Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To test the relationship between DMs and drug resistance in newly established AML cell lines, KY821, and its clone KY821A3, the latter had lost DMs during cloning, were cultured in increasing concentrations of MTX. KY821 became resistant against 2 x 10(-4) M MTX, whereas KY821A3 did against 2 x 10(-5) M MTX in a same period. Enhanced enzyme activities of DHFR were correspondent to the increased DMs numbers and DHFR gene amplification in both resistant clones. The amplified DHFR gene was located on DMs by in situ hybridization. These data indicated that the presence of DMs in KY821 would facilitate the acquisition of drug resistance.
 ...
PMID:A new myeloblastic leukemia cell line with double minute chromosomes. Induction of methotrexate resistance and dihydrofolate reductase gene amplification. 156 Jun 71

The hyperthermia as well as radiation responses of multidrug resistant (CEM/VLB100 with classical MDR and CEM/VM-1 with atypical MDR), methotrexate resistant (CEM/MTX) subclones of CCRF-CEM T-lineage ALL cell line were compared with those of a drug sensitive (CEM-1-3) subclone from the same parent cell line. Also analyzed were the hyperthermia as well as radiation responses of multidrug resistant (HL60/AR) and drug sensitive subclones of the HL60 AML cell line. Notably, the drug resistant subclones of CEM and HL60 were as sensitive to hyperthermia as were the drug sensitive subclones. Importantly, no thermotolerant plateau was observed in the hyperthermia survival curves of the drug resistant subclones, indicating that drug/multidrug resistance is not associated with a greater likelihood of thermal tolerance development during hyperthermia. Similarly, the drug resistant CEM and HL60 subclones were not more radiation resistant than the drug sensitive subclones. Thus, the classical or atypical forms of multidrug resistance or methotrexate resistance of the analyzed leukemic cell lines were not associated with radiation resistance. Furthermore, the radiation survival curves of the drug resistant subclones lacked a distinct initial shoulder and their n values were not greater than those of the drug sensitive subclones, suggesting that multidrug resistance is not associated with an increased ability to repair or accumulate sublethal radiation damage. Our findings provide evidence that there is no apparent association between drug/multidrug resistance and heat or radiation sensitivity of CEM T-lineage ALL or HL60 AML leukemia cells. The results of this study indicate that acquired resistance to methotrexate, vinblastine, vincristine, etoposide, actinomycin-D, adriamycin, or daunomycin, or pleiotropic multidrug resistance do not necessarily confer radiation resistance for human leukemic cells.
 ...
PMID:Radiation and heat sensitivity of human T-lineage acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) clones displaying multiple drug resistance (MDR). 157 9

The effects of methotrexate (inhibiting dihydrofolate reductase) and nitrous oxide (inactivating methionine synthase) on intracellular folate coenzyme levels of leukemic cells were studied. Blast cells from 10 cases of acute myeloid leukemia (AML) and 5 cases of acute lymphoid leukemia (ALL) were incubated with 5 x 10(-8) M [3H] 5-formyltetrahydrofolate (5-formylTHF) for 18 h to label intracellular folate pools, which were subsequently quantitated by high performance liquid chromatography (HPLC). In AML, 5-methylTHF made up 53% of the total folate pool followed by 10-formylTHF (26%), 5-formylTHF (10%), THF (9%) and DHF (1%). Cells from ALL differed from AML (p less than 0.05) with respect to 10-formylTHF (17%) and DHF (10%). Exposure to nitrous oxide (8 h) caused an equal decrease of 10-formylTHF and 5-formylTHF in both AML (30%) and ALL (45%), whereas 5-methylTHF increased (130%). Methotrexate (4 h, 10(-6) M) caused an accumulation of DHF and a decrease of 5-methylTHF in both AML (32%) and ALL (12%). A specific reduction of the 10-formylTHF (50%) and 5-formylTHF (25%) pools was noticed in ALL. Exposure to nitrous oxide prior to methotrexate treatment aggravated the reduction of 10-formylTHF and 5-formylTHF presumably by impaired replenishment from the 5-methylTHF pool. In conclusion, this study demonstrates a significant difference in folate coenzyme distribution between cells from AML and ALL. Moreover it is shown that nitrous oxide and methotrexate treatment of leukemic cells cause an accumulation of 5-methylTHF and DHF respectively at the expense of other folate forms. The presence of substantial amounts of DHF in cells from ALL together with the specific reduction of 10-formylTHF (necessary for purine synthesis) during MTX treatment may in part explain the efficacy of methotrexate in the treatment of ALL.
 ...
PMID:Effect of nitrous oxide and methotrexate on folate coenzyme pools of blast cells from leukemia patients. 201 7

From May 1985 to July 1989, 76 patients with leukemia (30 acute myelogenous leukemia, 24 acute lymphoblastic leukemia and 22 chronic myeloid leukemia) were randomized to receive either cyclosporin (CSP) alone (n = 39) or CSP combined with methotrexate (CSP + MTX, n = 37) for graft-versus-host disease (GVHD) prophylaxis. Patients were conditioned with total body radiation and cyclophosphamide followed by bone marrow infusion from an HLA-identical sibling. Engraftment of the transplanted bone marrow was similar in both groups. The incidence of moderate to severe acute GVHD was significantly higher in the CSP group compared with the CSP + MTX group (20 (51%) versus 9 (25%), chi 2 = 4.76, p less than 0.02). There was no significant difference in the incidence of chronic GVHD. Survival was significantly better for the CSP + MTX group (63 +/- 16%) compared to CSP alone (42 +/- 18%). Leukemia-free survival tended to be better for the CSP + MTX group (55 +/- 17% versus 32 +/- 16%).
 ...
PMID:Combination of cyclosporin and methotrexate for prophylaxis of acute graft-versus-host disease after allogeneic bone marrow transplantation for leukemia. 220 50

We report a single center experience of 222 patients (pts) less than 18 years old transplanted from 1973 to 1987. The median age was 11 years (1-18). The donor was a monozygotic twin (9 pts), an HLA-id sibling (193 pts), an HLA-id, parent (9 pts), a mismatched related donor (9 pts) and a matched unrelated donor (1 pt). Ninety-six pts were transplanted for SAA. Conditioning varied with time but the majority (59 pts) received CY 150 mg/kg and 6 Gy TAI. The long term actuarial survival is 66% with a median follow-up of 3 years. The group who received CY 200 mg/kg and MTX had a 33% long term survival (LTS). GVH was the main complication with 40% acute and 37% chronic GVHD. Chronic GVHD tended to improve with time after 2 to 4 years of evolution. Ninety pts were transplanted for leukemia (35 AML, 45 ALL and 11 CGL), 20 pts were in relapse. Pts in CR had a LTS of 40%, in pts in relapse, it was 12%. The main causes of death were: interstitial pneumonitis (30%), relapse (27%), GVH (15%). Thirty-five pts were transplanted for constitutional disease: Fanconi anemia (FA) (26 pts), Dyskeratosis congenita (2 pts), Blackfan-Diamond erythroblastopenia (2 pts), Glanzmann thrombasthenia (1 pt), osteopetrosis (1 pt) and Gaucher's disease (1 pt). In FA, the LTS is 70% with a CY 20 mg/kg, 5 Gy TAI regimen. In all disease categories, we did not find any influence of donor's sex on GVH and survival.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Pediatric bone marrow transplantation for leukemia and aplastic anemia. Report of 222 cases transplanted in a single center. 267 24

The mechanisms of action of MTX and 5-FU have been further elucidated. Such studies will be important for the design of drug combinations and for the development of novel antifolate and fluoropyrimidine analogs. A greater understanding of MTX and ara-C transport and drug levels required to optimize transport may also aid in these endeavors. Pharmacokinetic parameters have been found to be predictors of relapse in children with acute leukemia, particularly with respect to MTX, 6-MP and ara-C. The intracellular terminal half-life of ara-C was correlated with remission duration in AML. Assay systems aimed at uncovering response predictors through biochemical analysis of patient tumor samples are being developed, including an interesting use of NMR spectroscopy to study the pharmacokinetics of fluorine-19-labeled 5-FU in vivo. Such an approach may yield valuable information on 5-FU anabolism in tumors in situ. A high frequency of resistance to MTX apparently may be generated within a single cell cycle by transient exposures to DNA synthesis inhibitors. The resistance may be based on either target enzyme amplification or altered membrane transport. These important studies provided bases for the rapid emergence of clinical resistance. Further, the multidrug-resistant phenotype appears to be a much broader based phenomenon as MTX resistance was found to be a frequent event in cells selected for multidrug resistance. A variety of novel approaches have been proposed to overcome antimetabolite resistance and to improve the selectivity of these agents, including the use of guanosine nucleotides, leucovorin and allopurines as biochemical modulators of 5-FU. Efficient techniques for the transfection of resistant DHFR into tissues using retroviruses have been reported. These studies serve as starting point for the ultimate development of more effective strategies for the treatment of human malignancies.
 ...
PMID:Antimetabolites. 307 79

In Essen 142 bone marrow transplantations were carried out between December 1975 and February 1985. In 74 cases the indication was acute leukemia in relapse (n = 23) or in first or consecutive remission (n = 51). The conditioning regimen consisted of cyclophosphamide or the combination of cyclophosphamide and total body irradiation. All patients were treated under strict gnotobiotic care. To mitigate the risk of CMV infections, intravenous CMV-hyperimmune globulin and CMV-negative blood products have been applied routinely for 2 years. MTX was used as prophylaxis against GvHD. In the prognostically unfavorable group of acute leukemia in relapse, only one patient showed long-term survival. In this patient, leukemic relapse occurred 6 years after transplantation. The survival rate of AML patients grafted during the first remission is 55% (16/29) with a median observation time of 41 months. For patients grafted in first or consecutive remission of acute lymphoblastic leukemia, the survival rate is 50% (7/14) with a maximal observation time of 34 months. The overall incidence of GvHD in patients at risk was 28% in aplastic anemia, 26% in AML, 9% in ALL, and 63% in CML. In aplastic anemia, no patient developed an interstitial pneumonia. In leukemia, the risk of fatal interstitial pneumonia was 34%.
 ...
PMID:Bone marrow transplantation in acute leukemia. 330 98

In Essen 121 bone marrow transplantations were carried out. The indications were severe aplastic anemia (n = 18), acute leukemia in relapse (n = 20), acute leukemia in remission (n = 46) or chronic myeloid leukemia (n = 37). The conditioning regimen consisted of cyclophosphamide or the combination of cyclophosphamide and total body irradiation. All patients were treated under strict gnotobiotic care. To mitigate the risk of CMV infections intravenous CMV-hyperimmunoglobulin and CMV-negative blood products have been applied routinely since two years. MTX was used as prophylaxis against GVH-disease. In case of severe aplastic anemia 13 patients (72%) are still alive with a median observation time of 24 months. In the prognostically unfavourable group of acute leukemia in relapse only one patient showed long term survival. In this patient leukemic relapse occurred six years after transplantation. The survival rate of AML patients grafted during the first remission is 55% (15/27) with a median observation time of 40 months. For patients grafted in first or consecutive remission of ALL the survival rate is 42% (5/12) with a maximal observation time of 29 months. Out of 37 patients grafted because of CML, eight were in an advanced stage of the disease. 13 patients are still alive, the maximal observation time is 37 months. The overall incidence of GVHD in patients at risk was 28% in aplastic anemia, 26% in AML, 9% in ALL and 63% in CML. In aplastic anemia no patient developed an interstitial pneumonia. In leukemia the risk of fatal interstitial pneumonia was 34%.
 ...
PMID:Bone marrow transplantation in severe aplastic anemia and acute or chronic leukemia. 351 96

Only few patients (3,8%) affected by ANLL survive for more than 3 years from the time of diagnosis. In the present study the Authors try to determine which clinical and haematological factors can determine long-terme survival. The Authors describe the case of a male patient (25 years old) affected by ANLL (M2), who became and is still now a long-survivor (80 months from 1th complete remission). He has been treated with DNB, ARA-C and TG (TRA schedule) for two cycles. After CR he refused consolidation and reinduction therapy and was treated only with 6-MP and MTX for 3 years, as maintenance chemotherapy. The Authors suggest that important factors for a favourable prognosis are early diagnosis and young age. A relatively high number of platelets can be correlated with a good prognosis.
 ...
PMID:[Lung survival or healing? Description of a case of acute non-lymphoblastic leukosis]. 623 4

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)
 ...
PMID:[Acute leukemia]. 647 26


1 2 3 4 5 Next >>