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)

Drug resistance is a critical problem in the therapy of hematologic malignancies. Recent advances in the transplantation of human normal and transformed hematopoietic cells into severe combined immunodeficient (SCID) mice provide an opportunity to study the biologic and molecular events that mediate resistance. We studied the engraftment of several human myelogenous leukemia cell lines sensitive and resistant to amsacrine (mAMSA), vincristine, hycamptamine, methotrexate, or doxorubicine (KBM3/AMSA, K562/Vcr, HL60/Hy10, K562/MTX, HL60/Dox). The distribution and growth potential of these cells was evaluated using molecular and histologic techniques. Inoculation of 2 x 10(7) leukemic cells led to manifestation of disease, and subsequent tissue analysis showed evidence of leukemia. The survival of mice varied from 21 to 135 days. Terminally, the animals showed symptoms of wasting, development of local tumors, or both. Massive leukemic dissemination with infiltration of bone marrow and various organs including lungs, spleen, liver, ovaries, and brain was detected in most cases. No differences were observed in the tissue distribution of sensitive as compared to resistant leukemia cells. These findings demonstrated that human leukemic cells retain, in SCID mice, the clinico-pathologic picture of the original disease in humans. The development of numerous drug-resistant phenotypes in vitro does not alter the subsequent behavior of resistant cells in vivo when compared with sensitive counterparts. The levels of resistance are not modified by passage through SCID mice. This model offers an opportunity for developing new preclinical in vivo systems for modulation of drug resistance, and the combination of this in vivo model with gene transfer methods will also provide an important system for testing the molecular alterations involved in drug resistance and leukemic progression.
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PMID:Growth of sensitive and drug-resistant human myeloid leukemia cells in SCID mice. 786 Apr 33

A 49 year-old man was admitted to our hospital in May 1989, with a cervical tumor and leukocytosis. He had been pointed out leukocytosis for last two years. Peripheral blood examinations demonstrated an increase of leukocytes (39,500/microliters) with low neutrophil alkaline phosphatase, eosinophilia and immature cells. Examination of bone marrow revealed normoplasia with 5.6% eosinophils, 1.4% myeloblasts, 2.6% promyelocytes and 250/microliters megakaryocytes. Cytogenetic analysis disclosed 46, XY, t (12;13) (p13;q12). Southern blot analysis showed no BCR rearrangement. The tumor cells had infiltrated the lymph nodes. Pathological finding agreed with the specimen of the lymph node as in the clot section of bone marrow. He was diagnosed as having a chronic myeloproliferative disorder with tumor formation and was treated with anti-leukemia drugs, including BH-AC, THP, VDS, MTX, VP-16, BUS, 6MP and uvenimex. He showed hematological remission, temporary, but he did not reach cytogenetical remission and died in April 1990. Further study in a large series is necessary to define whether the abnormality of the chromosome with t(12;13) (p13;q12) is characteristic in cases with tumor formation.
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PMID:[Atypical chronic myeloproliferative disorder with translocation (12;13) (p13;q12) and tumor formation]. 786 15

Seventy-three leukemic HLA-identical siblings undergoing BMT received individualized prophylaxis against GVHD based on estimated risk of GVHD development. Patients with an estimated low risk of GVHD were given MTX. MTX + CsA were given to patients having a high risk of GVHD. CsA treatment was discontinued as early as possible after engraftment followed by weekly MTX until 3 months after BMT. Conditioning was busulfan + CY (BuCY, n = 35) or CY/TBI (n = 38). CY/TBI patients given MTX combined with CsA for 1 year served as retrospective controls (n = 39). The incidence of acute GVHD was similar in the three groups. The incidence of chronic GVHD was 59% in the BuCY group and 40% in the CY/TBI group compared with 25% in the controls (p = 0.002 vs BuCY). The incidence of relapse at 2 years was 6% in the BuCY group and 35% in the CY/TBI group (p = 0.01) vs 36% in the control group (p = 0.01 vs BuCY). Actuarial 2-year relapse-free survival was 76, 58 and 51% in the three groups, respectively (p = 0.06, BuCY vs controls). In multivariate analysis individualized prophylaxis was associated with chronic GVHD. Poor survival correlated with high risk leukemia and absence of chronic GVHD. Poor relapse-free survival was associated with high risk leukemia and TBI.
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PMID:Individualized prophylaxis against graft-versus-host disease in leukemic marrow transplant recipients. 795 Nov 24

Transplant related mortality and relapse after bmt have a negative influence on the outcome of patients transplanted for acute leukaemia in first remission. Transplant related mortality includes graft-versus-host disease, infections and graft failure. To prevent gvhd and associated infections without increased graft rejection, a protocol of combined in vivo/ex vivo T-cell depletion (Campath IgG 20 mg i.v. for 5 days and Campath IgM T-cell depleted graft) with no further immunosuppression was initiated. Up to now 22 adult patients (median age 39 years, range 21 to 51) have been transplanted. One graft failure most probably due to persistent leukaemia, three acute gvhd (grade I) and no chronic gvhd occurred. Two patients relapsed after bmt and died. Two further patients died due to idiopathic interstitial pneumonitis and acute liver failure, respectively. Eighteen patients are alive in complete remission. With a median follow up of 13 months (1-30) the probability of survival is 78%, disease free survival is 80% and transplant related mortality is 10%. We compared these results with 3 historical control groups with different regimens of gvhd prophylaxis. 1. MTX group (n = 15): With a median follow up of 135 (115-147) months after bmt the probability of survival is 40%, disease free survival is 40% and transplant related mortality is 60% (mainly gvhd and infection). 2. Campath group (only ex vivo T-cell depletion n = 25): With a median follow up of 86 (62-102) months probability of survival is 52%, disease free survival is 43% and transplant related mortality is 36% (mainly rejection and infection).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro and in vivo depletion of T cells. 812 50

Anti-metabolites are among the most important agents used in cancer chemotherapy. Ara-C, the thiopurines and MTX are active drugs for both induction and maintenance chemotherapy of childhood and adult leukaemia, while the new adenosine analogues are active against hairy cell leukaemia, with promising activity against other malignancies such as malignant lymphomas. Methotrexate and 5FU are being used in the treatment of several solid malignancies. Recent advances in the clinical pharmacology of widely used antimetabolites have shown a relationship among dose, plasma concentrations and clearance with the toxicity and anti-tumour activity. Thus, it has been shown that adaptative control of 5FU administration is possible, limiting the toxicity of this drug. Recent advances in the pharmacogenetics of, for example, 6MP and 5FU will possibly enable researchers to identify patients who may have an increased risk of toxicity. For ara-C, some evidence has been obtained to identify populations at risk of no response. In addition, for most anti-metabolites, convincing evidence of their intracellular (intratumour) metabolism has been obtained, thus making it possible to identify patients who are likely to respond to treatment. These studies (eg accumulation of active metabolites such as ara-CTP, thioguanine nucleotides, FdUMP, MTX-polyglutamates; and inhibition of target enzymes such as thymidylate synthase) have made it possible to develop the basis of biochemical modulation--that is, specific manipulation of intracellular metabolism of the drug. It is anticipated that new technical developments in molecular biology, biochemistry, cell biology and immunology will make it possible to improve the identification of resistant patients in order to modulate specifically drug metabolism in the tumour cells. Biochemical modulation has been successful in achieving significant improvements in treatment and currently is a keystone in cancer chemotherapy. Together with the development of promising new anti-metabolites, biochemical modulation (with other drugs, biologicals) will be a major strategy for the future.
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PMID:Clinical pharmacokinetics of anti-metabolites. 813 39

The carrier protein for methotrexate and tetrahydrofolate cofactors (GP-MTX) in CCRF-CEM human lymphoblastic leukemia cells in a 117 kDa glycoprotein containing both N- and O-linked oligosaccharides (Matherly et al., J Biol Chem 267: 23253-23260, 1992). Tunicamycin, an inhibitor of N-glycosylation, was used to investigate the roles of asparagine-linked oligosaccharides in the structure, intracellular routing, and transport function of GP-MTX. Tunicamycin was growth inhibitory toward CCRF-CEM cells (IC50-0.80 micrograms/mL) and caused a potent suppression of [3H]mannose incorporation into nascent glycoproteins. From 1-3 micrograms/mL, inhibition of [3H]mannose incorporation was 66-87%, exceeding that for [35S]methionine incorporation by 2 to 4-fold. Tunicamycin (1 and 2 micrograms/mL) exposures decreased the median molecular masses of GP-MTX on immunoblots (to 82 and 67 kDa, respectively) and were accompanied by reduced maximal rates of methotrexate uptake (31 and 37%, respectively, of control levels). Conversely, the Ki values for methotrexate binding to the transporter were unaffected by tunicamycin treatments. The effects of tunicamycin on methotrexate influx closely correlated with lower levels of immunoreactive GP-MTX in plasma membranes and specific [3H]methotrexate binding to intact cells, suggesting that the transport effect was due to decreased numbers of carrier proteins at the membrane surface. The reduced molecular mass values for GP-MTX, which accompanied tunicamycin exposures, were further decreased (to 55 and 50 kDa at 1 and 2 micrograms/mL, respectively) by digestions with N-glycanase. Hence, despite the large loss of N-glycan from GP-MTX in tunicamycin-treated cells, residual core oligosaccharides remained. The sizes of hypoglycosylated GP-MTX following both treatments were similar to that of the functionally homologous methotrexate membrane carrier previously identified in L1210 murine leukemia cells.
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PMID:Role of N-glycosylation in the structure and function of the methotrexate membrane transporter from CCRF-CEM human lymphoblastic leukemia cells. 814 10

Six novel antifolates with 2,4-diaminopyrimidine-fused five-membered rings containing either pyrrole or cyclopentene rings were characterized at the cellular and biochemical level. Five of these antifolates were more growth inhibitory to the CCRF-CEM human leukemia cell line than methotrexate [MTX; drug concentration effective at inhibiting cell growth by 50% relative to untreated control (EC50), 12 nM], the antifolate used in the clinic, and two were more potent than 10-ethyl-10-deazaaminopterin (EC50, 2.7 nM); similar patterns of response were obtained in the FaDu and A253 squamous carcinoma cell lines. In addition, the growth inhibitory potency of these antifolates was generally less dependent on exposure time than was MTX. Growth inhibitory effects could be reversed by leucovorin, indicating an antifolate mechanism. These antifolates targeted dihydrofolate reductase (DHFR) based on direct human DHFR inhibition assays [drug concentration inhibiting enzyme activity by 50% (IC50), 0.6-28 nM; MTX IC50, 0.8 nM] and the cross-resistance of MTX-resistant CCRF-CEM cells containing elevated DHFR. Inhibition of human thymidylate synthase was generally weak. These 6,5-fused ring heterocyclic antifolates utilized the reduced folate/MTX transporter for uptake, based on the cross-resistance of MTX uptake-impaired CCRF-CEM cells, and were efficient substrates for this uptake system, based on inhibition of [3H]MTX uptake (IC50, 0.3-5.8 microM; aminopterin IC50, 2.6 microM). These analogues were substrates for CCRF-CEM folylpolyglutamate synthetase, with several being among the most active substrates now known (highest Vrel/Km 0.73; MTX and 10-ethyl-10-deazaaminopterin, 0.013 and 0.24, respectively). Substrate activity for murine intestinal folylpolyglutamate synthetase was also assayed, and a different specificity pattern was observed. These new antifolates are apparently not substrates for aldehyde oxidase. Analogues containing the fused cyclopentene ring are preferred to those containing the fused pyrrole ring based on growth inhibitory potency, effectiveness against decreased uptake mutants and apparent affinity for transport, and inhibition of DHFR. In addition, fused cyclopentene-containing analogues are efficiently polyglutamylated. The data indicate that antifolates with 2,4-diaminopyrimidine-fused five-membered rings, especially those containing the fused cyclopentene ring, are an important new class of antifolates which warrant further exploration at the synthetic and preclinical levels.
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PMID:Novel 6,5-fused ring heterocyclic antifolates: biochemical and biological characterization. 816 96

One of the major complications after high-dose methotrexate (HDMTX) infusions is renal damage. We investigated the occurrence of proteinuria after HDMTX administration in children with pediatric malignancies (acute lymphoid leukaemia, osteosarcoma Burkitt's lymphoma). In the period 1989-1990 we gave 52 HDMTX courses to 24 children. During this period, prehydration and extra urinary alkalisation were performed only if the urinary specific gravity was over 1010 or if the urinary pH fell below 7. Using this schedule the mean values obtained for protein extraction were: before the therapy, 0.12 +/- 0.03 g/m2; on day 1 after MTX treatment, 0.38 +/- 0.06 g/m2; and on day 2 after the MTX infusion, 0.39 +/- 0.11 g/m2 (P < 0.01). A significant increase in proteinuria (> 0.2 g/m2 post- vs pretreatment) was detectable in 54% of the patients. In the period 1991-1992 we modified the hydration-alkalisation schedule to include i.v. prehydration for 18-24 h at 3 l/m2/day with a 0.45% NaCl-5% glucose solution along with sodium bicarbonate and posthydration for 72 h with the same solution. On this protocol the mean values determined for the urinary protein content were all in the normal range (pretreatment, 0.03 g/m2/day; day 1, 0.05 g/m2/day; and day 2, 0.08 g/m2/day). These findings were significantly different from the previous results (P < 0.05).
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PMID:Proteinuria due to suboptimal hydration with high-dose methotrexate therapy. 826 9

Fifteen patients with lymphoid blast crisis of chronic myelogenous leukemia (LyBC-CML) and five patients with acute lymphoblastic leukemia converting to Philadelphia-positive (Ph+) chronic myeloid leukemia (ALL Ph + CML) were followed. Seven of 15 (46.7%) LyBC-CML patients developed meningeal leukemia within a median period of 6 months (range 2-11 months), while there was no medullary relapse. Five of these responded well to triple intrathecal therapy. In the ALL Ph + CML patients, in spite of central nervous system (CNS) prophylaxis with IT MTX and 18 Gy cranial radiation, two of five patients (40%) experienced meningeal leukemia, one isolated and the other with medullary relapse. The data confirm that LyBC-CML patients experience a high incidence of meningeal leukemia. The role of CNS prophylaxis is not very clear, but its use may delay development and reduce morbidity due to CNS disease.
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PMID:High incidence of meningeal leukemia in lymphoid blast crisis of chronic myelogenous leukemia. 831 57

Three cases of acute myeloid leukemia associated with inv(16(p13q22) were followed up for over 5 years. This chromosome aberration is generally thought to be a good prognostic factor. However, it is also reported that these patients are apt to relapse and have relatively high frequency of central nervous system (CNS) involvement. The first patient (M4Eo), who died of gastric cancer about 5 years after the initial treatment without frank relapse, did not have prophylactic therapy for CNS involvement. The second patient (M5b) developed meningeal leukemia and myeloblastoma of the brain, showing similar findings on CT scan to cases reported by Holms et al. He was treated successfully with whole brain irradiation and intrathecal injection of ara-C and MTX, and intracranial tumor disappeared on CT and MR imaging. He has been enjoying a good quality of life without any complication for over ten years after the initial diagnosis. The third patient (M4Eo) relapsed once but reentered complete remission with relative ease and we used an intrathecal injection prophylactically. This case has been followed up as an outpatient for more than 5 years since onset. On the basis of these findings, it may be concluded that these leukemia patients with inv(16)(p13q22) have good prognosis and can be cured with chemotherapy.
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PMID:[Long term follow-up of three cases of acute myeloid leukemia associated with inv(16)(p13q22)]. 841 49


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