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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pyrimidine acyclonucleoside benzyloxybenzyloxybenzylacyclouridine (BBBAU) showed growth inhibitory activity against the human colon cancer HCT-8 cell line with a 50% inhibitory concentration of 55 microM. Unlike its parent compounds, BBBAU was an extremely weak inhibitor of uridine phosphorylase. This acyclonucleoside analogue is an inhibitor of thymidylate synthase (TS) as determined by inhibition of [6-3H]-2'-deoxyuridine incorporation into DNA, inhibition of 3H release from [5-3H]-2'-deoxyuridine, and decrease in both the free and total TS 5'-fluoro-2'-deoxyuridine 5'-monophosphate binding sites. Kinetic analysis revealed that BBBAUMP, the monophosphate analogue of BBBAU, is a competitive inhibitor of purified human recombinant TS with a Ki of 8.0 microM. Nucleoside transport and uptake studies revealed that BBBAU (30 microM) inhibited the initial rate of transport and the total uptake of thymidine (25 microM). In contrast, while BBBAU (30 microM) inhibited the initial rate of transport of 5-fluoro-2'-deoxyuridine (FdUrd, 25 microM), its intracellular accumulation was increased. BBBAU (10 and 50 microM, respectively) potentiated FdUrd growth inhibition of HCT-8 cells and significantly enhanced the cytotoxic effects of FdUrd (0.3 and 1 microM, respectively) against HCT-8 cells using a clonogenic assay system. This combination resulted in additive inhibitory effects on TS activity resulting in greater depletion of dTTP pools. Moreover, the incorporation of radiolabeled FdUrd into the DNA fraction of HCT-8 cells was enhanced. The potential importance of this novel combination for human colon cancer chemotherapy is discussed.
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PMID:Enhancement of 5-fluoro-2'-deoxyuridine antineoplastic activity by 5-benzyloxybenzyloxybenzylacyclouridine in a human colon carcinoma cell line. 153 44

We studied the cytotoxicity of arabinosyl-5-azacytosine (Ara-AC), a dCyd antagonist which inhibits DNA synthesis, in combination with 5-fluorouracil (FUra) in two human colon cancer cell lines, HCT 116 and SNU-C4. Clonogenic assays done following sequential or concurrent 24-hr exposures to Ara-AC and FUra showed that the sequence Ara-AC followed by FUra resulted in more than additive lethality in the HCT 116 cell lines and additive lethality in the SNU-C4 cells. In contrast, the reverse sequence, FUra followed by Ara-AC, was antagonistic in both cell lines. A similar interaction between FUra and 1-beta-D-arabinofuranosylcytosine (Ara-C) was evident in HCT 116 cells; at concentrations which individually diminished viability by 34 and 62%, respectively, the sequence Ara-C followed by FUra decreased viability by 97%. Pulse-labeling with [3H]dUrd showed profound inhibition of DNA synthesis by the sequence Ara-AC followed by FUra, with over 90% inhibition lasting for up to 48 hr following Ara-AC exposure. When FUra preceded Ara-AC, however, earlier recovery from inhibition of DNA synthesis occurred. FUra pretreatment did not appreciably alter the quantity or distribution of [3H]Ara-AC or [3H]Ara-C nucleotides after a 4- to 6-hr exposure. Pre-exposure to FUra decreased Ara-AC incorporation into DNA by 37 and 73% at 6 hr in HCT 116 and SNU-C4, respectively. FUra pretreatment also inhibited Ara-C incorporation into DNA by over 50% at 6 and 24 hr. The antagonism of Ara-AC and Ara-C cytotoxicity by FUra pretreatment can thus be explained by diminished incorporation of the dCyd analogs into DNA resulting from inhibition of DNA synthesis by FUra-induced dTTP and dCTP depletion. In contrast, when Ara-AC or Ara-C preceded FUra, their incorporation into DNA was not disturbed, and prolonged inhibition of DNA synthesis was observed.
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PMID:Sequence-dependent interaction of 5-fluorouracil and arabinosyl-5-azacytosine or 1-beta-D-arabinofuranosylcytosine. 171 59

Although 5-fluoro-2'-deoxyuridine (FdUrd) has been combined with hyperfractionated radiation therapy in clinical trials, the optimal method of delivering radiation therapy is not yet known. To determine the importance of the time interval between fractions on the survival of tumor cells exposed to FdUrd, we studied the effect of FdUrd on sublethal damage repair in HT29 human colon cancer cells in culture. Cells were exposed to clinically achievable concentrations of FdUrd (10-100 nM) for 14 hr followed by either single dose (8-12 Gy) or split dose (4-6 Gy x 2) external cobalt irradiation. The interval between radiation fractions was varied from 0.5 to 6 hr. FdUrd impaired sublethal damage repair in a dose dependent fashion. FdUrd had no effect on the induction of DNA double strand breaks (DSB's), but significantly reduced the rate of the repair of DNA DSB's. Exposure to 100 nM FdUrd decreased intracellular TTP pools but elevated dATP pools. These findings suggest that FdUrd may decrease sublethal damage repair by perturbing nucleotide triphosphate pools, which leads to a decrease in the ability of the cell to repair DNA DSB's. Furthermore, they suggest that hyperfractionated irradiation will be superior to once daily treatment when combined with regional delivery of FdUrd.
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PMID:The effect of fluorodeoxyuridine on sublethal damage repair in human colon cancer cells. 183 63

The halogenated pyrimidine, fluorodeoxyuridine (FdUrd), has been used in combination with radiation for the treatment of human neoplasms. In an attempt to improve the clinical use of this combination, FdUrd-radiation interactions were studied in vitro using human HT29 colon cancer cells. It was found that FdUrd produced radiosensitization at clinically achievable (1-100 nM) concentrations. Sensitization depended critically on the timing of exposure. When cells were irradiated after a 12-hr exposure to 100 nM FdUrd, marked sensitization was produced (mean inactivation dose (MID) = 2.01 +/- 0.01, compared to control of 4.35 +/- 0.16, p less than .01). No radiosensitization occurred when cells were irradiated 4 hr prior to incubation (MID = 3.95 +/- 0.05, p greater than 0.4). Radiosensitization appeared to result from an inhibition of thymidylate synthase since concentrations of FdUrd which produced radiosensitization depleted intracellular TTP pools and blocked the incorporation of deoxyuridine into DNA. Furthermore, radiosensitization was completely inhibited by co-incubation with thymidine. FdUrd also decreased the repair, but not the formation, of radiation-induced DNA double strand breaks (DSB's). These data are consistent with the hypothesis that FdUrd produces radiosensitization by depleting thymidine pools which leads to a decreased rate of DNA DSB repair. Furthermore, they suggest that in clinical trials FdUrd should be infused at least 8 hr before irradiation.
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PMID:Fluorodeoxyuridine-induced radiosensitization and inhibition of DNA double strand break repair in human colon cancer cells. 214 70

In HCT 116 cells, a human colon cancer cell line, the levels of thymidine (0.6 microM) and hypoxanthine (9 microM) contributed to the tissue culture medium by the fetal bovine serum significantly reduced the growth inhibition and lethality produced by 0.1 microM methotrexate. Dipyridamole, an inhibitor of nucleoside transport, potentiated the growth inhibitory effects of methotrexate when the cells were grown in medium that was changed daily. However, when the medium was supplemented with dialyzed serum, methotrexate cytotoxicity was not increased by dipyridamole. Similarly, in cloning experiments, dipyridamole increased the cell killing produced by methotrexate. The potentiation of methotrexate toxicity produced by dipyridamole was mediated through inhibition of thymidine uptake. The uptake of 1 microM thymidine was inhibited 50% by 0.12 microM dipyridamole but neither hypoxanthine nor guanine uptake was decreased by dipyridamole (5 microM). As a result, the decrease in dTTP pools produced by methotrexate was augmented by dipyridamole. In contrast, dipyridamole did not influence the effect of methotrexate on ribonucleoside triphosphate pools. HCT 116 cells avidly salvaged low concentrations of thymidine, and methotrexate increased this capacity. Conversion of 0.11 microM thymidine to thymidine triphosphate was increased by 55%, from 16.6 to 25.7 pmoles/10(6) cells, following exposure to 1.0 microM methotrexate. Dipyridamole blocked this pool expansion. This study suggests that the salvage of physiological levels of thymidine may diminish the cytotoxic effects of methotrexate on human colon cancer cells. Inhibition of thymidine uptake by dipyridamole may be an effective strategy to increase the cytotoxicity of methotrexate.
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PMID:Augmentation of methotrexate cytotoxicity in human colon cancer cells achieved through inhibition of thymidine salvage by dipyridamole. 356 84

The effect of dipyridamole (DP), an inhibitor of nucleoside transport, on the uptake and toxicity of 5-fluorouracil (FUra) was examined in a human colon cancer cell line (HCT 116). DP substantially increased the cytotoxicity of FUra in cell growth experiments and in viability assays measuring colony formation. The augmentation by DP was dose and time dependent. Several possible mechanisms by which DP enhanced FUra toxicity were investigated. DP did not alter the uptake of FUra into the acid-soluble and -insoluble fractions of HCT 116 cells. While DP did not affect the uptake of FUra, it did inhibit the transport of the nucleoside analogues, fluorouridine and fluorodeoxyuridine, of FUra. Although DP effectively inhibited the uptake of thymidine and uridine in a dose-dependent manner, several lines of evidence suggested that inhibition of nucleoside salvage was not the critical effect. (a) The toxicity of FUra was not prevented by thymidine, uridine, or the combination of thymidine and uridine. Thymidine triphosphate pools, decreased by 50% during the initial 8 h of exposure to FUra, were not further depleted by the addition of DP. The shrinkage in deoxythymidine triphosphate pools produced by FUra was prevented by concomitant exposure to thymidine; however, this did not translate into protection from FUra lethality. The use of dialyzed serum, which greatly diminished the availability of nucleic acid precursors, did not increase the toxicity of FUra. DP increased the cytotoxicity of FUra as effectively in experiments utilizing dialyzed serum as when nondialyzed serum was used. Surprisingly, however, the addition of sufficient thymidine to overcome the DP block did prevent the augmentation of FUra toxicity produced by DP. DP may provide a novel means of enhancing the cytotoxicity of FUra.
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PMID:Augmentation of 5-fluorouracil cytotoxicity in human colon cancer cells by dipyridamole. 400 34

The mechanism by which dietary cholesterol facilities colon carcinogenesis was investigated in the dimethylhydrazine-induced rat colon cancer model. Fifty female Wistar rats received a standard course of dimethylhydrazine (DMH) injections (40 mg/kg/week subcutaneously for ten weeks) while being fed Vivonex, a cholesterol-free elemental diet. Animals were allocated to one of five dietary regimens. One control group received Vivonex with added cholesterol (10 mg/100 ml Vivonex/rat/day) throughout the experiment, while another group received Vivonex alone. The remaining three groups received added cholesterol exclusively before, during or after the ten week DMH induction period. The experiment continued for over 500 days, and was evaluated by comparing, between groups, the time taken for the development of objective signs of colonic disease (time to tumour presentation or TTP). Animals either died spontaneously or were killed and autopsied. Colon cancers were confirmed histologically in every animal. The results showed that cholesterol feeding throughout the experiment or during the DMH induction period reduced the TTP compared to controls (p less than 0.05). Cholesterol prefeeding had no such effect. In the after group, the TTP was correspondingly delayed (p less than 0.05). Cholesterol-fed controls and groups receiving cholesterol during or after the DMH induction had more colon tumours and/or a greater incidence of metastases than cholesterol-free controls or those pre-fed cholesterol. The findings indicate a direct relationship between timing of cholesterol exposure and signs of colon cancer, and demonstrate that dietary cholesterol has promoter-like characteristics.
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PMID:An investigation into the mechanism of co-carcinogenesis of dietary cholesterol during the induction of colon cancer in rats by 1,2 dimethylhydrazine. 647 81

Thymidylate synthase (TS) is a target of critical importance to the survival of human colon cancer cells since, upon inhibition, cells subsequently undergo thymineless death induced by dTTP deficiency. Using genetically marked mutants deficient in TS (TS-) and a derived population (Thy4) that is resistant to commitment to thymineless death, resistance was conferred by the ability of cells to arrest at a point either in late G1 or at the onset of S induced by dThd deprivation. Thus, Thy4 cells initially synchronized in G0 by leucine deprivation and released in the absence of dThd remained viable at 5 days, demonstrated delayed onset of nucleosomal ladder formation, and retained clonogenic potential (cytostatic response). In contrast, TS- and asynchronous Thy4 cells lost 50% clonogenic potential in 65 h and > 90% in 5 days (cytotoxic response). [3H]DNA precursor studies indicated failure of synchronized Thy4 but not TS- cells to progress through S, with arrest of Thy4 close to the G1/S boundary. Cell cycle control processes including: (a) the locus of dThd deprivation in G1; and (b) a potential checkpoint close to the G1/S border, may dictate whether consequences of dThd or dTTP restriction become cytostatic or cytotoxic.
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PMID:Cell cycle control processes determine cytostasis or cytotoxicity in thymineless death of colon cancer cells. 806 64

Recombinant interferon-alpha (IFN) enhances the cytotoxic effects of the fluorinated pyrimidine, 5-fluorouracil (5FU), against two human colon cancer cell lines. The aspartate transcarbamylase (ATCase) inhibitor, N-(phosphonacetyl)-L-aspartate (PALA), was studied in combination with 5FU/IFN to determine whether further anti-pyrimidine effects would result in greater cytotoxicity. By median effects analysis PALA synergistically augmented the cytotoxic effects of 5FU/IFN against both human colon cancer cell lines. This occurred in the absence of any effects of 5FU/IFN on ATCase and without further potentiation of the PALA-mediated inhibition of ATCase. To explore the mechanism by which this interaction occurred, detailed studies of pools of dNTPs were performed. Both 5FU/IFN and PALA/5FU/IFN treatments resulted in early (2-8 hr) depletion of pools of dTTP, but no effects on pools of dCTP. PALA had no effect on dTTP pools either alone or in the combination. In contrast, both PALA and PALA/5FU/IFN treatments resulted in later (12-24 hr) depletion of pools of dCTP. 5FU/IFN treatment had no effect on these pools. When pools of dCTP and dTTP were repleted by treatment with cytidine or thymidine, 20 microM, however, there was only partial reversal of cytotoxicity induced by 5FU/IFN + PALA, suggesting that the synergy observed did not result solely from a sequential anti-pyrimidine effect. The incorporation of 5FU into RNA was also studied; PALA enhanced the incorporation of [6-3H]5FU into RNA by 83-150%, but not into DNA, suggesting an alternative mechanism of drug interaction.
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PMID:N-(phosphonacetyl)-L-aspartate synergistically enhances the cytotoxicity of 5-fluorouracil/interferon-alpha-2a against human colon cancer cell lines. 824 10

Interferon (IFN) augments the anabolism of 5-fluorouracil (5FU) to its active metabolite, fluorodeoxyuridylate (FdUMP), which inhibits thymidylate synthase (TS). We sought to determine whether this resulted in greater perturbations of nucleotide pools and if so, whether this was associated with an increase in cell lethality, specifically focussing on the lethal cellular lesion, DNA double strand breaks (dsb). To determine whether combination therapy with 5FU + IFN resulted in greater depletion of thymidine nucleotide pools than 5FU alone, a highly sensitive DNA polymerase assay was used. In two human colon cancer cell lines, treatment with 5FU + IFN resulted in a rapid decrease in levels of dTTP by 95%. The addition of IFN to 5FU resulted in greater depletion of dTTP levels over treatment with 5FU alone by up to fourfold, and markedly augmented the dATP/dTTP ratio. The addition of IFN to 5FU had no effect on 5FU-induced perturbations in dCTP, dGTP or dATP pools at 8 and 12 h. Measurement of DNA dsb demonstrated that treatment of HT-29 cells with 10 microM 5FU for 24 h did not increase DNA dsb versus control. The combination of 5FU + 500 U/ml IFN, however, resulted in an increased number of dsb versus both 5FU and untreated control cells (P < 0.01), equivalent to 0.74 +/- 0.12 Gy. The addition of IFN to 5FU resulted in a selective further depletion of pools of dTTP and an increase in the number of DNA dsb versus 5FU treatment alone.
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PMID:Effect of interferon on 5-fluorouracil-induced perturbations in pools of deoxynucleotide triphosphates and DNA strand breaks. 882 94


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