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

The present AML protocol which only applies one anthracycline associated with arabinosyl-cytosine gives a first remission plateau of 65% and a 75% survival plateau at five years. Contrary to other teams, we do not apply the allogenic bone marrow graft at the first remission but at the second one. The new protocol comprises application of two anthracyclines, adriamycin and aclacinomycin, a possible autologous bone marrow graft at first remission upon reinforcement, a combination of methotrexate and thioguanine as maintenance chemotherapy and immunotherapy with bestatine. The two protocols respectively applied to the ALL good prognosis and reserved prognosis, give 85% global survival. The autologous bone marrow graft is added at first remission to B or T forms or voluminous CALLA + types. The advantage of CNS radiotherapy is compared with its disadvantages. Bestatine is employed in immunotherapy. The immunoprevention protocol applied to CML blastic crisis (vaccination with a pool of CB blasts) from the second year has prolonged survival of patients suffering from this affection and also treated by splenectomy and hydroxyurea. Allogeneic or autologous bone marrow graft is added to the protocol. The same protocol is applied to not very aggressive LLC and LNH (lymphocytic and centrofollicular with small cleaved nucleus cells) and includes maximum remission induced by chemotherapy followed by immunotherapy (by thymuline and then, if immunity disorders are not corrected, by zinc, then bestatine and finally tuftsin). A similar sequence was applied to the myeloma, comprising MLP-PDN-CPM chemotherapy to induce remission, combination of MLP-PDN and CPM and, if there is resistance, CLB, 6-TG, PDN and TNP. Interferon is appropriate with certain cytopenic forms. A protocol comprising VCR, ADM, PDN, CPM and TNP is applied to centrofollicular NHL with small non cleaved nucleus cells or large cells. As Hoerni and Jones have obtained significant benefits with BCG, its terminal application is compared with that of bestatine. Finally a less mutagenic protocol than MOPP and/or ABVD is proposed for Hodgkin's disease. In this protocol, two cycles alternate, and they combine: a) firstly VCR, PDN, THP-ADM and VPS, and b) secondly VLB, DXM, ACM and TNP with alternatively BLM and PPM between the cycles. This chemotherapy is followed by the same immunorestoration protocol as that applied to LLC and myeloma.
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PMID:[Protocols for the treatment of leukemia and lymphoma: toward escalation or toward reduction of degree?]. 638 Jun 5

Twenty-seven children with Hodgkin's disease were treated with MVOPP (mustine, Velban [vinblastine], Oncovin [vincristine], procarbazine, prednisone) combination chemotherapy. All 11 children with Stage I or Stage II disease achieved complete remission and no relapses have occurred between 34 and 179 months of continuous follow-up. Of the 16 children with Stage III or Stage IV disease, two with partial remission and three nonresponding patients died with a median survival of 18 months. The remaining 11 (68%) achieved complete remission. Of these, 6 (55%) have relapsed with a median remission duration of 36 months; five have been retreated with MVOPP, and one with total nodal irradiation, and all achieved second complete remission. Three of the children have died of Hodgkin's disease, with a median survival of 55 months; one child died of acute myeloblastic leukemia while in remission; and one child remains disease-free off all therapy at 165 months; the sixth child treated with total nodal irradiation is disease-free at 166 months. The initial complete remission has been sustained in all 11 children with Stage I or Stage II Hodgkin's disease, suggesting that combination chemotherapy is an alternative to radiotherapy as the initial form of treatment in this group of individuals.
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PMID:Hodgkin's disease in children. A ten-year experience in South Africa. 654 99

Overexpression of P-glycoprotein (PGP), MRP or LRP has been characterized as the 'proximal', while overexpression of the anti-apoptosis Bcl-2 or Bcl-xL relative to the pro-apoptosis Bax protein has been recognized as the 'distal' mechanism of multidrug resistance in human AML cells. In the present studies, we examined whether these mechanisms can co-exist in human AML HL-60 cells. We also determined how these mechanisms would affect the accumulation and cytotoxicity of a PGP substrate, such as Taxol (paclitaxel). For this, immunoblot analyses were performed to determine the expression of PGP, MRP, Myc, Bcl-2, Bcl-xL and Bax on either the multidrug-resistant HL-60 sublines created under the selection pressure of doxorubicin (HL-60/AR), paclitaxel (HL-60/TAX1000) or vincristine (HL-60/VCR), or sublines created by transfection and overexpression of the bcl-2 (HL-60/Bcl-2) or bcl-xL gene (HL-60/Bcl-xL). As compared to the control HL-60, HL-60/AR cells possess high MRP while HL-60/TAX1000 and HL-60/VCR cells express high levels of the mdr-1 encoded PGP. In addition, these multidrug-resistant cells possess 1.5- to 2.5-fold higher Bcl-2, while their Bax and Myc levels are similar to those in the control HL-60 cells. HL-60/TAX1000 and HL-60/VCR cells also express three- and 2.5-fold higher Bcl-xL levels. PGP, but not MRP, overexpression significantly impaired paclitaxel accumulation and paclitaxel-induced apoptosis, as well as reduced its cytotoxic effects as determined by the MTT assay. In contrast, enforced and much higher expression of Bcl-2 in HL-60/Bcl-2 (five-fold) or Bcl-xL in HL-60/Bcl-xL cells (10-fold) significantly reduced paclitaxel-induced apoptosis and the loss of cell viability, without affecting its intracellular accumulation. These results confirm the possibility of co-expression of multiple mechanisms of multidrug resistance in human leukemic cells which had been selected by exposure to a single drug. The results also indicate that MRP overexpression does not confer resistance against paclitaxel. In addition, these findings suggest that, for Bcl-2 and Bcl-xL, enforced overexpression to high levels is necessary to induce paclitaxel resistance in HL-60 cells.
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PMID:Co-expression of several molecular mechanisms of multidrug resistance and their significance for paclitaxel cytotoxicity in human AML HL-60 cells. 900 89

We report here on treatment results of consecutive CCLSG NHL studies (NHL855, 1985-1989; NHL890, 1989-1996). The NHL855 protocol consisted of an induction phase of five drugs (VCR, PRD, CPM, DXR, and high-dose MTX) and a maintenance phase of 7 drugs. The probabilities of EFS at 7 years were 78% (SE, 10%) for the patients with localized disease, and 38% (SE, 7%) for those with advanced disease. In the NHL 890 protocol, the patients were assigned to two different treatment groups according to their histology and received different consolidation therapy; non-lymphoblastic subtype was treated almost identically to NHL855 while LASP and VP-16 were newly added for the lymphoblastic subtype. The 7-year EFS improved to 91% (SE, 6%) for localized disease, and 61% (SE, 6%) for advanced disease. A remarkable improvement was particularly evident for lymphoblastic type with mediastinal mass. Optional trial of high-dose sequential chemotherapy and peripheral blood progenitor cell auto grafting resulted in an unfavorable outcome. The 7-year EFS according to main histological subgroups were as follows: 84% (10%) for large cell type, 67% (11%) for Burkitt's-type, 58% (10%) for lymphoblastic type. Secondary cancer occurred in two of the 163 patients studied. Both patients were AML (M0/M4) and MLL rearrangement was detected in the M4 case.
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PMID:[Treatment of children with non-Hodgkin's lymphoma with CCLSG NHL 855/890 protocols long-term outcome and incidence of secondary malignancies]. 959 95

In this report, the molecular mechanisms involved in the overexpression of MDR1 mRNA in the multidrug resistant variant of the HL60 human acute myeloid leukemia cell line, HL60/VCR, were investigated. RT-PCR and nuclear run-on assays revealed that the expression of MDR1 mRNA is regulated by increased transcriptional initiation in HL60/VCR cells. Transient transfections with a 241 bp MDR1 promoter (spanning the -198 to +43 region) DNA fragment/pGL3-basic plasmid construct resulted in about 6-fold increased luciferase activity in HL60/VCR but not in HL60 cells. Moreover, ds CAAT-oligomer from the MDR1 promoter cloned upstream of the SV-40 promoter in the pGL3-promoter plasmid caused about a 7-fold increase in luciferase activity compared with plasmid constructs containing CAAT-deleted, GC-box, and nonspecific oligomers in HL60/VCR transfectants. These results were confirmed by transfecting HL60/VCR cells with the pGL3-basic plasmid containing a 237 bp mutated MDR1 proximal promoter lacking the CAAT sequence in which no change in luciferase activity was observed. However, a 5-6-fold increase in luciferase activity was measured in these cells when transfected with the wt MDR1 promoter DNA/pGL3-basic plasmid constructs. These results show that the CAAT-region is involved in upregulating the MDR1 promoter in HL60/VCR cells. A nuclear factor binding to the CAAT-region of the MDR1 promoter specifically was detected in electrophoretic mobility shift assays (EMSAs) in HL60/VCR but not in HL60 extracts. Two MDR1 promoter-associated polypeptides with molecular masses of about 130 and 162 kDa were identified in HL60/VCR cells by electroelution, specific DNA-affinity chromatography, and silver staining. Interestingly, cross-linking and Southwestern analysis indicate that only the 130 kDa protein, which we refer to as MDR1-promoter enhancing factor 1 (MEF1), has a strong DNA-binding ability, interacting with the 5'-GTCAATCC-3' element of the MDR1 promoter, as determined by DNase I protection assay. These data reveal that MEF1 upregulates the MDR1 promoter activity.
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PMID:Identification and characterization of the MDR1 promoter-enhancing factor 1 (MEF1) in the multidrug resistant HL60/VCR human acute myeloid leukemia cell line. 1062 94

The curability of pediatric cancer has been improved to nearly seventy percent. This change has been achieved by refinements in treatment strategy and supportive care. More than seventy percent of patients with ALL can be cured by modern chemo-radiotherapy with reduced late effects. The stratification of the patients by risk factor, introduction of CNS prophylaxis, shortening of the duration of chemotherapy and intensification of the chemotherapy with agents such as HD-MTX have contributed to this remarkable success. Burkitt's lymphoma is a tumor for which the curability has improved from almost zero to ninety percent. With Wilms' tumor, clinical trials have been used to optimally refine the treatment strategy. The NWTS first compared the efficacy of combined VCR and Act-D with the single use of each drug. The difference was significant. The results of the systematic trials were then used to improve the survival rate of patients with Wilms' tumor from twenty to ninety percent and shorten the duration of chemotherapy to six months. On the other hand, tumors remain with which less than half of patients can survive for long. Advanced neuroblastoma and AML are typical such tumors. With these diseases, refinements in the treatment based on evidence derived from clinical trials have been insufficient. Further intensification of the treatment or novel approaches to control tumor growth are warranted for these diseases. In this article, I would like to describe the "standard" therapy for each tumor and the evidence on which improvements in those strategies have been based.
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PMID:[Evidence based chemotherapy for pediatric cancers]. 1070 Aug 90

DT(388)-GM-CSF, a targeted fusion toxin constructed by conjugation of human granulocyte-macrophage colony-stimulating factor (GM-CSF) with the catalytic and translocation domains of diphtheria toxin, is presently in phase I trials for patients with resistant acute myeloid leukemia. HL-60/VCR, a multidrug-resistant human myeloid leukemia cell line, and wild-type HL-60 cells were used to study the impact of DT(388)-GM-CSF on metabolism of ceramide, a modulator of apoptosis. After 48 hours with DT(388)-GM-CSF (10 nM), ceramide levels in HL-60/VCR cells rose 6-fold and viability fell to 10%, whereas GM-CSF alone was without influence. Similar results were obtained in HL-60 cells. Examination of the time course revealed that protein synthesis decreased by about 50% and cellular ceramide levels increased by about 80% between 4 and 6 hours after addition of DT(388)-GM-CSF. By 6 hours this was accompanied by activation of caspase-9, followed by activation of caspase-3, cleavage of caspase substrates, and chromatin fragmentation. Hygromycin B and emetine failed to elevate ceramide levels or induce apoptosis at concentrations that inhibited protein synthesis by 50%. Exposure to C(6)-ceramide inhibited protein synthesis (EC(50) approximately 5 microM) and decreased viability (EC(50) approximately 6 microM). Sphingomyelinase treatment depleted sphingomyelin by about 10%, while increasing ceramide levels and inhibiting protein synthesis. Diphtheria toxin increased ceramide and decreased sphingomyelin in U-937 cells, a cell line extremely sensitive to diphtheria toxin; exposure to DT(388)-GM-CSF showed sensitivity at less than 1.0 pM. Diphtheria toxin and conjugate trigger ceramide formation that contributes to apoptosis in human leukemia cells through caspase activation and inhibition of protein synthesis.
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PMID:Enhanced ceramide generation and induction of apoptosis in human leukemia cells exposed to DT(388)-granulocyte-macrophage colony-stimulating factor (GM-CSF), a truncated diphtheria toxin fused to human GM-CSF. 1153 31

A 29-year-old male was diagnosed as having non-Hodgkin's lymphoma (NHL, diffuse, large cell, B-cell, stage IV) in June 1999. He underwent 7 courses of chemotherapy and double autologous peripheral stem cell transplantation (total dose: CPA 13,000 mg, BUS 892 mg, L-PAM 150 mg, MCNU 870 mg, MTX 60 mg, Ara-C 160 mg, DXR 350 mg, VP-16 11,190 mg, VCR 8 mg, CBDCA 700 mg, and MIT 22 mg) for NHL and obtained complete remission in April 2000. In September 2000, he suffered from progressive general malaise. Laboratory findings showed marked leukocytosis with 85% leukemia cells, which were positive for alpha-naphthyl butyrate esterase. Surface-marker analysis of the leukemia cells showed positive results for CD11b, CD11c, CD13, CD15, CD33, CD56, CD64, CD65, CD71 and HLA-DR, and chromosomal analysis revealed add(8) (p11), add(9) (p13). He was diagnosed as having AML (M5a) and was still in complete remission for NHL. He did not respond to chemotherapy and died in December 2000, believed to be from therapy-related leukemia induced by the VP-16 used for treating NHL, judging by the patient's short clinical course and monocytic type of leukemia.
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PMID:[Therapy-related acute myeloid leukemia following double autologous peripheral blood stem cell transplantation for non-Hodgkin's lymphoma]. 1213 6

Drug resistance is one of the most significant impediments in the treatment of hematological malignancies. There have been a number of studies on the incidence of P-GP expression in tumor cells or tissues, where detectable level of P-GP has been found in all types of hematological malignancies. P-GP expression and significance in the patients varies widely between reported studies on patients with different ages and different disease types. Some of this validation can be accounted for by the threshold used to consider a sample positive for P-GP. However, mdr-1 is likely important in determining therapeutic outcome in patients with AML, NHL, and MM, although there is a suggestion of a different "behavior" between adult and childhood AML. In contrast, the significant prognostic association with expression of MRP and LRP is not consistent with disease types and disease stages. Clinical trials of modulation of MDR have been limited by following major factors. One is inability of achieving adequate blood levels of the modulator to reverse MDR, and the other is presence of other resistance mechanisms in addition to P-GP. The fact that P-GP modulators alter the pharmacokinetics of anti-cancer drugs can potentially increase toxicities if the dose of anticancer drugs is not appropriately reduced. Recently, MDR modulators such as valspodar have demonstrated substantial inhibition of P-GP. In this presentation, a number of characteristics in VCR-resistant cells are reported. We demonstrate that acquisition of MDR or recovery from MDR phenotypes differ in one cell type to another, a marked correlation between P-GP and susuceptibility to oxygen radicals, and altered gene expression of cell membrane antigen and apoptosis cascade genes. The efficacy of immunotherapies depends on the altered or unchanged target molecules of MDR cells. Thus, immunotherapies or reversal agents that aim at these substances in tumor cells should be useful to overcome MDR phenotypes.
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PMID:Biology and modulation of multidrug resistance (MDR) in hematological malignancies. 1243 Sep 27

The survival of patients with aggressive non-Hodgkin lymphoma (NHL) is increasing, but the incidence of secondary cancer and late toxicity is poorly defined for those treated with cyclophosphamide-hydroxydaunomycin/doxorubicin-Oncovin-prednisone (CHOP)-like chemotherapy. From February 1984 to January 1998, 2837 patients with aggressive NHL received the control-arm chemotherapy adriamycin-cyclophosphamide-vindesine-bleomycin-prednisone (ACVBP) in 3 consecutive Groupe d'Etude des Lymphomes de l'Adulte (GELA) studies. With a median follow-up time of 74 months, the 5-year overall and event-free survival rates were 60% and 52%. Two hundred two occurrences of nonneoplastic late toxicity were reported, resulting in a 5.35% cumulative probability of incidence at 7 years. Eighty-one second tumors developed, for which the 7-year cumulative incidence rate was 2.75%; 64 were solid tumors, and 17 were hematologic malignancies. In multivariate analysis, age was the only risk factor for the second development of cancer. Epidemiologic analysis allowed a comparison of this NHL group with the general population. Considering all tumors, no excess of second cancer was observed. In the male population, however, there was an excess of lung cancer (standardized incidence ratio [SIR], 2.45; P <.001) and myelodysplastic syndrome/acute myelocytic leukemia (MDS/AML) (SIR, 5.65; P =.006), and in the female population there was an excess of MDS/AML (SIR, 19.9; P <.001). With a long follow-up, the ACVBP regimen was highly effective for the treatment of aggressive NHL. Increases occurred in secondary MDS/AML and in lung cancer among men.
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PMID:Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients. 1457 60


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