Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Blood lymphocytes from eight patients with chronic lymphatic leukaemia (CLL) were stimulated by phytohaemagglutinin (PHA). The effect was defined as a pronounced increase of 3H-thymidine incorporation, and a concomitant blast transformation of a large portion of surface Ig-positive, E-rosette-forming (E-RFC) negative cells. E-RFC depletion reduced these effects to nearly background levels, and the pooled data strongly suggest that malignant B-lymphocytes in CLL are capable of responding to a PHA-induced T cell factor. A possible use for this factor in characterizing different subpopulations of CLL cells is discussed.
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PMID:PHA-induced soluble factor(s) can activate B-cells from patients with chronic lymphatic leukaemia. 31 47

Mixed Rauscher leukemia virus (RLV) and M. arthritidis infection of (C57BL/6xA/Sn)f1 mice-hybrids, highly resistant to RLV, was accompanied by a progressive inhibition of rosette-forming cells (RFC) and plaque-forming cells (PFC), resulting in the induction of malignant erythroblastosis identical by cytology to Rauscher leukemia. The mice-hybrids infected with A. laidlawii and RLV developed significant splenomegaly on the 21st day of the infection, and their immune response was almost entirely suppressed, but both RFC and PFC populations as well as the spleen weight returned to the initial level by the 62d day the infection. A possible role of mycoplasm in the induction and development of Rauscher leukemia is discussed.
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PMID:[Immune response of (C57BL/6xA/Sn)F1 mice in mycoplasm-virus infection]. 51 25

Immunoglobulin (Fc) receptors were detected on leucocytes from patients with acute myeloid leukaemia (AML) by rosette formation with human cDE/cDE erthyrocytes (HE) sensitized with Rhesus (Rh) antisera (HEA). Of 7 Rh antisera tested, erythrocytes sensitized with anti-d (Gm10) detected the highest numbers of rosette-forming cells (HEA-RFC) in normal and AML leucocyte preparations. Using this assay, HEA-RFC was studied in 22 untreated AML patients and ce assay detected 11-6% lymphocyte and 2-1% granulocyte HEA-RFC in normal peripheral blood. Leucocytes from 16 to 22 AML patients had a similar or lower percentage than normal lymphocyte HEA-RFC, which could be explained by the dilution of peripheral blood leucocytes by poorly or non-rosetting leukaemic blasts. Ten of these 16 patients were diagnosed as having acute myeloblasts leukaemia. Six of the 22 AML patients had high HEA-RFC values of which 5 were diagnosed as having myelomonocytic leukaemia. Cytocentrifuge preparations of HEA-RFC showed that the proportion able to form rosettes was lower in myeloblasts than in monoblasts. Enzyme treatment (pronase), inhibition or simultaneous labelling of surface Ig and Fc receptors showed that the characteristic surface Ig found to AML cells is, at least in part, bound to Fc receptors. The HEA-RFC test described in this paper could be useful in the immuno-diagnosis of myelomonocytic leukaemia.
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PMID:Receptors for human immunoglobulin on acute myeloid leukaemic leucocytes. 82 53

Immunoglobulins (Ig) on cells of the immune system: The cytotoxicity test, with class-specific and type-specific anti-Ig sera, identifies kappa and micro determinants on mouse lymphocytes. The proportion of kappa(+) cells is characteristic for each source of cells: 30% of bone marrow cells, 40% of cells from peripheral lymph nodes, 45% of lymphocytes from peripheral blood or peritoneal cavity, and 50% of spleen cells. No Ig was demonstrable on thymocytes or on leukemia cells (most of which arise from thymus-derived [T] cells). Cytotoxicity tests were performed on various myelomas secreting different Ig; the only positive reactions were given by kappagamma1 myelomas (all four kappagamma1 myelomas tested were sensitive to both anti-kappa and anti-gamma1). Hemolytic plaque-forming cells (PFC) of IgG type had no demonstrable surface Ig, but a proportion of IgM PFC were kappa(+)micro(+). Virtually all rosette-forming cells (RFC) have surface Ig, more than 90% of them being inhibited by anti-kappa, 50% by anti-micro, and 10-30% by antisera to other heavy chains. Anti-lambda sera gave no positive reactions with any cell type, which is in keeping with the low level of this light chain in mouse serum. Ig and other differentiation antigens as markers for T and B cells: Thymocytes are hallmarked by the alloantigens TL, theta, and the Ly series, and it is generally held that extrathymic lymphoid cells that bear them are derived from thymocytes. There is one alloantigen marker for the thymus-independent (B) cell, and that is PC, which appears late in differentiation. (The mouse-specific lymphocyte (MSLA) and mouse-specific bone marrow-derived lymphocyte (MBLA) antigens recognized by heteroantisera, not used in the present study, are other candidates for T and B cell markers.) Making use of antisera to these surface antigens to inhibit the function of cells that carry them, we find the following: Approximately 30% of RFC, 60% of IgM PFC, and 90% of IgG are PC(+) and so are identified as B cells. No T markers were demonstrable on these cell populations. Thus if T cells do become RFC or PFC they presumably lose their T surface markers in the process (cf. the quantitative reduction of T markers accompanying the thymocyte --> lymphocyte transition). Cells that have the potential to initiate graft-versus-host (GVH) reactions have the T cell surface phenotype theta(+)Ig(-). Adoptive transfer of thymus-dependent antibody-forming capacity (response to sheep erythrocytes) required theta(+) cells but transfer of a thymus-independent immune response to Brucella antigen did not. Cells with surface Ig were involved in both types of adoptive transfers. Thus the presently available T markers do not provide evidence for T cells carrying surface Ig. Suppression of the Ig phenotype by antibody: antigenic modulation? A phenotypic change from Ig(+) to Ig(-) occurs when Ig(+) lymphocytes or myeloma cells are incubated with anti-Ig sera in vitro in the absence of complement (C). As with antigenic modulation in the TL system, which it resembles, this phenomenon is temperature dependent and in the case of lymph node cells (LNC) can be inhibited by high doses of actinomycin D.
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PMID:Immunoglobulin and other surface antigens of cells of the immune system. 410 85

Cl-920 is a structurally novel antitumor antibiotic which has activity against a wide spectrum of tumor cells in vitro and is curative in L1210 leukemia in vivo. Several lines of evidence indicate that this drug penetrates L1210 cells via the reduced folate carrier system. Reduced folates (100 microM) including leucovorin and 5-methyltetrahydrofolate completely protected L1210 cells from growth inhibition by Cl-920. Protective effects were not observed, however, with folic acid, a compound which is transported by a process distinct from that for reduced folates. Cl-920 was a potent inhibitor of methotrexate influx exhibiting a mixture of competitive and noncompetitive inhibition and having a Ki (slope) of 30.0 microM and a Ki (intercept) of 58.8 microM. The inhibition appeared to be irreversible since, after cells were preincubated with drug, the inhibitory effects persisted after cells were washed in drug-free media. The irreversibility could be eliminated, however, by dithiothreitol, suggesting that Cl-920 may interact with a thiol which is essential to this transport system. Cells made 71-fold resistant to Cl-920 by continuous exposure to increasing concentrations of this drug were 245-fold cross-resistant to methotrexate but were collaterally sensitive to the lipophilic antifolate trimetrexate and contained normal levels of dihydrofolate reductase. This mutant cell line had a severely impaired reduced folate carrier system exhibiting methotrexate influx rates of less than 1% of control cells. Finally, inhibition of methotrexate influx by a number of Cl-920 analogues showed that the intact lactone ring and the presence of the phosphate ester were required for maximum interaction with the carrier system and that the degree of inhibition correlated with relative antitumor potency. These observations are compatible with the concept that Cl-920 utilizes the folate carrier system and could be of fundamental importance for understanding the cytotoxicity and selectivity of Cl-920.
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PMID:Transport of the antitumor antibiotic Cl-920 into L1210 leukemia cells by the reduced folate carrier system. 654 36

The influence of drug exposure conditions on the development of resistance to methotrexate (MTX) or ZD1694 was studied by treating MOLT-3 human lymphoblastic-leukaemia cells in a continuous or a pulsatile (high-dose, short term) drug-exposure schedule. Continuous exposure of the cells to MTX with stepwise escalation of the drug concentrations resulted in a MTX-resistant sub-line (MOLT-3/MTX(10000)) with impaired reduced-folate carrier (RFC) and increased dihydro-folate-reductase (DHFR) activity. Conversely, a MTX-resistant clone (MOLT-3/MTX. P-9) with unaltered RFC and DHFR activity, but with decreased cellular accumulation of anti-folates, was selected by high-dose short-term treatment of the cells with MTX. MTX resistance in the latter cells was pronounced after short-term rather than continuous-exposure incubation with MTX, suggesting defective polyglutamation of the drug. On the other hand, 2 ZD1694-resistant sub-lines which were established by continuous (MOLT-3/ZD1694. C) or by pulsatile drug-exposure schedule (MOLT-3/ZD1694.P-9) demonstrated extremely low accumulation and poor retention of [3H]ZD1694, with no change in initial drug uptake and little or no increase of thymidylate-synthase (TS) activity irrespective of drug exposure conditions for their establishment. HPLC analysis displayed a virtual absence of ZD1694 polyglutamates in both ZD1694-resistant sub-lines and low accumulation in MOLT-3/MTX.p-9 as compared to the parent line. However, folylpolyglutamate-synthetase(FPGS) mRNA was only moderately decreased in the 2 ZD1694-resistant sub-lines and to an even lesser extent in MOLT-3/MTX.p-9. In addition, gamma-glutamyl-hydrolase(GGH) activity was not increased, but was slightly down-regulated in the polyglutamation-defective sub-lines. These results indicate that the mechanism(s) of the resistance developed may depend not only on drug-exposure conditions while raising resistance but also on the biochemical properties of the drug.
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PMID:The influence of drug-exposure conditions on the development of resistance to methotrexate or ZD1694 in cultured human leukaemia cells. 860 62

The biological activity and cellular metabolism of ZD1694, a novel folate-based thymidylate synthase (TS) inhibitor, were analyzed in a human leukemia cell line, MOLT-3, and its antifolate-resistant sublines with different mechanisms of resistance to methotrexate (MTX), trimetrexate (TMQ) and N10-propargyl-5,8-dideazafolic acid (CB3717). MOLT-3/CB3717(40), which was selected for CB3717 resistance, demonstrated impaired membrane drug transport via reduced folate carrier (RFC) and lower accumulation of [3H]ZD1694-polyglutamates in the cells with a shift in the polyglutamate distribution profile to shorter chain length polyglutamates, indicating an alteration in polyglutamation capacity in this subline. Impaired RFC and reduced rate of polyglutamation could explain the cross-resistance (12-fold) of this subline to ZD1694. On the other hand, there was little or no cross-resistance to this drug in a subline (MOLT-3/TMQ800) reportedly resistant to TMQ through impaired membrane transport for TMQ and an increase in dihydrofolate reductase (DHFR) activity. Total amount of ZD1694 polyglutamated to a level higher than diglutamate was approximately 1.7-fold higher in the TMQ-resistant cells than that in the parent cells, but a low degree of increase in TS activity in the cells counteracted the supposed increase in sensitivity to ZD1694. MOLT-3/TMQ800-MTX10000 cells, which were established by sequential exposure of the TMQ-resistant cells to MTX and were previously shown to amplify mutated DHFR with low affinity for MTX, showed a decreased accumulation of polyglutamated ZD1694 as compared with the parent line and this was consistent with cross-resistance to ZD1694 in this subline. Overproduction of variant DHFR scarcely influenced the sensitivity to this drug. These results indicate that ZD1694 could overcome antifolate resistance through a mechanism such as amplified DHFR activity, and the biological activity of this drug against the cells paralleled the amount of polyglutamated drug inside the cells. Determination of polyglutamation capacity in tumor cells may allow prediction of sensitivity to this drug.
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PMID:Biological activity and intracellular metabolism of ZD1694 in human leukemia cell lines with different resistance mechanisms to antifolate drugs. 869 29

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

Prolonged cell culture of human leukemia cells at folate concentrations in the (sub)physiological range (1-5 nM) rather than at 'standard' supraphysiological concentrations of 2-10 microM folic acid elicited a number of regulatory aspects of the reduced folate carrier (RFC), the membrane transport protein for natural reduced folate cofactors and folate-based chemotherapeutic drugs such as methotrexate (MTX). One subline of human CCRF-CEM leukemia cells grown under folate-restricted conditions (CEM-7A) exhibited a 95-fold increased Vmax for uptake of [3H]-MTX. The increased uptake of MTX in CEM-7A cells is based on at least two factors: (a) a constitutive 10-fold overexpression of the RFC1 gene and RFC1 message; and (b) a 7-9-fold up-regulation of RFC transport activity under low intracellular reduced folate concentrations. This second component appeared to be regulatable by changes in the cellular folate, purine and methylation status as judged from a 7-9 fold down-regulation of RFC transport activity after short term (1-2 hr) incubation of CEM-7A cells with reduced folate cofactors (25 nM LV), purines (100 microM adenosine) or S-adenosylmethionine (100 microM), respectively. Gradual folate restriction in the cell culture medium of CEM/MTX cells, a subline of CCRF-CEM resistant to MTX due to defective transport via the RFC, revealed the up-regulated expression of an altered RFC protein that is characterized by a 35-fold decreased Km for folic acid and a 10-fold decreased Km for the reduced folate cofactor LV compared to the RFC expressed in CCRF-CEM and CEM-7A cells. As a result of the markedly increased efficiency of folic acid uptake in CEM/MTX cells, intracellular folate pools were 7-fold higher than in CCRF-CEM cells when both cell lines were incubated in the presence of 2 microM folic acid. The high intracellular folate pools in CEM/MTX cells appeared to impair the polyglutamylation of antifolates and confer resistance to ZD1694, an antifolate drug that depends on polyglutamylation for its biological activity. Collectively, these studies provide a better insight into the basic regulation of RFC-mediated membrane transport of clinically active antifolates. In addition, these studies may also provide an opportunity to exploit the transport system as a target for biochemical modulation by which it may contribute to an improved efficacy of folate-based chemotherapy in a clinical setting.
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PMID:Regulation of carrier-mediated transport of folates and antifolates in methotrexate-sensitive and-resistant leukemia cells. 938 86

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


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