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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Cancer chemotherapy and pharmacology 30 (1992), S. 370-376 
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Combination of low doses of de novo pyrimidine biosynthesis inhibitors with 5-fluorouracil (FU) has been proposed to increase the antitumor activity of FU. Brequinar is such an inhibitor that has little clinical antitumor effect when used alone. We determined the clonogenic survival of MGH-U1 cells treated with FU±leucovorin (LV)±brequinar and examined the effects of these treatments on thymidylate synthase (TS). After 24 h exposure, the concentrations resulting in 50% inhibition of cell growth (IC50) for brequinar, FU, and FU+LV (100 μm) were 0.4, 20, and 10 μm, respectively. Both 24 h pretreatment and 48 h continuous treatment with the IC10 (0.1 μm) of brequinar increased the cytotoxicity of FU but did not enhance that of FU+LV. Simultaneous 24 h exposure to 0.1 μm brequinar and FU±LV did not increase the cytotoxicity of FU±LV. Intracellular cytidine triphosphate (CTP) and uridine triphosphate (UTP) pools, free TS binding sites, and levels of free fluorodeoxyuridine monophosphate (FdUMP) and deoxyuridine monophosphate (dUMP) were measured in cells pretreated with 0.1 μm brequinar for 24 h alone or followed by a 2-h exposure to FU (25 μm)±LV (100 μm). In brequinar-treated cells, CTP and UTP pools amounted to 68% and 46% of control values, respectively. The free TS binding sites remaining amounted to 70% of control values in cells treated with FU and 9% of control levels in those treated with FU + brequinar. Free FdUMP levels increased 5-fold in cells pretreated with brequinar as compared with those treated with FU alone. The increased formation of FdUMP was inhibited by simultaneous exposure to 100 μm hypoxanthine and 25 μm FU. Intracellular dUMP levels were not affected by brequinar. We conclude that a low dose of brequinar increases the cytotoxicity of FU but does not enhance that of FU+LV when exposure to brequinar precedes FU treatment. This potentiation appears to be mediated by the increased formation of FdUMP as a consequence of an increase in the cosubstrate phosphoribosyl pyrophosphate (PRPP).
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 51-56 
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. Thymidylate synthase (TS) is a critical enzyme in the synthesis of DNA and an important target for cancer chemotherapy. 5-Fluorouracil (5FU) combined with leucovorin (LV) has been used to inhibit TS, and inhibition is dependent on the formation of a ternary complex between a folate cofactor, TS, and 5-fluorodeoxyuridine monophosphate (FdUMP), a metabolite of FU. The folate-based TS inhibitors CB3717, its analogs, and BW1843U89 have been synthesized as specific inhibitors of TS that do not require activation or the presence of a cofactor. We have compared the cytotoxicity of 5FU±LV with that of these folate-based TS inhibitors in human bladder cancer MGH-U1 cells using a colony-forming assay. After a 6-h exposure, FU+LV, CB3717, dCB3717, or C2 methyl dideazafolate analogs demonstrated similar cytotoxic potency that was 0.96 to 2.9 times that of 5FU alone. A 24-h exposure did not increase the potency of 5FU+LV relative to 5FU alone, but there was a marked increase in the cytotoxicity of the dideazafolates as compared with 5FU+LV. Similarly, BW1843U89 was more cytotoxic than 5FU+LV. This was reflected in a 3.2- to 1333-fold decrease in the 50% inhibitory concentration (IC50). Simultaneous exposure to LV and thymidine (TdR) protected MGH-U1 cells from the cytotoxicity of CB3717, its analogs, and BW1843U89. We conclude that (a) the folate-based TS inhibitors are more potent than 5FU+LV after a 24-h exposure, (b) protection by LV and TdR indicates that TS inhibition is the primary site of action, and (c) BW1843U89 is more potent than D1694 in MGH-U1 cells.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 51-56 
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Thymidylate synthase (TS) is a critical enzyme in the synthesis of DNA and an important target for cancer chemotherapy. 5-Fluorouracil (5FU) combined with leucovorin (LV) has been used to inhibit TS, and inhibition is dependent on the formation of a ternary complex between a folate cofactor, TS, and 5-fluorodeoxyuridine monophosphate (FdUMP), a metabolite of FU. The folate-based TS inhibitors CB3717, its analogs, and BW1843U89 have been synthesized as specific inhibitors of TS that do not require activation or the presence of a cofactor. We have compared the cytotoxicity of 5FU ± LV with that of these folate-based TS inhibitors in human bladder cancer MGH-U1 cells using a colony-forming assay. After a 6-h exposure, FU+LV, CB3717, dCB3717, or C2 methyl dideazafolate analogs demonstrated similar cytotoxic potency that was 0.96 to 2.9 times that of 5FU alone. A 24-h exposure did not increase the potency of 5FU+LV relative to 5FU alone, but there was a marked increase in the cytotoxicity of the dideazafolates as compared with 5FU+LV. Similarly, BW1843U89 was more cytotoxic than 5FU+LV. This was reflected in a 3.2- to 1333-fold decrease in the 50% inhibitory concentration (IC50). Simultaneous exposure to LV and thymidine (TdR) protected MGH-U1 cells from the cytotoxicity of CB3717, its analogs, and BW1843U89. We conclude that (a) the folate-based TS inhibitors are more potent than 5FU+LV after a 24-h exposure, (b) protection by LV and TdR indicates that TS inhibition is the primary site of action, and (c) BW1843U89 is more potent than D1694 in MGH-U1 cells.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Cancer chemotherapy and pharmacology 35 (1995), S. 387-390 
    ISSN: 1432-0843
    Keywords: Key words: AZT ; AG-331 ; Thymidylate synthesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  We have reported that noncytotoxic concentrations of 3′-azido-3′-deoxythymidine (AZT) increase the cytotoxicity of ICI D1694, a folate-based thymidylate synthase (TS) inhibitor, with increasing AZT incorporation into DNA. We postulated that the inhibition of TS by ICI D1694 would decrease 5’-deoxythymidine triphosphate (dTTP) pools, which compete with AZT triphosphate (AZT-TP) as a substrate for DNA polymerase. Furthermore, the inhibition of TS would increase the activity of both thymidine kinase (TK) and thymidylate kinase (TdK). Each of these consequences of TS inhibition would favor more incorporation of AZT into DNA. Thus, we reasoned that other TS inhibitors should also result in increased AZT incorporation into DNA and, perhaps, in increased cytotoxicity. N 6-[4-(Morpholinosulfonyl)benzyl]-N 6-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. This potent TS inhibitor causes minimal cytotoxicity in MGH-U1 human bladder cancer cells. A 24-h exposure to 5 μM AG-331 causes almost complete TS inhibition but only 35% cell kill. The combination of AZT and AG-331 in MGH-U1 cells resulted in an enhanced antitumor effect relative to that of each agent alone; 50 μM AZT, noncytotoxic alone, increased the cell kill of induced by AG-331 from 35% to 50%. Biochemical studies of this combination revealed that simultaneous treatment with 5 μM AG-331 plus 1.8 μM [3H]-AZT produced as much as a 68%±7% increase in AZT incorporation into DNA. This observation was associated with an increase in DNA single-strand breaks, measured as comet tail moment, of up to 6.6-fold. These studies support our original premise that TS inhibition favors increased incorporation of AZT into DNA and that the combination causes more cell kill than either drug alone in MGH-U1 cells.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0843
    Keywords: 5-Fluorouracil ; Interferon ; Colorectal cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Modulation of 5-fluorouracil (FUra) using leucovorin (LV) is a standard treatment approach in patients with metastatic colorectal cancer. Modulation of FUra with interferon alfa has also shown some promise. Laboratory data have demonstrated increased cytotoxicity when FUra is combined with both LV and interferon. The current study examined the effects of double modulation of FUra using LV and interferon. Patients with measurable advanced colorectal cancer received bolus FUra 375 mg/m2 plus LV 20 mg/m2 daily for 5 days, repeated every 28 days. Recombinant human interferon alfa-2a, 3 million IU/m2 subcutaneously, was given daily on the days of chemotherapy then three times weekly. There was one complete response and nine partial responses (10/41) seen for an overall response rate of 24% (95% CI 12.0–40.0%). Overall, 70% of patients experienced one or more episodes of nonhematologic toxicity of grade 3 or more. Weight loss was common, with a mean decrease of 2.9 kg over the first two months (P〈0.0001). Improvements in tumor-related symptoms were balanced by increased fatigue and a deterioration in body weight and performance status. There was no evidence of progressive changes in FUra metabolism from interferon usage.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0843
    Keywords: Key words Irinotecan ; Deoxynucleotide pools ; Thymidylate synthase ; Fluoropyrimidines ; Colon cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: To determine the effect of combined treatment with 7-ethyl-10-hydroxycamptothecin (SN-38, the active metabolite of irinotecan) and 5-fluorouracil/folinic acid (5FU/FA) in vitro using HCT-8 human intestinal adenocarcinoma cells. Methods: Cell survival was examined using colony forming assays. Cell cycle distribution before and after treatment was assessed by flow microfluorimetry. Levels of thymidylate synthase (TS) and topoisomerase I (topo I) in untreated and treated cells were determined by immunoblotting. Changes in deoxynucleotide pools were examined by high-performance liquid chromatography. Results: Clonogenic assays revealed that colony formation was decreased by 50% after a 24-h exposure to 8 ± 2 nM SN-38 or 12 ± 3 μM 5FU, the latter being assayed in the presence of 2 μM FA. When treatment with 5FU/FA was followed by SN-38, the cytotoxicity was similar to that observed with 5FU/FA alone. In contrast, when HCT-8 cells were exposed to both agents simultaneously or to SN-38 followed by 5FU/FA, the cytotoxicity was greater than that of SN-38 or 5FU/FA treatment alone. Investigation of the mechanistic basis for this sequence dependence revealed that SN-38 treatment was associated with a dose- and time-dependent decrease in conversion of [5-3H]-2′-deoxyuridine to [3H]-H2O and thymidylate in intact cells. Immunoblotting failed to reveal any decrease in TS protein that could account for the decreased activity. High-performance liquid chromatography revealed that SN-38 treatment was associated with increased levels of the deoxynucleotide dTTP and decreased levels of dUTP. Flow microfluorimetry revealed that a 24-h treatment with 10 nM SN-38 resulted in accumulation of HCT-8 cells in late S and G2 phases of the cell cycle, with a further increase in the G2 fraction during the 24 h after SN-38 removal. Conclusions: These observations are consistent with a model in which SN-38 sequentially induces diminished DNA synthesis, elevated dTTP pools, inhibition of dUMP synthesis and enhanced toxicity of 5FU/FA. Accordingly, sequencing of irinotecan and 5FU/FA might be important in combining these agents into an effective treatment for colorectal cancer.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0843
    Keywords: Key words 5-Fluorouracil ; Interferon ; Colorectal cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Modulation of 5-fluorouracil (FUra) using leucovorin (LV) is a standard treatment approach in patients with metastatic colorectal cancer. Modulation of FUra with interferon alfa has also shown some promise. Laboratory data have demonstrated increased cytotoxicity when FUra is combined with both LV and interferon. The current study examined the effects of double modulation of FUra using LV and interferon.Patients with measurable advanced colorectal cancer received bolus FUra 375 mg/m2 plus LV 20 mg/m2 daily for 5 days, repeated every 28 days. Recombinant human interferon alfa-2a, 3 million IU/m2 subcutaneously, was given daily on the days of chemotherapy then three times weekly. There was one complete response and nine partial responses (10/41) seen for an overall response rate of 24% (95% CI 12.0–40.0%). Overall, 70% of patients experienced one or more episodes of nonhematologic toxicity of grade 3 or more. Weight loss was common, with a mean decrease of 2.9 kg over the first two months (P〈0.0001). Improvements in tumor-related symptoms were balanced by increased fatigue and a deterioration in body weight and performance status. There was no evidence of progressive changes in FUra metabolism from interferon usage.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The disposition of total and ultrafilterable cisplatin was determined in 12 women with ovarian carcinoma receiving cyclophosphamide 500 mg/m2, adriamycin 50 mg/m2 and cisplatin 50 mg/m2 during their first and second course. Plasma samples were obtained over 96 h following the completion of the cisplatin infusion and assayed for total platinum by atomic absorption spectroscopy. Plasma samples obtained up to 4 h after cisplatin infusion contained measurable ultrafilterable (free) cisplatin. The mean disposition of free cisplatin conformed to a two-compartment model with a mean terminal half-life (±SD) of 46.2±20.2 min during the first course and 37.8±18.0 min during the second course of therapy. The mean disposition of total cisplatin conformed to a three-compartment model with a mean terminal half-life (±SD) of 57.8±19.3 h during the first course and 86.6±33.3 h during the second course of therapy. We found that the mean total cisplatin levels were significantly higher during the second course than the first course and the total body clearance of total platinum decreased from the first to the second course. Divided urine collections were obtained over 24 h after completion of cisplatin infusion, but cisplatin was not always detectable at all time intervals. The total fraction recovered was 0.14 and 0.12 of administered dose after the first and the second course, respectively. Renal clearance was 0.61±0.32 l/h/m2 and 0.45±0.16 l/h/m2 for the first and the second course, respectively. We conclude that: (1) urinary platinum excretion is variable between patients and with time; (2) a trend to decreased renal clearance of platinum from first to second course may be due to a decrease in renal excretion of cisplatin; and (3) the body's elimination pathways clear less platinum upon repeat administration.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Cancer chemotherapy and pharmacology 35 (1994), S. 109-114 
    ISSN: 1432-0843
    Keywords: Key words Thymidylate synthase ; Inhibitors ; Antifolate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The TS-inhibitory effects induced by a 24-h exposure to the folate-based TS inhibitors CB3717, C2-desamino analogs of CB3717 including D1694, and BW1843U89 were quantitated using the MGH-U1 human bladder carcinoma. The effects of D1694 on the time course of TS inhibition and on intracellular deoxyuridine monophosphate (dUMP) accumulation and deoxyuridine (dUrd) production were evaluated. D1694 and BW1843U89 were the most active TS inhibitors with IC50 values of 2.4 and 0.5 nM, respectively. The C2-desamino C2-methyl dideazafolates were 27–292 times more potent than the parent CB3717 as TS inhibitors. A methyl group at the C2 position of CB3717 had the most dramatic effect, whereas a thiazole substitution for a benzyl added a small benefit and N10 substitution had a limited impact on TS-inhibitory potency and clonogenic survival. There was a significant correlation between the IC50 values for TS inhibition and those for cytotoxic potency obtained for these drugs. LV and thymidine protected cells from these folate-based TS inhibitors. Intracellular dUMP levels following 24 h D1694 (IC50) exposure increased 7-fold. Levels of dUrd effluxing into the media increased up to 4.5 μM following a 24-h exposure to D1694 (IC90). We conclude that (a) C2-desamino C2-methyl dideazafolates are potent TS inhibitors, (b) TS inhibition requires prolonged exposure with these folate TS inhibitors, (c) survival is correlated with inhibition of TS for the folate-based TS inhibitors and (d) the biochemical consequences of TS inhibition include increased dUMP and dUrd levels.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Cancer chemotherapy and pharmacology 35 (1994), S. 109-114 
    ISSN: 1432-0843
    Keywords: Thymidylate synthase ; Inhibitors ; Antifolate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The TS-inhibitory effects induced by a 24-h exposure to the folate-based TS inhibitors CB3717, C2-desamino analogs of CB3717 including D1694, and BW1843U89 were quantitated using the MGH-U1 human bladder carcinoma. The effects of D1694 on the time course of TS inhibition and on intracellular deoxyuridine monophosphate (dUMP) accumulation and deoxyuridine (dUrd) production were evaluated. D1694 and BW1843U89 were the most active TS inhibitors with IC50 values of 2.4 and 0.5 nM, respectively. The C2-desamino C2-methyl dideazafolates were 27–292 times more potent than the parent CB3717 as TS inhibitors. A methyl group at the C2 position of CB3717 had the most dramatic effect, whereas a thiazole substitution for a benzyl added a small benefit and N10 substitution had a limited impact on TS-inhibitory potency and clonogenic survival. There was a significant correlation between the IC50 values for TS inhibition and those for cytotoxic potency obtained for these drugs. LV and thymidine protected cells from these folate-based TS inhibitors. Intracellular dUMP levels following 24 h D1694 (IC50) exposure increased 7-fold. Levels of dUrd effluxing into the media increased up to 4.5 μM following a 24-h exposure to D1694 (IC90). We conclude that (a) C2-desamino C2-methyl dideazafolates are potent TS inhibitors, (b) TS inhibition requires prolonged exposure with these folate TS inhibitors, (c) survival is correlated with inhibition of TS for the folate-based TS inhibitors and (d) the biochemical consequences of TS inhibition include increased dUMP and dUrd levels.
    Type of Medium: Electronic Resource
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