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  • 1
    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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  • 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 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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  • 4
    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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  • 5
    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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