UMLS:C0023418 - FACTA Search

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Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The types of folates used during the development of resistance to methotrexate have been suggested to play an important role in the mechanisms of established resistance. In this study, effects of reduced and oxidized folates on the development of resistance to a thymidylate synthase (TS) inhibitor, N10-propargyl-5, 8-dideazafolic acid (CB3717), were examined in the human leukemia cell line MOLT-3. MOLT-3 cells were made resistant to CB3717 by soft-agar cloning in RPMI-1640 medium with either pteroylglutamic acid (PGA) or a more physiological folate (10 nM leucovorin). A 40-fold CB3717-resistant subline developed in PGA (MOLT-3/CB3717(40)-PGA) showed amplification of the TS gene with a concomitant increased level in the gene expression. A 200-fold CB3717-resistant subline (MOLT-3/CB3717(200)-PGA), which was derived from MOLT-3/CB3717(40)-PGA, showed further enhancement of amplification of the TS gene. In contrast, even a 200-fold CB3717-resistant subline developed in leucovorin (MOLT-3/CB3717(200)-LV) showed neither amplification nor overexpression of the TS gene. Both MOLT-3/CB3717(200)-PGA and MOLT-3/CB3717(200)-LV cells showed decreased membrane transport of PGA as well as methotrexate. These results suggest that the types of folates used during the development of CB3717 resistance may play a role in resistance, and that impaired transport of PGA, in CB3717-resistant MOLT-3 cells developed in PGA, might have accelerated amplification of the TS gene.
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PMID:Amplification of the thymidylate synthase gene in an N10-propargyl-5,8-dideazafolic-acid-resistant human leukemia, MOLT-3 cell line developed in pteroylglutamic acid, but not in leucovorin. 889 75

Suramin, a bis-hexasulfonated napthylurea, was studied as an inhibitor of human folylpolyglutamate synthetase (FPGS), a crucial enzyme in folate metabolism. Suramin is a more potent (IC50, 0.9 microM) inhibitor of FPGS partially purified from CCRF-CEM human leukemia cells than is bromosulfophthalein (IC50, 17 microM), the first reported nonsubstrate-analog inhibitor of FPGS (J. J. McGuire et al., Adv. Exptl. Med. Biol. 163, 199, 1983). FPGS inhibition by suramin is reversed by bovine serum albumin (which binds suramin). Suramin is a noncompetitive inhibitor with aminopterin (K(ii) = 0.9 microM; K(is) = 1.1 microM) and glutamic acid (K(ii) = 1.0 microM; K(is) = 5.2 microM) as the variable substrates; suramin inhibition tends toward being competitive with respect to the third FPGS substrate, ATP (K(ii) = 3.4 microM; K(is) = 0.35 microM), since the major effect is on its K(m). Suramin is a much less potent inhibitor of two other folate-dependent enzymes, dihydrofolate reductase (IC50, 38 microM; methotrexate (MTX), 0.6 nM) and thymidylate synthase (IC50, 87 microM; MTX, 48 microM). The effects of suramin on growth of CCRF-CEM cells and a MTX-resistant subline (R30dm) expressing low levels of FPGS activity were determined. R30dm is slightly collaterally sensitive to suramin consistent with FPGS inhibition contributing to the cytotoxic mechanism. These data, and those of Rideout et al. (Int. J. Cancer 61, 840, 1995), demonstrating that the reduced folate carrier system of CCRF-CEM is inhibited, suggest that inhibition of folate metabolism could be involved in the mechanism of action of suramin.
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PMID:Potent inhibition of human folylpolyglutamate synthetase by suramin. 891 44

Confocal microscopy was used to visualize the intracellular uptake of the fluorescent methotrexate analogue, fluorescein-MTX (F-MTX), in human leukaemic cell lines and leukaemic blasts. Cytosolic labelling of wild-type K562 human erythroleukaemia cells was detected during 3-60 min incubations with F-MTX (1 microM) and was completely inhibited by co-exposure to either methotrexate or the thymidylate synthase inhibitor, ZD1694. There was no significant intracellular F-MTX accumulation over this period in a K562 subline (K500E) with a documented defect (approximately 10% of wild type) in membrane transport by the reduced folate carrier (RFC). F-MTX uptake was re-established in K500E cells transfected with a cDNA to human RFC, establishing a role for RFC in the cellular uptake of this compound. High levels of intracellular labelling were detected in all cell lines after prolonged (24 h) F-MTX incubations, however F-MTX accumulation at this time was not inhibited by ZD1694. F-MTX uptake by RFC was also detected in leukaemic blasts from children with acute lymphoblastic leukaemia and could be blocked with ZD1694. In leukaemic blasts with a documented defect in MTX uptake, F-MTX accumulation was abolished in almost all the cells. These results display the power of confocal microscopy for directly visualizing RFC-mediated anti-folate uptake. Over short intervals, F-MTX uptake is mediated by RFC, however, RFC-independent processes predominate during long drug exposures. Direct assay by confocal microscopy may be better suited than other indirect methods (i.e. flow cytometry) for detecting low levels of RFC transport in leukaemic blasts from patients undergoing chemotherapy with methotrexate.
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PMID:Confocal microscopy visualization of antifolate uptake by the reduced folate carrier in human leukaemic cells. 931 Feb 38

Cytotoxicity of trimetrexate (TMQ), a lipophilic dihydrofolate reductase inhibitor, was examined in antifolate-resistant human T-cell leukemia cell lines developed in oxidized or reduced folate. An approximately 60-fold methotrexate (MTX)-resistant subline was developed in oxidized folate (pteroylglutamic acid: PGA) (CCRF-CEM/MTX60-PGA) from human T-cell leukemia cell line CCRF-CEM; this line exhibited impaired membrane transport of the drug. Further enhancement of MTX resistance resulted in selection of an approximately 5000-fold MTX-resistant subline (CCRF-CEM/ MTX5000-PGA), which showed increased dihydrofolate reductase activity due to gene amplification in addition to further impairment of MTX transport. An approximately 140-fold MTX-resistant subline, and then a 1500-fold MTX-resistant subline were developed in reduced folate (10 nM leucovorin) (CCRF-CEM/MTX140-LV and CCRF-CEM/MTX1500-LV); they exhibited increased dihydrofolate reductase due to gene amplification accompanied by increased intracellular drug accumulation of MTX. While CCRF-CEM/MTX140-LV and CCRF-CEM/MTX1500-LV cells showed cross-resistance to TMQ, CCRF-CEM/MTX60-PGA and CCRF-CEM/MTX5000-PGA cells were at least as sensitive to TMQ as the parent cells. TMQ was more potent against approximately 200-fold N10-propargyl-5,8-dideazafolic-acid (CB3717)-resistant human T-cell leukemia MOLT-3 sublines developed in PGA (MOLT-3/CB3717(200)-PGA) or leucovorin (MOLT-3/CB3717(200)-LV), as compared to the parent cells; MOLT-3/CB3717(200)-PGA and MOLT-3/CB3717(200)-LV cells were resistant to CB3717 by virtue of impaired transport, only the former possessing gene amplification of thymidylate synthase. The cytotoxicity of TMQ in both MOLT-3/CB3717(200)-PGA and MOLT-3/CB3717(200)-LV cells was reduced by addition of leucovorin in a dose-dependent manner, suggesting intracellular folate deficiency as a cause of TMQ sensitivity. These results demonstrate that TMQ overcomes transport-impaired antifolate resistance, irrespective of gene amplification of dihydrofolate reductase or thymidylate synthase. Types of folate used during the development of antifolate resistance seem to be important in relation to the mechanism of TMQ responsiveness as well as that of antifolate resistance.
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PMID:Cytotoxicity of trimetrexate against antifolate-resistant human T-cell leukemia cell lines developed in oxidized or reduced folate. 936 39

ZD1694 (Tomudex, raltitrexed) is a specific quinazoline antifolate thymidylate synthase inhibitor that relies on polyglutamation for high potency. Antibodies to ZD1694 have been used to establish a sensitive radioimmunoassay as an alternative to high-performance liquid chromatography (HPLC). The radioimmunoassay is reproducible, accurate and provides a means of determining low levels of ZD1694 in plasma (< 1 nM). By virtue of the high cross-reactivity of the antibodies with polyglutamated forms of ZD1694, it is also possible to measure the total concentration of drug in tissues. Results obtained in L1210 mouse leukaemia cells and in mouse tissues were similar to those previously determined using radiolabelled drug. Pharmacokinetic studies in mice have confirmed that the compound is rapidly eliminated from the plasma and that there is a prolonged terminal elimination phase. ZD1694 was measured in plasma (0.56 ng ml(-1); 1.2 pmol ml(-1)) up to 7 days after a single i.p. dose of 100 mg kg(-1) ZD1694. Liver, kidney and gut epithelium had a substantially higher level of ZD1694 immunoreactivity than plasma. For example, 24 h after a single i.p. dose at 1, 10 and 100 mg kg(-1), total drug levels in the liver were 480, 325 and 152 times higher than plasma levels respectively. In kidney and gut epithelium, total drug levels at these doses were approximately 55 and 34 times those of plasma. The high tissue to plasma ratios were maintained for at least 7 days after administration. Similarly, high tissue to plasma ratios (> 100) were found in dogs treated with a clinically relevant dose of ZD1694. These were maintained for 4 weeks in liver and kidney tissue (> 100). Total gastrointestinal concentrations of ZD1694 were approximately 10 times higher than plasma 3 days after administration, but levels were near to the limit of detection at 4 weeks. These results are consistent with extensive polyglutamation of ZD1694 within tissues in both mice and dog and provide further support for the infrequent schedule that has been used clinically. Although it has not been possible to measure individual polyglutamated forms of ZD1694, the radioimmunoassay provides a convenient means of assessing total drug levels in tissues and is currently the only method suitable for measuring the extent of drug retention in normal tissue and tumour biopsies obtained from patients treated with ZD1694.
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PMID:Comparison of plasma and tissue levels of ZD1694 (Tomudex), a highly polyglutamatable quinazoline thymidylate synthase inhibitor, in preclinical models. 946 Sep 92

The synergistic effect of two different inhibitors of thymidylate synthase-FdUrd and sulphonamide derivatives on murine leukemia cells-5178Y (parental subline) and 5178Y/F (its fluorodeoxyuridine resistant subline) in culture was examined. Upon the exposure of cultures from both lines to a slightly inhibitory concentration of FdUrd (1 nM) in combination with 2-desamino-2-methyl-10-propargyl-5,8-dideaza-pteroylsulphogluta mine or -glycine a synergistic effect of antimetabolites on cell growth was observed. This was accompanied by a marked reduction in intracellular concentration in both cell lines of 5,10CH2H4PteGlu; the intracellular concentration of 5,10CH2H4PteGlu(n) in the resistant subline was 3 times higher than in parental line. The inhibitory effect of combined drugs on the cellular pool of 5178Y of the two antimetabolites also depends on the sequence of their addition; however in the FdUrd resistant cell-line the dependence on the sequence of the addition was not observed. The results obtained strongly suggest that under certain conditions inhibition of thymidylate synthesis by antifolates is intensified by proprior use of FdUrd.
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PMID:Effect of combined inhibitors of thymidylate synthase-5-fluorodeoxyuridine and quinazoline antifolates on murine leukemia cells cultured in vitro. 949 61

The resistance to folate-based antifolates is associated with impaired function of the reduced folate carrier (RFC), one of the major routes of folate transport into cancer cells. To clarify the importance of RFC functions in the antifolate resistance, we have examined the expression of RFC1 and its phenotype as a folate transporter in human leukemia cell lines resistant to various antifolates. MOLT-3 cells resistant to ZD9331 (a thymidylate synthase (TS) inhibitor that utilizes the RFC for cell entry) (MOLT-3/ZD9331) showed decreased expression of RFC1 concomitant with diminished cellular uptake of [3H]methotrexate (MTX). K562 cells resistant to raltitrexed (ZD1694, another TS inhibitor that utilizes the RFC for cell entry) (K562/ ZD1694 x C) scarcely expressed RFC1, which is in accordance with the impaired uptake of folate analogs and the high degree of resistance to ZD1694 and MTX. On the other hand, no apparent decrease of RFCI1 expression was found in transport-deficient MTX-resistant MOLT-3 cells (MOLT-3/MTX10000) though its phenotype showed defective transport of MTX or ZD1694. In these cell lines with impaired RFC function, [3H]leucovorin (LV) uptake was only moderately decreased as compared to [3H]MTX or [3H]ZD1694 uptake. These cells grew with a minimal retardation in folate-free medium supplemented with 10 nM LV, suggesting that these cell lines with impaired RFC function had enough folate transporters to transport LV. In contrast to downregulation of RFC, the much greater uptake of [3H]MTX was observed in the MOLT-3/trimetrexate (TMQ)800-MTX10000 in parallel with increased RFC1 expression. These cell lines with the altered expression of RFC1 may serve as models useful for investigating the regulation of RFC1 expression and for understanding the molecular mechanism(s) behind the transport-mediated antifolate resistance.
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PMID:Variable expression of RFC1 in human leukemia cell lines resistant to antifolates. 950 Feb 2

The effect of thymidylate synthase inhibitors, fluorodeoxyuridine (FdUrd) and its two sulphonamide derivatives was examined in the culture of murine leukemia cells -- 5178Y (parental subline) and its fluorodeoxyuridine resistant subline 5178Y/F. A synergistic effect of the antimetabolites on cell survival was observed on exposure of the culture of either line to a slightly inhibitory concentration of FdUrd (1 nM) in combination with 2-desamino-2-methyl-10-propargyl-5,8-dideaza-pteroylsulphogluta mate or 2-desamino-2-methyl-10-propargyl-5,8-dideaza-pteroylsulphoglyci ne. This effect was accompanied by a marked reduction, in both cell lines of intracellular concentration of 5,10-methylenetetrahydro-pteroyl-polyglutamate, although its concentration in the resistant subline was 3 times as high as in the parental line. The inhibitory effect of combined drugs on the cellular pool of folates in 5178Y line depended also on the sequence of drug addition, whereas in the FdUrd resistant line this sequence was without any effect. The results obtained strongly suggest that under certain conditions inhibition of thymidylate synthesis by antifolates is intensified by a prior use of FdUrd.
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PMID:Synergistic effect of 5-fluorodeoxyuridine and quinazoline antifolates on murine leukemia self-cultured in vitro. 958 53

The synergistic effect of trimetrexate (TMTX) and sulphonamide derivatives of quinazoline on the cultured 5178Y murine leukemia cells was examined. On exposure to the slightly inhibitory concentrations of TMTX (0.1 nM) in combination with 2-desamino-2-methyl-10-propargyl-5,8-dideaza-pteroyl-sulphoglyc ine (DMPDDSF) (0.02 microM) a synergistic inhibitory effect of the antifolates on cell growth was observed. These two drugs in the same combination caused also synergistic inhibition of de novo synthesis of thymidylate in intact cells as measured by tritium release from [5-(3)H]deoxyuridylate. This was accompanied by a marked reduction in intracellular concentration of 5,10-methylenetetrahydro-pteroyl-polyglutamate (5,10CH2H4PteGlu(n)) (0.2 microM) and dihydropteroyl-polyglutamate (0.12 microM). In these conditions de novo biosynthesis of purine was decreased by 50%. These observations show that growth inhibition by combined antifolates is mediated by intracellular depletion of the substrate of thymidylate synthase -- 5,10CH2H4PteGlu(n). The results obtained strongly suggest that under certain conditions inhibition of thymidylate synthesis by DMPDDSF is intensified by prior application of TMTX -- an inhibitor of dihydrofolate reductase.
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PMID:The effects of combined antifolates on inhibition of growth of murine leukemia cells cultured in vitro. 958 54

The quinazoline antifolate N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N- methylamino]-2-thenoyl)-L-glutamic acid (ZD1694; Tomudex) is a potent inhibitor of thymidylate synthase and causes cell death through disruption of DNA synthesis and repair by blocking the obligatory thymidine nucleotide synthesis. B43(anti-CD19)-PAP immunotoxin is a potent inhibitor of protein synthesis in CD19+ B-lineage acute lymphoblastic leukemia (ALL) cells and causes apoptosis. In this model, 100% of SCID mice challenged with 1 x 10(6) human NALM-6 B-lineage ALL cells develop overt and invariably fatal leukemia. All of the 22 control SCID mice treated with phosphate-buffered saline died of disseminated human leukemia between 31 and 61 days with a median survival of 41.2 days. Treatment with ZD 1694 resulted in improved leukemia-free survival with a median survival of 69.2 days (P < 0.001, log-rank test). B43-PAP treatment was more effective than ZD1694 (P=0.026) and resulted in 51.0% long-term leukemia-free survival with a median survival of 187.5 days (P < 0.0001. log-rank test). The combination of ZD1694 and B43-PAP was more effective than either agent alone and resulted in 100% long-term leukemia-free survival. To our knowledge, this preclinical study is the first to demonstrate the feasibility and therapeutic advantage of combining an anti-leukemia immunotoxin with a thymidylate synthase inhibitor.
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PMID:Combined therapeutic efficacy of the thymidylate synthase inhibitor ZD1694 (Tomudex) and the immunotoxin B43(anti-CD19)-PAP in a SCID mouse model of human B-lineage acute lymphoblastic leukemia. 961 80

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