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  • Folate compounds  (1)
  • Key words 10-Propargyl-10-deazaaminopterin  (1)
  • edatrexate  (1)
  • 1
    Electronic Resource
    Electronic Resource
    Phase I study of the sequential administration of edatrexate and paclitaxel in patients with advanced solid tumors (1999)
    Springer
    Annals of oncology 10 (1999), S. 601-603 
    Details
    ISSN: 1569-8041
    Keywords: chemotherapy ; edatrexate ; paclitaxel ; synergism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: The antifolate edatrexate and the microtubule-stabilizing agent paclitaxel have both demonstrated single-agent activity in lung and breast cancer. In vitro, the sequential combination of edatrexate followed by paclitaxel produced synergistic antitumor effects. This trial was designed to find the maximum tolerated doses of edatrexate and paclitaxel when given every two weeks utilizing this sequential schedule. Patients and methods: Thirty-four patients with solid tumors received edatrexate intravenously on days 1 and 15 and paclitaxel intravenously as a three-hour infusion on days 2 and 16 of each 28-day cycle. Edatrexate was escalated from 40 to 120 mg/m2 and the paclitaxel dose fixed at 135 mg/m2. When the maximum-tolerated dose was not reached, edatrexate was fixed at 120 mg/m2 and paclitaxel escalated to 175 and 210 mg/m2. Results: All 34 patients were assessable. The maximum tolerated doses were 120 mg/m2 of edatrexate and 210 mg/m2 of paclitaxel. Grade 3 myalgia, peripheral neuropathy, leukopenia, and an infusion-related reaction occurred. Eight patients with non-small-cell lung cancer and one with bladder cancer achieved major objective responses. Conclusions: The recommended phase II doses are 120 mg/m2 of edatrexate days 1 and 15 and 175 mg/m2 of paclitaxel as a three-hour infusion days 2 and 16 of a 28 day cycle. These results warrant phase II trials of the combination leading to phase III studies comparing the two drugs to a single agent to confirm the preclinical evidence of synergy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026404812699
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    A new analogue of 10-deazaaminopterin with markedly enhanced curative effects against human tumor xenografts in mice (1998)
    Springer
    Cancer chemotherapy and pharmacology 42 (1998), S. 313-318 
    Details
    ISSN: 1432-0843
    Keywords: Key words 10-Propargyl-10-deazaaminopterin ; Cytotoxicity ; Efficacy ; Human tumors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: These studies sought to evaluate the biochemical and cellular pharmacokinetic properties, cytotoxicity and antitumor efficacy of a new analogue of 10-deaza-aminopterin (PDX) against human tumors. Methods: Studies were conducted with a group of human tumor cell lines in culture examining PDX and other folate analogues as permeants for mediated membrane transport, as inhibitors of dihdrofolate reductase and as substrates for folylpolyglutamate synthetase. These same analogues were examined for their cytotoxicity following a 3-h pulse exposure, in experiments providing a value for IC50. Other studies with these analogues were conducted in nude mice bearing subcutaneously implanted human tumors. Treatment of the mice was initiated 4 days after implantation of the tumor using a schedule of administration of one dose per day for 5 days. The tumors were measured 6 days after cessation of therapy and compared to controls for assessment of response. Results: In the CCRF-CEM cell system, PDX was 2- to 3-fold less effective as an inhibitor of dihydrofolate reductase than aminopterin (AMT), methotrexate (MTX) or edatrexate (EDX) but much more effective as a permeant for one-carbon, reduced folate transport inward (PDX 〉AMT ≃ EDX 〉MTX) and substrate for folylpolyglutamate synthetase (PDX 〉AMT 〉EDX 〉MTX). As predicted by these results, PDX was 15- to 40-fold more cytotoxic than MTX and 3- to 4-fold more cytotoxic than the highly potent EDX following a 3-h pulse exposure in culture of CCRF-CEM cells and cells from a panel of three human breast and two human nonsmall-cell (NSC) lung cancers. The same relative differences were shown for the therapeutic efficacy of these three analogues at equitoxic doses in studies with the human MX-1 and LX-1 tumors and the human A549 NSC lung tumor xenografted in nude mice. On a schedule of qd × 5 given 3–4 days posttransplant, MTX was minimally active (modest tumor growth delay) against all three tumors. EDX was highly active (25–35% complete regressions and 5–10% cures) against the MX-1 and LX-1 tumors but very modestly active (no regressions) against the A549 tumor. In contrast, PDX was even more active (75–85% complete regressions and 25–30% cures) than EDX against the MX-1 and LX-1 tumors and highly active (30% complete regressions and 20% cures) against the A549 tumor. Conclusions: These studies showed significantly enhanced antitumor properties of PDX compared with MTX and EDX. Based upon these results, clinical trials of PDX in patients with metastatic breast and NSC lung cancer appear to be warranted.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050823
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Relationships between carrier-mediated transport of folate compounds by L1210 leukemia cells: Evidence for multiplicity of entry routes with different kinetic properties expressed in plasma membrane vesicles (1983)
    Springer
    The journal of membrane biology 75 (1983), S. 11-20 
    Details
    ISSN: 1432-1424
    Keywords: Folate compounds ; transport multiplicity L1210 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Summary Various independent kinetic criteria for indicating multiplicity of carrier-mediated entry of folate compounds into L1210 cell plasma membrane vesicles are studied. We find a marked inconsistency between values for influxK m andK ix in reciprocal experiments measuring competition between various folate compounds as well as inconsistent effects of transloading shown for 5-formyltetrahydrofolate influx, but not folic acid influx. These results argue strongly against a one-carrier model for transport of folate compounds. The most straightforward interpretation of our data is that two distinct transport systems mediate entry of folate compounds in L1210 plasma membrane vesicles. If a two-carrier model is correct, then our data indicate that one of the carriers has low capacity and high affinity for folate coenzymes and methotrexate. This system is apparently negligible as a transport route for folic acid. Transtimulation of initial influx by substrates of the low capacity system is obtained following transloading with coenzymes but not by transloading with folic acid. Our data indicate that the second folate transport system postulated by the two-carrier model has a low affinity for all the folate compounds studied. Nevertheless, the putative second system is significant, especially for folic acid transport, because it has a much higher capacity than the first transport system. In contrast to the first system, transloading with any of the folate compounds studied had no effect on initial influx mediated by the second folate transport system. The two systems are also differentially inhibited bypCMBS, DIDS and SITS and the influxV max for the high-affinity/low-capacity system was altered in a vesicle preparation derived from a methotrexate resistant L1210 cell line.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01870795
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    Paper (German National Licenses)
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