UMLS:C0699790 - FACTA Search

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

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.
...
PMID:Enhancement of 5-fluoro-2'-deoxyuridine antineoplastic activity by 5-benzyloxybenzyloxybenzylacyclouridine in a human colon carcinoma cell line. 153 44

The fluoropyrimidines fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd) have shown activity in a variety of malignancies. Nevertheless, even in initially responsive tumors, the development of resistance is a frequent problem. To understand the biochemical basis for acquired resistance, two pairs of cell lines were investigated. MCF7/Adr cells were obtained from the breast cancer cell line MCF7 by incubation with increasing concentrations of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH). These cells are resistant to Adriamycin (200- to 600-fold) and cross-resistant to 5-FU (25-fold) and FdUrd (67-fold). The resistant cells showed significantly increased levels of thymidylate synthase, the target enzyme of the fluoropyrimidines' active metabolite, 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP). Other biochemical characteristics, including folate pools, drug uptake, metabolism, and retention, were unchanged. Fd9XR cells have been selected from a human colon cancer cell line (HCT-8) by exposure to FdUrd. These cells are resistant to FdUrd (1,000-fold) but not 5-FU. Biochemical evaluations show that the resistant cells are deficient of thymidine kinase and are thus unable to convert FdUrd to FdUMP. This understanding of the various biochemical mechanisms is essential for the design of specific modulations to overcome resistance to fluoropyrimidines.
...
PMID:Mechanisms of resistance to fluoropyrimidines. 153 73

Leucovorin and interferon are capable of modulating the cytotoxicity of fluorouracil (5-FU). Preclinical studies demonstrate that d,l-leucovorin is rapidly metabolized in human breast and colon cells into the various one-carbon substituted folate pools and to the polyglutamated state. While increases in intracellular folate pools are proportional to the exposure concentration of leucovorin, relatively large increases in leucovorin concentrations (50- to 100-fold) are required to produce small intracellular changes (twofold). Polyglutamation is favored by prolonged exposures to leucovorin. Polyglutamate forms have a prolonged intracellular retention and a higher affinity for the target enzyme, thymidylate synthase. Ratios of up to 20:1 inactive to active leucovorin stereo-isomers had essentially no effect on the intracellular metabolism of the active isomer. Interferon gamma interacts with 5-FU in H630 colon cancer cells at the level of thymidylate synthase and enhances cytotoxicity of 5-FU by eliminating the 5-FU-induced acute overexpression of the target enzyme. No alterations in the intracellular metabolism or nucleic acid incorporation of 5-FU could be demonstrated with the addition of interferon gamma. A clinical trial combining interferon-alfa-2a (IFN-alpha-2a) (subcutaneous days 1 to 7) with 5-FU and leucovorin (given IV days 2 to 6) demonstrated that these agents could be combined with acceptable toxicity. While the addition of interferon did not allow dose escalation of 5-FU, it resulted in a significant increase in drug exposure (1.5-fold) compared with matched cycles of 5-FU plus leucovorin without interferon. The overall response rate in this pilot study of 13 untreated patients with gastrointestinal adenocarcinoma was 46%, including two complete responses. There were no responses in eight patients who had previously failed therapy with 5-FU.
...
PMID:Biochemical modulation of fluorouracil with leucovorin and interferon: preclinical and clinical investigations. 155 56

Although the thymidine analogues 5-bromo-2'-deoxyuridine (BrdUrd) and 5-iodo-2'-deoxyuridine (IdUrd) have been used successfully as radiation sensitizers in clinical trials, it is not clear which of these agents is the more promising to pursue. To begin to assess this question with regard to colorectal cancer metastatic to the liver, a study was carried out using HT29 human colon cancer cells in culture and implanted in nude mice as xenografts. Cells and animals were treated with BrdUrd +/- the thymidylate synthase inhibitor 5-fluoro-2'-deoxyuridine (FdUrd), and the results compared to our previous studies with IdUrd +/- FdUrd (T. S. Lawrence, M. A. Davis, P. E. McKeever, J. Maybaum, P. L. Stetson, D. P. Normolle, and W. D. Ensminger. Cancer Res., 51: 3900-3905, 1991). Using cultured cells, it was found that FdUrd (at concentrations of greater than 10 nM) increased: (a) the incorporation of BrdUrd into the DNA of cultured tumor cells; (b) BrdUrd-mediated radiosensitization; (c) BrdUrd-mediated increase in radiation-induced DNA damage; and (d) BrdUrd-mediated decrease in the repair of radiation-induced damage. The incorporation of BrdUrd was greater than or equal to the incorporation of IdUrd previously determined under the same exposure conditions. Studies using nude mice bearing HT29 xenografts showed that FdUrd increased BrdUrd incorporation more into tumors than into the normal liver. Most tumor cells incorporated BrdUrd (labeling index after a 4-day infusion = 87 +/- 2%; SE); in the liver, labeling was confined chiefly to nonparenchymal cells. In both the presence and absence of FdUrd, the incorporation of BrdUrd into tumors was significantly and consistently greater than the incorporation of IdUrd measured under the same conditions of drug administration (by a factor of 1.2-3.6). Furthermore, the administration of BrdUrd +/- FdUrd tended to produce less weight loss and hematological toxicity than IdUrd +/- FdUrd. These findings suggest that BrdUrd may be superior to IdUrd as a radiation sensitizer in the treatment of colorectal cancer metastatic to the liver.
...
PMID:The potential superiority of bromodeoxyuridine to iododeoxyuridine as a radiation sensitizer in the treatment of colorectal cancer. 161 42

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.
...
PMID:Induction of thymidylate synthase associated with multidrug resistance in human breast and colon cancer cell lines. 170 99

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.
...
PMID:Fluorodeoxyuridine-induced radiosensitization and inhibition of DNA double strand break repair in human colon cancer cells. 214 70

Reduced folates have been shown to increase the cytotoxicity of 5-fluorouracil (FUra) by stabilizing the fluorodeoxyuridine monophosphate:thymidylate synthase complex, thus increasing the block in the DNA synthetic pathway. Using an in vitro tetrazolium colorimetric (MTT) cytotoxic assay, we tested the effects of FUra and 5-fluorodeoxyuridine (FUdR) with and without leucovorin (LV) on a panel of 7 human lung cancer cell lines. LV at a concentration of 20 microM enhanced the cytotoxicity of FUra and of FUdR in all of the cell lines. Quantitatively, LV had a higher degree of enhancement on FUdR than on FUra cytotoxicity in 6 cell lines. There was equivalent enhancement in the only remaining line. The differential effects of LV on the cytotoxicity of FUra vs. FUdR in these lung carcinoma lines contrasts with a quantitatively similar enhancement of cytotoxicity between FUra and FUdR in colon cancer lines previously reported from our laboratory. This suggests that the metabolism of FUra may be different in these lung cancer cell lines.
...
PMID:Enhancement of fluorinated pyrimidine-induced cytotoxicity by leucovorin in human lung cancer cell lines. 216 87

Preliminary in vitro studies suggest that the combination of 5-fluorouracil (FUra) and 3'-azido-3'-deoxythymidine (AZT) is more cytotoxic than either agent alone. Therefore, a biochemical and therapeutic evaluation of this combination was initiated. Quantitation of the cytotoxicity of FUra plus AZT against the growth of HCT-8 cells in vitro revealed that 1 microM FUra (approximately 10% inhibitory concentration) increased the cytotoxicity of AZT and decreased its 50% inhibitory concentration by 60%. Similarly, incubating HCT-8 cells in 5 microM AZT (approximately 10% inhibitory concentration) decreased the 50% inhibitory concentration of FUra by over 50%. Biochemical analysis indicated that AZT did not affect FUra-induced inhibition of thymidylate synthase or [3H]-FUra incorporation into nucleic acids. In contrast, incubation in 5 microM FUra increased the incorporation of [3H]-AZT (5 microM) into the nucleic acid fraction of these cells by 52% (P less than 0.05). Therapeutic evaluation of this combination in athymic (nude) mice bearing HCT-8 xenographs revealed that, while weekly FUra (85 mg/kg) or AZT (600 mg/kg) exerts minimal antineoplastic activity (after 4 courses, treatment/control = 0.81 and 0.70, respectively), their combination, at the same doses, inhibited tumor growth by nearly 70% (P less than 0.01 versus FUra alone). FUra-related host toxicity was not increased by the addition of AZT. Higher doses of FUra alone were not more effective than FUra plus AZT. In vivo, AZT did not affect the incorporation of [3H]-FUra into the nucleic acid fraction of various murine tissues, including HCT-8 xenografts. FUra, however, increased [3H]-AZT incorporation into nucleic acids in a tissue-specific manner. In the presence of FUra, the incorporation of [3H]-AZT in spleen, liver, and gut increased 40, 21, and 4%, respectively, while in HCT-8 xenografts [3H]-AZT incorporation increased more than 2-fold. Analysis of the activities of selected enzymes involved in pyrimidine metabolism suggests that this tissue-specific effect may be related to the pyrimidine salvage capacity of these tissues. These findings are described in light of their potential impact on human colon cancer chemotherapy.
...
PMID:5-Fluorouracil enhances azidothymidine cytotoxicity: in vitro, in vivo, and biochemical studies. 235 52

Fluorouracil (Adrucil) has been used for more than 20 years to treat metastatic colorectal carcinoma and has provided significant palliation of symptoms to some patients. Investigators are attempting to exploit pharmacologic aspects of fluorouracil that will provide further benefits. Prolonged infusion of the drug appears to overcome the problems of its brief half-life and the small percentage of cancer cells that are susceptible to the drug at any one time. The addition of leucovorin increases fluorouracil's ability to inhibit thymidylate synthase and thus colon cancer cell replication. It is hoped that the increased response rates produced by these advances will produce increased survival rates as well.
...
PMID:Treatment of metastatic colorectal carcinoma. Recent advances in use of fluorouracil. 281 19

Inhibition of thymidylate synthase (TS) may increase incorporation of thymidine analogues into DNA, leading to increased inhibition of colony formation in tumor cells. We have reported previously that TS inhibition by N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6,-ylmethyl)-N -methylamino]-2 - thenoyl)-L-glutamic acid (ICI D1694 or Tomudex), a folate-based TS inhibitor, increases the cytotoxicity of iododeoxyuridine (IdUrd), a thymidine analogue, in MGH-U1 human bladder and HCT-8 human colon cancer cells. N6-[4-(Morpholinosulfonyl)benzyl]-N6-methyl-2,6-diaminobenz[ cd]-indole glucuronate (AG-331) differs from ICI D1694 in that it is a de novo designed lipophilic TS inhibitor, it does not require a specific carrier for cellular uptake, and it does not undergo intracellular polyglutamation. Exposure of MGH-U1 cells to 5 microM AG-331 for 24 hr decreased clonogenic survival by 30%, but almost completely inhibited TS activity. IdUrd is a cytotoxic thymidine analogue, with IC50 and IC90 values after 24-hr exposures in MGH-U1 cells of 13 and 81 microM, respectively. The combination of IdUrd and AG-331 resulted in an enhanced antitumor effect, as compared with the effect of either agent alone. The cytotoxic IC50 of IdUrd decreased from 13 to 1.5 microM, and the IC90 decreased from 81 to 5 microM with the addition of 5 microM AG-331. Biochemical studies of the combination revealed that pretreating MGH-U1 cells with 5 microM AG-331 increased IdUrd incorporation into cellular DNA by 3.8-fold. This increased incorporation was associated with a greater proportion of DNA single-strand breaks than observed with either agent alone, and the combination of 5 microM AG-331 plus IdUrd produced up to a 2.5-fold increase in DNA single-strand breaks as compared with IdUrd alone. The effects of AG-331, IdUrd, and the combination of IdUrd and AG-331 on the colony-forming ability of normal human bone marrow CFU-GM cells was determined as a measure of myelosuppression. The combination of IdUrd and AG-331, at the same concentrations as those used in the MGH-U1 cells, produced a wider therapeutic index relative to that of IdUrd alone, and the therapeutic index for the combination was 6.5, as compared with 4.0 for IdUrd plus ICI D1694 in previous studies from this laboratory. These observations suggest that the combination of IdUrd and AG-331 may enhance antitumor effects with minimal myelosuppression in vivo.
...
PMID:Biochemical modulation of iododeoxyuridine by N6-[4-(morpholinosulfonyl)benzyl]-N6-methyl-2,6-diaminobenz[cd]indole glucuronate (AG-331) leading to enhanced cytotoxicity. 760 45

1 2 3 4 5 6 7 8 9 10 Next >>