to the novel compounds; inhibition of RR occurs at 6- to 73-fold higher drug concentrations than that of inhibition of cell proliferation; the pattern of cell cycle arrest in S phase induced by the RR inhibitor hydroxyurea is not observed after treatment with the novel compounds; and a COMPARE analysis with the related compounds 2-acetylpyrazine benzothiazol-2-ylhydrazone (EPH95) and 3-acetylisoquinoline benzoxazol-2-ylhydrazone (EPH136) showed that the pattern of these compounds is not related to any of the standard antitumor drugs. Therefore, these novel compounds show inhibition of colon cancers and exhibit a novel mechanism of action.
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PMID:2-benzoxazolyl and 2-benzimidazolyl hydrazones derived from 2-acetylpyridine: a novel class of antitumor agents. 1166 83

Detection of genomic differences predictive of drug response or resistance in individual patients may allow therapy to be customized to the characteristics of particular tumors. Preliminary findings are that non-small cell lung cancer patients overexpressing ERCC1 mRNA have lower response to cisplatin chemotherapy, while those overexpressing ribonucleotide reductase mRNA have limited benefit from gemcitabine. In addition, overexpression of beta-tubulin III and stathmin can influence the sensitivity to microtubule interacting drugs, like vinorelbine and paclitaxel. The introduction of biological agents which target highly specific intracellular pathways offers the promise of enhancing the efficacy of cytotoxic chemotherapy. Among many promising biological agents is the monoclonal antibody C225, which blocks the EGFR receptor. The addition of C225 appears to induce responses in a proportion of colon cancer patients refractory to 5-FU or irinotecan, supporting pre-clinical evidence of synergistic activity. It also appears from xenograft data that C225 enhances the sensitivity of tumors to radiation and docetaxel or the combination.
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PMID:Molecular markers and targeted therapy with novel agents: prospects in the treatment of non-small cell lung cancer. 1248 Jan 94

Mounting evidence suggests that the position in the cell cycle of cells exposed to an oxidative stress could determine their survival or apoptotic cell death. This study aimed at determining whether nitric oxide (NO)-induced cell death in colon cancer cells might depend on their position in the cell cycle, based on a clone of the cancer cell line HT29 exposed to an NO donor, in combination with the manipulation of the cell entry into the cell cycle. We show that PAPA NONOate (pNO), from 10(-4) m to 10(-3) m, exerted early and reversible cytostatic effects through ribonucleotide reductase inhibition, followed by late resumption of cell growth at 5 x 10(-4) m pNO. In contrast, 10(-3) m pNO led to late programmed cell death that was accounted for by the progression of cells into the cell cycle as shown by (a) the accumulation of apoptotic cells in the G(2)-M phase at 10(-3) m pNO treatment; and (b) the prevention of cell death by inhibiting the entry of cells into the cell cycle. The entry of pNO-treated cells into the G(2)-M phase was associated with actin depolymerization and its S-glutathionylation in the same way as in control cells. However, the pNO treatment interfered with the build-up of a high reducing power, associated in control cells with a dramatic increase in reduced glutathione biosynthesis in the G(2)-M phase. This oxidative stress prevented the exit from the G(2)-M phase, which requires a high reducing power for actin deglutathionylation and its repolymerization. Finally, our demonstration that programmed cell death occurred through a caspase-independent pathway is in line with the context of a nitrosative/oxidative stress. In conclusion, this work, which deciphers the connection between the position of colonic cancer cells in the cell cycle and their sensitivity to NO-induced stress and their programmed cell death, could help optimize anticancer protocols based on NO-donating compounds.
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PMID:Position in cell cycle controls the sensitivity of colon cancer cells to nitric oxide-dependent programmed cell death. 1520 35

The nucleotide metabolism enzyme ribonucleotide reductase is composed of a regulatory subunit (RRM1) and a catalytic subunit (RRM2). The RRM1 locus has frequent loss of heterozygosity in lung cancers, ectopic expression of RRM1 suppresses proliferation of ras-transformed mouse fibroblasts, and high levels of RRM1 expression are associated with a significant survival benefit in patients with lung cancer. In RRM1 transgenic human lung and colon cancer cell lines, we observed induction of G(2) cell cycle arrest, apoptosis, and efficient DNA damage repair. We generated strains of RRM1 transgenic mice and found that carcinogen-induced lung tumor formation was significantly suppressed. The tumor suppression was more pronounced in strains with high levels of RRM1 expression than in those with low levels of expression. DNA damage repair capacity in transgenic animals was determined, and RRM1 transgenic animals repaired chemically induced DNA damage with greater efficiency than control animals. We conclude that the regulatory subunit of ribonucleotide reductase has tumor suppressor activity that is mediated through efficient DNA damage repair.
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PMID:Suppression of lung tumor formation by the regulatory subunit of ribonucleotide reductase. 1681 20

Tezacitabine is a nucleoside analogue characterized by a dual mechanism of action. Following intracellular phosphorylation, the tezacitabine diphosphate irreversibly inhibits ribonucleotide reductase, while the tezacitabine triphosphate can be incorporated into DNA during replication or repair, resulting in DNA chain termination. In the present study we have investigated the effect of the combination of tezacitabine and 5-fluorouracil (5-FU) or 5-fluoro-2'-deoxyuridine (FUdR) on HCT 116 human colon carcinoma cells and xenografts. We used response surface analysis (RSA) and clonogenic assay to evaluate combination effects of tezacitabine and 5-FU. Tezacitabine is antagonistic when combined with 5-FU in the RSA assay and does not effect the clonogenicity of HCT 116 cells when compared with cells treated with 5-FU alone. However, when combined sequentially with FUdR, tezacitabine leads to potentiation of cell killing in the clonogenic assay, additivity in the RSA assay, and increased apoptosis when compared to FUdR alone, suggesting that cytotoxicity of fluoropyrimidines such as FUdR that have more DNA-directed effects can be potentiated by tezacitabine. We also report that oral administration of the fluoropyrimidine capecitabine, an oral prodrug of 5-FU, in combination with tezacitabine shows statistically significant additivity in the HCT 116 xenograft model. This interaction may be explained by the finding that tezacitabine elevates activity of thymidine phosphorylase (TP), the enzyme required for activation of the capecitabine prodrug in tumors. Our results provide evidence that tezacitabine enhances the DNA-directed effects of fluoropyrimidines in human colon cancer cells and may modulate the antitumor activity of fluoropyrimidines.
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PMID:Tezacitabine enhances the DNA-directed effects of fluoropyrimidines in human colon cancer cells and tumor xenografts. 1704 20


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