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  • 1990-1994  (5)
  • 1994  (5)
  • 1
    Electronic Resource
    Electronic Resource
    Comparative cytotoxicity of folate-based inhibitors of thymidylate synthase and 5-fluorouracil ± leucovorin in MGH-U1 cells (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 51-56 
    Details
    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
    URL: http://dx.doi.org/10.1007/BF00686111
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
  • 2
    Electronic Resource
    Electronic Resource
    Comparative cytotoxicity of folate-based inhibitors of thymidylate synthase and 5-fluorouracil ± leucovorin in MGH-U1 cells (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 51-56 
    Details
    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
    URL: http://dx.doi.org/10.1007/BF00686111
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 3
    Electronic Resource
    Electronic Resource
    Biochemical effects of folate-based inhibitors of thymidylate synthase in MGH-U1 cells (1994)
    Springer
    Cancer chemotherapy and pharmacology 35 (1994), S. 109-114 
    Details
    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
    URL: http://dx.doi.org/10.1007/BF00686631
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 4
    Electronic Resource
    Electronic Resource
    Biochemical effects of folate-based inhibitors of thymidylate synthase in MGH-U1 cells (1994)
    Springer
    Cancer chemotherapy and pharmacology 35 (1994), S. 109-114 
    Details
    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
    URL: http://dx.doi.org/10.1007/BF00686631
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 5
    Electronic Resource
    Electronic Resource
    Phase II trial of 5-fluorouracil and folinic acid in the treatment of advanced breast cancer (1994)
    Springer
    Breast cancer research and treatment 30 (1994), S. 205-209 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; folinic acid ; 5FU ; metastatic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Standard combination chemotherapy for metastatic breast cancer produces response rates between 30–60% with limited impact on survival. We undertook a phase II trial to determine the activity of 5 fluorouracil (5FU) and folinic acid (FA) in patients with measurable metastatic or recurrent breast cancer who had received no prior chemotherapy. Patients meeting the eligibility criteria received 5FU 370 mg/m2/day and FA 200 mg/m2/day for 5 days repeated every 28 days, toxicity allowing. Response defined by standard criteria was assessed every 8 weeks and toxicity according to WHO criteria was determined on every course. Thirty-three patients were entered on trial. Thirty-two patients were evaluable for response and 33 for toxicity. The dose limiting toxicity was stomatitis with 7/32, 19/32, and 5/32 patients experiencing grade 1, 2, and 3 toxicity. Grades 1 and 2 diarrhea occurred in 17/32 and 11/32 patients respectively. Myelosuppression was not significant. Two complete and 11 partial responses were observed. The overall response rate was 41% (95% CI, 24–58%). Responses were seen in soft tissue and visceral sites. Patients who had received adjuvant chemotherapy more than 6 months prior to receiving 5FU and FA responded also. Six of 29 patients receiving standard combination chemotherapy as second line treatment responded subsequently. We concluded: 1) 5FU and FA is an active combination in the treatment of breast cancer warranting further evaluation in combination with other drugs; 2) the dose-limiting toxicity of stomatitis is tolerable; 3) patients receiving 5FU and FA as first line therapy can respond to conventional combination chemotherapy as second line treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00666065
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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