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 effects of methotrexate, 5-fluorouracil, 5-fluoro-2'-deoxyuridine on the growth of human leukemic T-lymphoblasts, CCRF-CEM, were determined as a function of drug concentration and exposure time. Substantial inhibition of cell growth (greater than or equal to 90%) was obtained with short duration of exposure (4 h) for MTX (ED90 = 4.3 microM). 5-fluorouracil was a relatively ineffective cytotoxic agent for exposure of short duration (4 h). Only exposure of 24 and 72 h resulted in cell growth inhibition greater than or equal to 90% with this drug. In terms of a ED90, 5-fluoro-2'-deoxyuridine was about 190- and 1300-fold more active than 5-fluorouracil for 24 and 72 h exposures, respectively (0.4 vs 75 microM and 0.01 vs 26 microM). Sequential exposure to methotrexate (4 h) and 5-fluorouracil during the last 2 h of methotrexate exposure resulted in synergistic inhibitory effects on cell growth. Antagonistic inhibitory effects on cell growth of methotrexate and 5-fluoro-2'-deoxyuridine combinations were observed independently of drug concentrations. Pretreatment (4h) with 5-methyltetrahydrofolate, the reduced folate to which leucovorin is rapidly converted in vivo, potentiated cell growth inhibitory effects of subsequently administered 5-fluorouracil or 5-fluoro-2'-deoxyuridine. These results provide information on scheduling of methotrexate or reduced folates and fluoropyrimidines that might have potential importance in the development of clinical trials designed for patients with leukemia and lymphoma.
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PMID:Modulation of fluoropyrimidine cytotoxicity by methotrexate or 5-methyltetrahydrofolate in human leukemia cells in vitro. 624 7

This article summarizes studies conducted in children with acute lymphoblastic leukemia (ALL) who received intrathecal methotrexate (IT MTX) to prevent or treat central nervous system (CNS) leukemia. To better understand the pharmacologic requirements of intrathecal chemotherapy directed against CNS leukemia, this report begins with a review of the pathophysiology of CNS leukemia and the clinical aspects of this disease manifestation that influence IT MTX therapy. The pharmacokinetics of IT MTX are then presented and the review is concluded with observations on the importance of the dosage regimen.
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PMID:Intrathecal methotrexate versus central nervous system leukemia. 639 86

Within a few years of the introduction of effective systemic chemotherapy for the treatment of acute leukemia, central nervous system (CNS) leukemia emerged as a significant problem. The strategy for treatment of leukemia is that one achieves cure by destruction of all leukemic cells, through this cannot be verified with present technology. The incidence of CNS-leukemia and the factors influencing this complication have been studied in a group of 131 cases with acute childhood leukemia. The overall incidence of CNS-leukemia was 30% in acute lymphocytic leukemia (ALL), 8% in acute myeloblastic leukemia (AML). However, cumulative incidence of CNS-leukemia calculated by modified Life-Table Method showed 56.8% in children who survived over 48 months after diagnosis of ALL. It was considered that the chief cause of the increased incidence of this complication was prolongation of survival. The CNS-leukemia was significantly greater in patients with under 10 year of age (p greater than 0.05), high initial leukemic cell counts (p less than 0.025), high appearance rate of leukemic cells in peripheral blood (over 50%) (p less than 0.005), and hepatosplenomegaly, especially lymph node enlargement (p less than 0.05). Blood-borne metastasis was considered to be probably the chief route of leukemic infiltration to the CNS. Between 1972 and 1978, 153 children with ALL were treated with multiple methods of CNS-prophylaxis, and were analyzed in relation to treatment regimens, age, sex and initial hematologic status. Patients received CNS-prophylaxis; Group I: three doses of intrathecal methotrexate (MTX 12 mg/m2) and hydrocortisone (HDC 12 mg/m2), Group II: same as in Group I followed by cyclic MTX and HDC, Group III: same as in Group I plus 2,400 rads of cranial irradiation. CNS-leukemia terminated complete remission 25 of 153 patients (16.3%). The cumulative incidence of CNS-leukemia at 4 year calculated by the Kaplan-Meier Method was 40.5% in Group I, 26.9% in Group II, and 14.5% in Group III. Development of CNS-leukemia was more frequent in male than in female (p less than 0.05), and in patients with initial high leukocyte counts (WBC greater than 25,000/mm3). We conclude that the combination of cranial irradiation and intrathecal MTX and HDC was highly efficacious. However, more intensive CNS-prophylaxis should be needed for such a high risk patients in male with high initial WBC.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Acute leukemia]. 647 26

Studies were undertaken to investigate the relationship between cell-mediated and humoral immune responses in the rejection of L1210/MTX-Rev (LR) leukemia cells in CD2F1 mice. The anti-LR antibody (humoral) response was defined by both its cytotoxic antibody titer and isotype composition, assessed by a complement-dependent cytotoxicity assay and radioimmune assay, respectively. The cytotoxic thymus (T)-derived lymphocyte response in the spleen was quantitated by 125I release by 125I-IUdR-labelled target cells. Analysis of the sera of tumor-bearing mice indicated that the LR leukemia cells elicited a wide spectrum of anti-tumor antibody isotypes. In mice that mounted a rejection response, the IgM anti-LR response was transient, while in those that did not, the IgM response persisted. Antibody titers for all isotypes remained low until the onset of LR rejection. At that time, high titers of IgG anti-LR antibodies, predominantly of the IgG2a subclass, were detected in sera of tumor-free mice. Thus, the LR rejection response coincided best with the appearance of high titers of IgG2a anti-LR antibodies. A single i.p. injection of viable LR cells elicited a potent cell-mediated immune response; neither the appearance nor the magnitude of the cell-mediated immune response as measured in the spleen correlated well with the onset or the strength of the LR rejection response in the peritoneal cavity. The LR peritoneal cell population grew unabated in the presence of an intense spleen cell-mediated immune response, and the rejection process began at a time when little cellular immunity could be detected. These results suggest that in the rejection response IgM antibodies contribute little, if any, to the process, and the role of cytotoxic T lymphocytes is questionable (uncertain). The rejection of LR cells appears to be primarily mediated by IgG2a antibodies.
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PMID:Immune rejection mechanisms in murine leukemia. I. Timing of tumor cell rejection process relative to the development of humoral and cell-mediated cytotoxic immune responses. 650 Jul 45

In acute lymphoblastic leukemia (ALL), central nervous system (CNS) prophylaxis with cranial irradiation plus 5 doses of intrathecal methotrexate (i.t. MTX) reduces the incidence of CNS relapse to 7%-15%. However, increased evidence of CNS delayed toxicity started to be recognized as CT scan abnormalities and neuropsychologic alterations, mainly in children. Two questions were analyzed in the present report: (1) Will further doses of i.t. methotrexate and dexamethasone (i.t. MTX-DMT) decrease the incidence of CNS relapse in patients treated early in remission with cranium irradiation plus i.t. MTX-DMT even more? (2) Is i.t. MTX-DMT given during induction and maintenance equally as effective as cranium irradiation plus i.t. MTX-DMT? A randomized study was designed to answer the first question. Incidence of primary CNS relapse in i.t. MTX-DMT-treated patients with a WBC count less than 50,000 was 11% (15 of 135 patients) and was 11% (17 of 150) in the untreated group. In patients with a WBC count greater than 50,000, it was 16% (6/37) in the treated group and 19% (6/31) in the control group. No difference was observed according to treatment in both prognostic groups. Patients in this study were retrospectively compared with a consecutive protocol in which patients received 3 doses of i.t. MTX-DMT alone during induction plus 3 doses weekly during the first month of remission and every 3 mo thereafter. The incidence of primary CNS leukemia at 60 mo in patients with a WBC count less than 50,000 was 20% in the irradiated group and 32% in the group with i.t. MTX-DMT alone. This difference was not significant. However, the relapse-free survival at 60 mo was 26% and 41%, respectively, (p less than 0.0005). The incidence of primary CNS relapse in patients with a WBC count more than 50,000 at 48 mo was 28% in the irradiated group and 42% in the nonirradiated group. The difference was not significant. The duration of complete remission was similar, remaining at 15% and 16% of patients disease-free at 48 mo, respectively. We conclude that (A) after cranial irradiation plus i.t. MTX-DMT X 5, the use of additional doses of i.t. MTX-DMT is not of further benefit in preventing CNS relapse; (B) the use of i.t. MTX-DMT alone compares similarly with cranial irradiation plus i.t. MTX-DMT in the incidence of CNS relapse; and (C) relapse-free survival and survival in patients with a WBC count less than 50,000 were significantly longer in those without cranial irradiation.
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PMID:Comparison of central nervous system prophylaxis with cranial radiation and intrathecal methotrexate versus intrathecal methotrexate alone in acute lymphoblastic leukemia. 657 36

Fourteen children were treated for isolated meningeal relapse occurring seven to 44 months (median, 14 months) after prophylactic cranial irradiation (2,400 rad/12 fractions) and intrathecal methotrexate (IT MTX, 12 mg/m2 for four doses during cranial irradiation). Eight had "high-risk" acute lymphocytic leukemia with age less than 2 years, white blood cell counts greater than 20,000, or T cell markers. Treatment for central nervous system leukemia included IT MTX (12 mg/m2 twice weekly until clearance of spinal fluid cytology) followed by craniospinal irradiation (CSI, 3,000 rad/20 fractions to the cranium and 1,800 rad/12 fractions to the spine). No maintenance IT MTX was given. Systemic chemotherapy was continued or reinstituted for a minimum of one year after CSI. No instance of second meningeal relapse has occurred. Five patients remain in secondary complete remission 66+, 54+, 36+, 26+, and 24+ months after meningeal relapse. Disease-free survival was limited by marrow relapse in eight patients (2-20 months after CSI) and testicular relapse in one. No acute toxicities were noted with CSI. Myelosuppression occurred in seven patients. Infections within two months of CSI were noted in five. No neurologic sequelae are apparent. Serial neuropsychometric studies in 10 patients revealed a significant decline in mean values on Global IQ scales. Long-term survival with acceptable toxicity is possible following aggressive, prompt treatment of meningeal relapse occurring after prophylactic cranial irradiation. Hematologic relapse remains the major obstacle to long-term disease-free survival.
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PMID:Treatment of meningeal relapse in childhood acute lymphoblastic leukemia. I. Results of craniospinal irradiation. 658 15

58 children were admitted to a prospective randomized leukemia induction and CNS-prophylaxis three different protocols were followed for maintenance. A (n = 20): 6-MP (50 mg/m2) p.o. daily + MTX (20-30 mg/m2) p.o. weekly; B (n = 20): 6-MP (50 mg/m2) p.o. daily + MTX (75-150 mg/m2) i.v. every two weeks; C (n = 18): 6-MP (50 mg/m2) p.o. daily + alternating 8-week-courses of four biweekly i.v. injections of MTX (75-150 mg/m2) and four biweekly i.v. injections of Cyclo (600 mg/m2). After all patients have been followed for at least 48 months, the rates of continuous complete remission are 42% in protocol A, 63% in protocol B, and 29% in protocol C. No encephalopathies have been observed with regimen B.
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PMID:[Which is the best methotrexate schedule for maintenance therapy of childhood ALL? A randomized study]. 675 58

Children suffering from leukaemia in Hungary are treated according to uniform therapeutic protocols in the framework of a national multi-centre study. Their most important clinical data are stored in the central registry and are analyzed by computerized methods. Since January, 1971, 846 new patients were entered in the registry. Initially treatment results were very poor but showed gradual improvement during the past few years, somewhat parallel to more intensive chemotherapy. The latest treatment protocol includes medium-dose MTX and the combination of ARA-C and VM-26. Preliminary data are encouraging.
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PMID:The treatment of childhood leukaemia in Hungary. On behalf of the Hungarian Working Party on Childhood Leukaemia. 681 80

Central nervous system (CNS) "prophylaxis" is critical in the treatment of acute lymphocytic leukemia (ALL). The standard method employed combines cranial radiation (CRT) and intrathecal methotrexate (IT MTX). Recently, a 52% incidence of abnormal computed tomography (CT) brain scans was found in asymptomatic children with ALL whose CNS prophylaxis consisted of CRT and either IT MTX or intrathecal cytosine arabinoside (IT Ara-C). In the present study, CT brain scans were studied in 43 asymptomatic children with ALL in continuous complete remission. The CNS prophylaxis consisted of IT MTX alone in 10 patients and IT MTX combined with intermediate-dose intravenous MTX in 33 patients. No patient had received CRT. The patients' ages at the time of diagnosis ranged from 22 months to 17 years, 7 months. The time interval from completion of CNS prophylaxis to CT scanning ranged from ten to 59 months. Only one CT scan was clearly abnormal; it showed mildly dilated ventricles and visualization of the cortical sulci. The CT scans of 7 additional patients were classified as abnormal because of borderline dilatation of the lateral ventricles (3 patients) and/or visualization of the cortical sulci (7 patients). No patient demonstrated areas of decreased cerebral attenuation coefficient or intracerebral calcification--findings previously ascribed to the use of methotrexate. Clinical leukoencephalopathy has not been observed in any of our patients. This would suggest that MTX alone in the absence of CNS leukemia or CRT is highly unlikely to produce structural CNS abnormalities detectable by CT.
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PMID:Computed tomography brain scans in children with acute lymphocytic leukemia receiving methotrexate alone as central nervous system prophylaxis. 692 24

Thirty eight patients with acute lymphoblastic leukemia were treated protocol 0171 (VCR, PRED, MTX, cyclophosphamide +/- +/- 6-MP) and protocol 0276/A (VRC, PRED, L-ASP, MTX, 6-MP, cyclophosphamide). Overall complete remission rate in both studies was 84--85%, and additional treatment in protocol 0171 resulted in complete remission rate of 92%. Median duration of complete remission in protocol 0171 was 23 months and median survival of all patients was 33 months. Six patients randomized to regimen "A" (without 6-MP in intensification) had median duration of complete remission 8 months and media survival was 13 months. Seventeen patients treated with regimen "B" (with 6-MP in intensification) had median duration of complete remission 25 months and median survival was 39 months. Median survival of patients allocated on protocol 0276/A in 21+ months and median duration of complete remission is 23 months at present. Twelve percent of patients treated with the best regimen have survived more than 66 months in continuous complete remission. The incidence of drug related death in complete responders was 6%. The relapses were most frequent during the first two years of remission. Extramedullary leukemia as the initial site of relapse was observed in 9% of patients.
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PMID:Treatment of adult acute lymphoblastic leukemia: results of two trials. 702 59


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