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)

The membrane impermeant protein cross-linker 3,3'-dithiobissulfosuccinimidyl propionate (DTSSP) is a well-known inhibitor of human erythrocyte band 3-mediated inorganic anion transport. We observed that DTSSP is also a potent inhibitor of reduced folate/methotrexate transport in human CCRF-CEM leukemia cells. An interaction of DTSSP with the reduced folate/MTX is substantiated by findings that: (a) like MTX transport itself, the concentration of DTSSP required for half-maximal inhibition of [3H]methotrexate transport varied substantially with the anionic composition of the external medium. In a saline buffer and an anion-deficient buffer the I50 values were 7 and 1 microM, respectively; (b) saturation of the carrier with 1-5 microM methotrexate completely protected the transport system from interaction by DTSSP; (c) methotrexate transport activity in DTSSP-treated cells could be restored after cleavage of the disulfide bond in DTSSP under mild reducing conditions; and (d) pretreatment of cells with DTSSP reduced the incorporation of [3H]methotrexate after labeling with an N-hydroxysuccinimide ester of [3H]methotrexate (NHS-MTX), another potent inhibitor of methotrexate transport. Comparison of DTSSP- and NHS-MTX-induced inhibition of methotrexate transport showed that DTSSP inhibition, in contrast to NHS-MTX inhibition, was (a) less potent, (b) dependent on buffer conditions, (c) reversible by reducing agents, and (d) required only a very low molar ratio of methotrexate over DTSSP to afford maximal protection.
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PMID:Interaction of N-hydroxy(sulfo) succinimide active esters with the reduced folate/methotrexate transport system from human leukemic CCRF-CEM cells. 280 8

Japanese patients with leukemia who received bone marrow from human leukocyte antigen (HLA)-compatible siblings had a low incidence of acute graft-versus-host disease (GVHD). Twenty-five (21%) of 120 patients developed moderate (grade II) to severe (grades III to IV) acute GVHD. Severe GVHD was only seen in patients older than 20 years of age. It is also notable that only 2 (5%) of 39 patients who received the combination of methotrexate and cyclosporine (MTX/CSP) for the prevention of GVHD developed grade II acute GVHD, and none developed grades III to IV acute GVHD. Thirteen (30%) of 44 patients receiving MTX alone and 10 (27%) of 37 patients receiving CSP alone developed grades II to IV acute GVHD. Multivariate life-table analysis indicated that the prophylaxis by MTX/CSP was the risk factor for the low incidence of grades II to IV acute GVHD. Compared with the reported incidence of acute GVHD in the patients of the United States, lower incidence of acute GVHD in Japanese BMT patients might be attributable to a lesser degree of genetic diversity in histocompatibility antigens among Japanese.
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PMID:Low incidence of acute graft-versus-host disease by the administration of methotrexate and cyclosporine in Japanese leukemia patients after bone marrow transplantation from human leukocyte antigen compatible siblings; possible role of genetic homogeneity. The Nagoya Bone Marrow Transplantation Group. 280 62

Twenty-four patients with Down syndrome and leukemia were studied. A strong male predominance (79%) was found. Age ranged between 18 months and 15 years (mean: 5 6/12); 54% of the patients were less than 4 years of age at the time of diagnosis. A preleukemic phase was noted in 6/24 patients. This phase, characterized essentially by thrombocytopenia, lasted from 2-8 months. Patients with preleukemia had unusual blast cell morphology and involvement of more than one cell line (dyserythropoiesis, hypolobulated megakaryocytes) and were probably M7 leukemias. All patients demonstrated severe methotrexate toxicity at standard methotrexate doses. Toxicity, manifesting as mouth ulcerations and bone marrow depression was seen regardless of the route of administration (oral, intrathecal or intravenous). A 30%-50% reduction of the standard dose was tolerated. Methotrexate absorption and clearance were studied in two patients and were found to be normal. We postulate that the observed toxicity of methotrexate may be due to a gene dosage effect for enzymes known to be on chromosome 21 and intervening in purine metabolism. Increased purine synthesis implies greater tetrahydrofolic acid demands and therefore greater sensitivity to an antifolate agent.
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PMID:Down syndrome and leukemia: unusual clinical aspects and unexpected methotrexate sensitivity. 295 83

The mechanisms of acquired resistance to MTX were studied in P388 murine leukemia cell lines that were sensitive or resistant to ADR. The rate of MTX accumulation in ADR-sensitive cells that have acquired resistance to MTX was found to be lower than that measured in cells that were sensitive to both drugs. Furthermore, in contrast to drug-sensitive cells, in the ADR-sensitive MTX-resistant cells, most of the intracellular MTX (86.2%) was bound and MTX polyglutamation was not detected. The initial rate of MTX accumulation in cells that were resistant to both drugs was comparable to that measured in cells that were sensitive to both drugs or that were resistant only to ADR. However, in the cells that were resistant to both drugs, the rate of MTX accumulation was maintained at its initial level for a period that was considerably longer than that found in the other cell lines. After 3 h of exposure to MTX, the accumulation of MTX in cells that were resistant to both drugs was fourfold higher than that measured in cells that were sensitive to both drugs. Furthermore, while 65 to 70% of the intracellular MTX was free, in cells sensitive to both drugs, or resistant only to ADR, the corresponding value in cells that were resistant to both drugs was less than 1.5%, and a much lower proportion of the MTX was polyglutamated. The sensitivity to TMQ of ADR-sensitive, MTX-resistant cells was similar to that found in cells that were sensitive to ADR and MTX. However, ADR-resistant cells, sensitive or resistant to MTX, were markedly resistant to TMQ. The sensitivity of ADR-resistant MTX-sensitive cells to TMQ was restored by the presence of 10 microM verapamil. Such an effect was not observed in cells resistant to both drugs. It is suggested that P388 cells that have previously acquired resistance to ADR, when now selected by MTX, retain the MTX-transport system (in contrast to ADR-sensitive, MTX-resistant cells) and become resistant to MTX by increasing the activity of DHFR. The results obtained in ADR-resistant cells also suggested that resistance to TMQ was part of the multidrug resistance phenomenon.
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PMID:Mechanism of acquired resistance to methotrexate in P388 murine leukemia cells and in their doxorubicin-resistant subline. 297 48

Twenty-three children with haematological malignancies and a poor prognosis underwent bone-marrow transplantation. Thirteen children had acute lymphoblastic leukaemia, eight had acute nonlymphoblastic leukaemia, one had chronic myeloid leukaemia and one had malignant histiocytosis. One child was in relapse at the time of transplant and 22 were in first or subsequent remission. Before transplantation all patients received cyclophosphamide (60 mg/kg) on two consecutive days followed by total body irradiation given as a single dose of 10 Gy at 0.18 Gy/min (one patient) or 0.07 Gy/min (three patients), or as a fractionated dose of 10-12 Gy at 0.07-0.1 Gy/min (19 patients). One child with malignant histiocytosis also received two doses of etoposide (5 mg/kg). Methotrexate was given after transplantation to prevent or modify graft-versus-host disease (GVHD). One patient who received a transplant in relapse died early from overwhelming bacterial sepsis. Twenty-two patients engrafted, and of these 11 developed acute GVHD; five developed chronic GVHD; seven developed interstitial pneumonitis, with four deaths; and five relapsed between three and 12 months after transplantation, with three deaths. Fifty-nine per cent (13/22) of patients who received a transplant during remission remain in continuous complete remission and 68% (15/22) have survived for a median of 18 months (range, four to 73 months). Bone-marrow transplantation that is undertaken during remission of disease offers a prolonged disease-free survival in selected childhood malignancies.
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PMID:Bone-marrow transplantation for haematological malignancy in childhood. 300 53

Methotrexate-induced hepatotoxicity is well recognised in the treatment of leukaemia, psoriasis and rheumatoid arthritis. The pathological lesions are non-specific, consisting of fatty change, nuclear pleomorphism, hepatocyte necrosis, portal chronic inflammatory infiltrate, fibrosis and cirrhosis. The mechanism of liver injury is poorly understood; intracellular accumulation of methotrexate polyglutamate and consequent folate depletion are suspected to play a role. Early studies in psoriasis clearly established a relationship of the hepatic injury with the frequency of methotrexate administration. With weekly low dose therapy, however, consensus is lacking regarding the incidence of hepatotoxicity because studies have had disparate control groups, used variable dosage regimens and often failed to document pre-existing liver disease or categorised patients at risk, i.e. elderly patients, alcoholics and obese diabetics. Moreover, current methods of assessing the degree of hepatic injury are subjective, relying on interpretation by an experienced histopathologist. Preliminary evidence suggests less frequent and less severe hepatotoxicity occurs in patients with rheumatoid arthritis, probably as a result of lower methotrexate doses and better patient selection. Nevertheless, until the risk of serious liver disease is better defined it is recommended that patients have a pretreatment liver biopsy, a follow-up biopsy after a cumulative dose of 1500 mg, and then biopsies approximately every 2 years in the absence of other evidence of liver disease or risk factors.
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PMID:Hepatotoxicity of methotrexate in rheumatic diseases. 304 Dec 45

With one exception, the risk and severity of neurotoxicity is directly proportional to the number of therapeutic modalities used. Three are worse than two, and two are worse than one. Combinations of therapeutic modalities which include CNS RT appear to be the most neurotoxic. The least neurotoxic combination of two modalities appears to be the IT MTX with high-dose intravenous MTX. Thus far, high-dose MTX appear to be the safest single modality, in terms of acute, subacute, and delayed neurotoxicity. The improved outcome in intellectual and academic performance in the NCI-191/CCG-134P conjoint trial of the CCSG and the Pediatric Branch described above (see section of Presymptomatic CNS Therapy) appears to confirm this observation. Whether triple IT chemotherapy will have the same result remains to be established. If CNS RT must be combined with MTX therapy, the least neurotoxic approach appears to be to administer these modalities in sequence, IT MTX, or high-dose intravenous MTX followed by CNS RT. MTX given during or after CNS RT appears from the clinical data to be more likely to produce severe neurologic sequelae. An ultimate goal would be to avoid both ionizing RT and IT chemotherapy. To this end, the NCI/CCSG study has demonstrated that this may be possible, except for those patients who are at the highest risk for CNS relapse despite conventional CNS prophylaxis. Meanwhile, for presymptomatic therapy, either cranial RT (18 Gy total dose at 120-180 cGy per day) in conjunction with IT MTX, or frequent IT chemotherapy with MTX, cytarabine, and hydrocortisone combined and administered throughout induction, consolidation, and maintenance is eminently justified in the majority of children with ALL. On a worldwide basis, chemoradiotherapy with cranial RT and IT MTX remains the established method of preventing overt CNS leukemia. The benefits of this intervention, in terms of prevention of symptomatic CNS leukemia, prolongation of complete remission, and increased cure rates, are clearly worth the risks.
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PMID:Central nervous system leukemia. 304 54

Graft-versus-host disease (GvHD) prophylaxis using methotrexate (23 patients) and T-cell depletion of the graft (40 patients) was compared in 63 allogeneic bone marrow transplantations (BMT) for leukaemia. T-cell depletion significantly reduced (p = 0.001) the incidence of GvHD from 68% to 11% and the GvHD-associated mortality from 79% to 5%. Actuarial disease-free survival for low-risk patients (57% with T-cell depletion and 47% with MTX) was not significantly improved, due to graft failure and possibly due to a higher leukaemic relapse rate after T-cell depletion. Prevention of graft failure after T cell-depleted BMT is essential and could also reduce the risk of leukaemic relapse by improved engraftment.
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PMID:T-cell depletion versus methotrexate as GvHD-prophylaxis in allogeneic bone marrow transplantation for leukaemia. 305 41

In clinical practice, cancers refractory to chemotherapy commonly appear to be comparatively radioresistant. One mechanism by which cancer cells become resistant to chemotherapy is pleiotropic multidrug resistance, characterized by cross resistance to a number of otherwise unrelated heterocyclic antineoplastic agents, including vinca alkaloids, anthracyclines, dactinomycin, and others. We have studied a drug sensitive human leukemia cell line, CEM; a pleiotropic multidrug resistant subline of CEM, CEM/VLB100; VLB-1, a drug sensitive revertant subline arising during in vivo passage of CEM/VLB100; and a methotrexate resistant subline of CEM, CEM-MTX. Using soft-agar colony formation after graded doses of X rays as an endpoint, we found that CEM, CEM-MTX, and CEM/VLB100 had similar terminal slopes (D0 = 0.66 Gy). However, the CEM/VLB100 survival curve had a broader initial shoulder (n = 3.0, Dq = 0.75 Gy) than did CEM (n = 1.6, Dq = 0.25 Gy) or CEM/MTX (n = 1.0, Dq = 0 Gy), suggesting that CEM/VLB100 has an increased capacity to repair radiation-induced DNA damage. This was tested by comparing the cell lines' abilities to accumulate sublethal damage. In split dose recovery experiments, CEM/VLB100 demonstrated increased ability to repair sublethal radiation damage following fractionated irradiation compared with the CEM parental line. Although it no longer demonstrated multidrug resistance, VLB-1 still displayed diminished radiation sensitivity. On the basis of these and other investigators' results, we suggest that diminished radiation sensitivity is separate from, but can be closely associated with, the multidrug-resistant phenotype.
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PMID:Radiation resistance in a multidrug resistant human T-cell leukemia line. 318 32

Methotrexate (MTX) and 6-mercaptopurine (6MP) have been used since 30 years in the maintenance treatment of acute lymphoblastic leukemia (ALL) of childhood. A synergistic effect of this combination was demonstrated in mouse and childhood leukemia. In this article an overview is given of our investigations, concerning the biochemical basis of this synergism. This synergism is caused by a selective inhibition of the purine de novo synthesis in malignant lymphoblasts by MTX, associated with an enhanced intracellular uptake of 6MP. Pharmacokinetic studies of MTX in various schemes of prophylactic central nervous system treatment in ALL are discussed. Treatment with 24-hr infusions of MTX in a dosage of 5 g/m2, as recommended in the new BFM-86/SNWLK ALL VII protocol, seems to be optimal. Pharmacokinetic studies of intravenous 6MP infusions demonstrated a good cerebral fluid penetration. Exploiting the synergistic action of the combination of MTX and 6MP may offer an improvement of the prophylactic central nervous systems treatment in ALL in the future, using intravenous administration of both MTX and 6MP.
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PMID:[Biochemical and clinico-pharmacological aspects of antimetabolites in the treatment of leukemia]. 328 84


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