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  • L1210 cells  (2)
  • 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
    Two-compartment behavior during transport of folate compounds in L1210 cell plasma membrane vesicles (1982)
    Springer
    The journal of membrane biology 68 (1982), S. 19-28 
    Details
    ISSN: 1432-1424
    Keywords: folate transport ; plasma membrane vesicles ; L1210 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Summary The transport of [3H] 1,l 5-formyltetrahydrofolate, [3H] folic acid, and [3H]methotrexate by L1210 cell plasma membrane vesicles exhibited multicompartmental behavior. Two separate vesicular compartments (parallel relationship) of approximately equal volume were revealed during measurements of influx and efflux. Flux in one compartment was rapid, saturable, highly temperature-sensitive, and inhibited by pCMBS. Flux in the other compartment exhibited all of the characteristics of passive diffusion. These results imply that our plasma membrane vesicle preparations consist of a mixture of two functional species. Transport of folate into one of these species occurs by passive diffusion alone, whereas transport into the other kind of vesicle occurs by both passive diffusion and carrier-facilitated transport.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01872250
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    Paper (German National Licenses)
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  • 4
    Electronic Resource
    Electronic Resource
    Effects of metabolic deprivation on methotrexate transport in L1210 leukemia cells: Further evidence for separate influx and efflux systems with different energetic requirements (1984)
    Springer
    The journal of membrane biology 78 (1984), S. 9-17 
    Details
    ISSN: 1432-1424
    Keywords: methotrexate ; transport ; L1210 cells ; nonidentical influx ; efflux routes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Summary Measurements of methotrexate transport in L1210 cells in the presence and absence ofd-glucose reveal that both influx and efflux are depressed in the absence ofd-glucose, whereas the steady-state accumulation of drug is enhanced. The reason for the increase in steady state is that the relative decline in efflux is greater than the decline in influx. Analysis of the concentration dependence of steady-state methotrexate accumulation ind-glucose-deprived cells indicates a linear relationship consistent with a one-carrier active transport model. Similar data in nondeprived cells is highly nonlinear and strongly supports the postulate that under physiological conditions influx and efflux of methotrexate are mediated by separate carrier systems. These results indicate that the efflux system, preferentially transporting methotrexate under normal conditions, cannot operate in the absence ofd-glucose, whereas the influx system is only partially inhibited under conditions of glucose deprivation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01872527
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    Paper (German National Licenses)
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