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Joseph R. Bertino - One of the best experts on this subject based on the ideXlab platform.
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intrinsic and acquired resistance to methotrexate in acute leukemia
1996Co-Authors: Richard Gorlick, Debabrata Banerjee, Erdem Goker, Mark Waltham, Tanya M Trippett, Joseph R. BertinoAbstract:Methotrexate, a folic acid antagonist, is used extensively not only for the treatment of cancer but also for the treatment of rheumatoid arthritis, psoriasis, and autoimmune disease and for the prevention of graft-versus-host disease after transplantation. The drug is also used as an abortifacient.1,2 Other folate antagonists are used to treat bacterial infections (trimethoprim), malaria (pyrimethamine), and Pneumocystis carinii infection (Trimetrexate with leucovorin).3,4 As with other drugs used to treat infectious diseases or cancers, the development of resistance limits the effectiveness of these folate antagonists. An understanding of the mechanisms of resistance to this class of drugs is . . .
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a phase ii study of continuous infusion of Trimetrexate in patients with refractory acute leukemia
1995Co-Authors: A Kheradpour, Ellin Berman, Erdem Goker, James T Lin, William P Tong, Joseph R. BertinoAbstract:Trimetrexate, a second-generation folate antagonist, is a potent inhibitor of dihydrofolate reductase with a broader spectrum of activity and different mechanism of entry and intracellular accumulation than methotrexate. Six patients with refractory or relapsed acute leukemia were treated with a 5-day continuous infusion of Trimetrexate of 8 mg/m2 /day after an initial loading dose of 4 mg/m2 to achieve a target plasma concentration of 0.2–0.5 μM. In 4 patients with peripheral blasts at study entry, transient decrease or disappearance of blasts was observed, although no decrease of bone marrow blasts occurred. Mucositis was dose-limiting and severe in 4 patients. Neutrophil and platelet nadirs occurred on day 5–12 postinfusion. Because of dose-limiting mucositis, this dose schedule of Trimetrexate is not recommended for further studies in refractory acute leukemia. However, other dose schedules (24– to 72-hr infusions) and its use as a modulating agent with thiopurines or leucovorin in patients that are r...
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inability of leucovorin to rescue a naturally methotrexate resistant human soft tissue sarcoma cell line from Trimetrexate cytotoxicity
1992Co-Authors: Joseph R. BertinoAbstract:Abstract A human lymphoblastoid line (RPMI-1788), a methotrexate-sensitive human fibrosarcoma cell line (HT-1080), and a naturally resistant mixed mesodermal human sarcoma cell line with impaired methotrexate polyglutamylation (HS-42), recently established in our laboratory, were used to compare the ability of leucovorin to prevent Trimetrexate cytotoxicity. Growth inhibition and an in situ thymidylate synthesis activity assay showed that inhibitory effects of Trimetrexate (1 to 10 µ m), 24-h exposure, were prevented by 10 µ m leucovorin in the RPMI-1788 and HT-1080 cell lines but not in the HS-42 cell line. Total intracellular reduced folates increased about 2-fold in the three cell lines after exposure to leucovorin (10 µ m) for 4 h, and after a 6-hour efflux remained elevated (1.5- and 1.3-fold of control levels) in RPMI-1788 and HT-1080 cells but decreased to 80% of control levels in HS-42 cells. Although uptake of leucovorin and levels of N 5 , N 10 -methylenetetrahy-drofolate achieved after leucovorin administration were similar in RP-MI-1788 and HS-42 cells, polyglutamylate forms of this coenzyme were less in the HS-42 cells as compared to RPMI-1788 cells. Based on these studies, the combination of Trimetrexate with leucovorin should be further investigated as a way to increase the therapeutic index in some patients with soft tissue sarcomas. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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MOLECULAR PHARMACOLOGY, 44:13-21 Mutations Leading to Antifolate Resistance in Chinese Hamster Ovary Cells after Exposure to the Alkylating Agent
1992Co-Authors: Renato Fanin, Debabrata Banerjee, Matthias Volkenandt, Mark Waltham, Adam P. Dicker, Barry I. Schweitzer, Joseph R. BertinoAbstract:Chinese hamster ovary cells with a single allele for dihydrofolate reductase were used as a model system to study the effect of exposure to an alkylating agent, ethylmethanesulfonate, on rates and types of mutations at the dihydrofolate reductase locus leading to antifolate resistance. After overnight exposure to 400,g/ml ethylmethanesulfonate, cells were allowed to recover for 3 days, and resistant colonies were selected in 8 x 10_8 M tnmetrexate. Trimetrexate, rather than methotrexate, was used as the selecting agent to increase the probability of obtaining mutations in dihydrofolate reductase, rather than in the reduced folate transport carrier protein. Seven of several hundred surviv-ing colonies were selected at random, and cell lines were estab-lished. Cell lines 1-3 were maintained in culture in the presence of 8 x 1 0-8 M Trimetrexate and were 66-1 70-fold resistant to the drug. Cell lines 4-7 were initially expanded in 8 x 1 0_8 M Trimetrexate but were then maintained in the absence of th
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Copyright Cby The American S(iclety for Pharmaciilogv and Experimental Therapeutics All rights of reproduction in any form reserved. MOLECULAR PHARMA(OL0(;Y, 40:854-858 Mechanisms of Sensitivity and Natural Resistance to Antifolates in a Methylcholanthren
1991Co-Authors: James T Lin, Barry I. Schweitzer, Joseph R. BertinoAbstract:A methylcholanthrene-induced rat sarcoma that can be propa- studies showed poor uptake of both methotrexate and 10-ethyl-gated in vitro or in vivo was evaluated for resistance to antifolates 1 0-deazaaminopterin. In contrast, Trimetrexate achieved high and was found to be relatively resistant to methotrexate and 1 0- intracellular levels. The poor uptake of methotrexate was not ethyl-i 0-deazaaminopterin but sensitive to Trimetrexate. Rat sar- due to lack of polyglutamylation. Thus, the basis for natural coma cell extracts contained low levels of dihydrofolate reduc- resistance to methotrexate and 10-ethyl-i 0-deazaaminopterin, tase activity, the target enzyme of methotrexate, and inhibition compared with Trimetrexate, in this rat sarcoma cell line was due of this enzyme by these three antifolates was similar. Transport to decreased transport of these drugs. MTX is used to treat acute lymphocytic leukemias, diffuse of sensitivity to MTX. This tumor can be propagated both in lymphomas, head and neck cancer, breast cancer, and osteo- vivo and in vitro, thus allowing the opportunity to compare genic sarcoma but has little activity against soft tissue sarcoma. results obtained in cells from both conditions. The data pre-Acquired resistance to MTX has been reported to be due to sented in this paper indicate that this rat sarcoma is relatively one or more of five mechanisms, 1) increase in DHFR due to resistant to MTX and lO-EDAM, as a consequence of poor gene amplification (1-3), 2) an alteration in DHFR resulting uptake ofthese drugs, whereas it is sensitive to TMTX because in decreased binding of MTX (4, 5), 3) decreased thymidylate of the high intracellular drug levels achieved. synthase activity (6), 4) reduced formation of MTX polygluta
Sherry F. Queener - One of the best experts on this subject based on the ideXlab platform.
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design synthesis computational prediction and biological evaluation of ester soft drugs as inhibitors of dihydrofolate reductase from pneumocystis carinii
2001Co-Authors: Malin Graffnernordberg, Sherry F. Queener, Karin Kolmodin, Johan Aqvist, Anders HallbergAbstract:A series of lipophilic soft drugs structurally related to the nonclassical dihydrofolate reductase (DHFR) inhibitors Trimetrexate and piritrexim have been designed, synthesized, and evaluated in DHFR assays, with special emphasis on the inhibition of P. carinii DHFR. The best inhibitors, encompassing an ester bond in the bridge connecting the two aromatic systems, were approximately 10 times less potent than Trimetrexate and piritrexim. The metabolites were designed to be poor inhibitors. Furthermore, molecular dynamics simulations of three ligands in complex with DHFR from Pneumocystis carinii and from the human enzyme were conducted in order to better understand the factors determining the selectivity. A correct ranking of the relative inhibition of DHFR was achieved utilizing the linear interaction energy method. The soft drugs are intended for local administration. One representative ester was selected for a pharmacokinetic study in rats where it was found to undergo fast metabolic degradation to the predicted inactive metabolites.
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lipophilic antifolates as agents against opportunistic infections 1 agents superior to Trimetrexate and piritrexim against toxoplasma gondii and pneumocystis carinii in in vitro evaluations
1996Co-Authors: James R Piper, Sherry F. Queener, Cheryl A Johnson, Charles A Krauth, Ronald L Carter, Carla A Hosmer, Susan E Borotz, E R PfefferkornAbstract:2,4-Diaminopteridines (21 compounds) and 2,4-diamino-5-methyl-5-deazapteridines (34 compounds) along with three 2,4-diamino-5-unsubstituted-5-deazapteridines and four 2,4-diaminoquinazolines, each with an aryl group attached to the 6-position of the heterocyclic moiety through a two-atom bridge (either CH 2 NH, CH 2 N(CH 3 ), CH 2 S, or CH 2 CH 2 ), were synthesized and evaluated as inhibitors of the growth of Toxoplasma gondii in culture and as inhibitors of dihydrofolate reductase enzymes from T. gondii, Pneumocystis carinii, and rat liver. Exceptionally high levels of combined potency and selectivity as growth inhibitors of T. gondii and as inhibitors of the microbial enzymes relative to the mammalian enzyme were found among the 5-methyl-5-deazapteridines but not for the other heterocyclic types. Thirty of the 34 5-methyl-5-deaza compounds gave growth inhibition IC 50 values lower than that of pyrimethamine (0.4 μM) with 14 compounds below 0.1 μM, values that compare favorably with those for piritrexim and Trimetrexate (both near 0.02 μM). As inhibitors of T. gondii DHFR, all but three of the 34 5-methyl-5-deaza compounds gave IC 50 values in the order of magnitude with those of piritrexim (0.017 μM) and Trimetrexate (0.010 μM), and 17 compounds of this group gave IC 50 values versus P. carinii DHFR similarly comparable with those of piritrexim (0.031 μM) and Trimetrexate (0.042 μM). Thirteen of these congeners gave both T. gondii growth inhibition and DHFR inhibition IC 50 values of 0.10 μM or less, thus indicating facile penetration of the cell membrane. Eleven of these inhibitors of both T. gondii growth and DHFR have selectivity ratios (IC 50 rat liver divided by IC 50 T. gondii) of 5 or greater for the parasite DHFR. The highest selectivity ratio of nearly 100 belongs to the 5-methyl-5-deaza compound whose 6-substituent is CH2CH2C6H3(OCH3)2-2,5. This compound is over 10 3 -fold more selective for T. gondii DHFR than bridge homologue piritrexim (selectivity ratio 0.088), a compound now in clinical trials. The candidate with CH 2 NHC 6 H 3 (CH 3 ) 2 -2,5 in the 6-position gave the highest P. carinii DHFR selectivity ratio of 4.0, which is about 60-fold more selective than Trimetrexate (0.071) and 80-fold more selective than piritrexim (0.048) toward this enzyme. The 10 best compounds with respect to potency and selectivity includes six compounds bearing 2,5-disubstituted phenyl groups in the side chain (with little, if any, difference in effects of methyl, methoxy, or ethoxy), two side chains bearing 1-naphthyl groups, and two with 5,6,7,8-tetrahydro-1-naphthyl groups. Bridge groups represented in the 10 choice compounds are CH 2 NH, CH 2 N(CH 3 ), CH 2 CH 2 , and CH 2 S. The high levels of both potency and selectivity among these agents suggest that in vivo studies now underway may lead to agents that could replace Trimetrexate and piritrexim in treatment of toxoplasmosis and P. carinii pneumonia.
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Pneumocystis carinii dihydrofolate reductase used to screen potential antipneumocystis drugs.
1991Co-Authors: M. C. Broughton, Sherry F. QueenerAbstract:Pneumocystis carinii was obtained in high yield from the lungs of immunosuppressed rats by rupturing mammalian host cells, washing away the soluble mammalian dihydrofolate reductase, and harvesting intact organisms in association with the mammalian plasma membranes. P. carinii dihydrofolate reductase, measured in the 100,000 x g supernatant from sonicated organisms, was obtained in yields ranging up to 62 IU per rat. The enzyme prepared in the presence of protease inhibitors was stable when frozen in liquid nitrogen. P. carinii dihydrofolate reductase differed from the mammalian enzyme in that the former was slightly inhibited by 150 mM KCl, whereas the latter was stimulated over twofold by 150 mM KCl. The standard assay for P. carinii dihydrofolate reductase contained 0.12 mM NADPH and 92 microM dihydrofolic acid. Under these conditions, the 50% inhibitory concentrations of the known inhibitors trimethoprim, Trimetrexate, and pyrimethamine were 12 microM, 42 nM, and 3.8 microM, respectively. These standard compounds were also tested against dihydrofolate reductase from rat liver to allow an assessment of the selectivity of the drugs. Although it was the least potent, trimethoprim was the most selective. Pyrimethamine was more potent but was nonselective. Trimetrexate was extremely potent but was selective for mammalian dihydrofolate reductase. A series of experimental compounds was obtained from the National Cancer Institute and other sources through the Developmental Therapeutics Branch of the Division of AIDS at the National Institute of Allergy and Infectious Diseases. Among the first 87 compounds tested, 11 had 50% inhibitory concentrations below that of Trimetrexate and 3 were more selective than trimethoprim. The most promising compounds in this original group were chemically related to methotrexate.
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Inhibition of Pneumocystis dihydrofolate reductase by analogs of pyrimethamine, methotrexate and Trimetrexate.
1991Co-Authors: Sherry F. QueenerAbstract:Dihydrofolate reductase was obtained from Pneumocystis carinii isolated from heavily infected lungs of female Sprague-Dawley rats infected by transtracheal inoculation. The enzyme differed significantly from other forms of dihydrofolate reductase in response to KCl and to antifolate drugs. Dihydrofolate reductase from P. carinii was used to assess activity of analogs of pyrimethamine, methotrexate, and Trimetrexate. One pyrimethamine analog was selective for P. carinii dihydrofolate reductase; potency was in the micromolar range. In contrast, 21 methotrexate analogs and 2 Trimetrexate analogs were selective for P. carinii dihydrofolate reductase; potencies for these were in the nanomolar range.
Charles D Blanke - One of the best experts on this subject based on the ideXlab platform.
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s9511 a southwest oncology group phase ii study of Trimetrexate 5 fluorouracil and leucovorin in unresectable or metastatic adenocarcinoma of the stomach
2009Co-Authors: Charles D Blanke, James L Abbruzzese, Kari Chansky, Kathy L Christman, Scott A Hundahl, Brian F Issell, Peter J Van Veldhuizen, Thomas G Budd, John S MacdonaldAbstract:Objective The primary objective of this trial was to evaluate the response rate for Trimetrexate (TMTX) in conjunction with 5FU and leucovorin (LV) (=TFL) in the treatment of advanced gastric cancer in a phase II, cooperative group setting.
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phase ii study of Trimetrexate fluorouracil and leucovorin for advanced colorectal cancer
1997Co-Authors: Charles D Blanke, B Kasimis, P Schein, R Capizzi, M KurmanAbstract:PURPOSEA phase II study to evaluate the response rate and toxicities of a Trimetrexate, fluorouracil (5FU), and leucovorin regimen in patients with advanced incurable colorectal cancer.PATIENTS AND METHODSThirty-six patients with unresectable or metastatic colorectal cancer who had not been treated for advanced disease received the following chemotherapy regimen weekly for six courses every 8 weeks: Trimetrexate 110 mg/m2 intravenously (I.V.) on day 1, leucovorin 200 mg/m2 I.V. on day 2 (24 hours later), 5FU 500 mg/m2 on day 2 immediately following leucovorin, and oral leucovorin 15 mg every 6 hours for seven doses starting 6 hours after 5FU. Patients were treated until progression or unacceptable toxicity.RESULTSThirty patients were assessable for response, and all 36 were assessable for toxicity. Two patients (7%) achieved a complete response (CR) and 13 (43%) a partial response (PR), for an overall response (OR) rate of 50% (95% confidence interval [CI], 32% to 68%). Analysis by intent to treat demonst...
Karen H Antman - One of the best experts on this subject based on the ideXlab platform.
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phase ii trial of Trimetrexate in patients with advanced soft tissue sarcoma
1991Co-Authors: Jonathan D Licht, Rene Gonin, Karen H AntmanAbstract:Trimetrexate, a lipophilic, 2,4-diaminoquinazoline derivative of methotrexate, enters cells by passive diffusion rather than via a transport system. Trimetrexate has shown promising activity in animal model systems. A total of 16 patients with metastatic soft-tissue sarcoma who had received only one prior chemotherapy regimen were treated with Trimetrexate (8 mg/m2 given intravenously daily for 5 days) every 3 weeks. Treatment-related toxicity included ≥ grade 2 neutropenia (8/16), thrombocytopenia (3/16), mucositis (4/16) and skin rash (3/16). No partial or complete responses were observed in 15 evaluable patients (95% confidence interval for true response rate, 0–22%) Six subjects showed stabilization of disease for periods ranging from 2 to 9 months. At this dose and on this schedule, Trimetrexate appears to have little activity against refractory soft-tissue sarcomas.
E D Kreuser - One of the best experts on this subject based on the ideXlab platform.
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sequential Trimetrexate 5 fluorouracil and folinic acid are effective and well tolerated in metastatic colorectal carcinoma the phase ii study group of the aio
2000Co-Authors: H Szelenyi, Peter Hohenberger, H Lochs, N Haboubi, W E Berdel, Eckhard Thiel, E D KreuserAbstract:Trimetrexate (TMTX) is a new antifolate which avoids competition for cellular uptake with folinic acid (FA). A regimen of sequential TMTX, FA and 5-fluorouracil (5-FU) has shown efficacy in patients w
