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)

By all-trans retinoic acid (ATRA) and chemotherapy over 70% of patients with newly diagnosed acute promyelocytic leukemia (APL) may be cured; 20-30% of patients still relapse and require salvage therapy. For relapsed or refractory APL, a standard treatment has not yet been defined. However, several effective drugs and approaches have been described. Treatment options for relapsed APL include chemotherapy regimens used in the treatment of relapsed acute myeloid leukemia usually combined with ATRA or of other differentiating agents such as liposomal ATRA or synthetic retinoids. Presently, allogeneic peripheral stem cell or bone marrow transplantation is the treatment of choice for younger patients who have a histocompatible donor, as it gives the chance of cure in second or further relapse. For patients without a donor or for those who are not suitable for allogeneic transplantation, autologous stem cell or bone marrow transplantation may offer at least the possibility of a prolongation of remission, if the harvested cells are negative in the RT-PCR of PML/RAR alpha. Arsenic compounds have a high antileukemic effectiveness on APL cells. Arsenic trioxide has recently been approved for relapsed or refractory APL. With this drug, complete hematologic remission rates of 80-92% and long-lasting molecular remissions were achieved in relapsed patients. For patients who do not qualify for these treatment options, monoclonal anti-CD33 antibodies may represent further treatment options.
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PMID:Treatment of relapsed acute promyelocytic leukemia. 1297 6

The WHO classification of adultory acute myeloid leukemia puts the main emphasis on prognosis, based mainly upon cytogenetic findings and gene-expression profiles. The complex prognostic assessment provides a more solid basis for early therapeutic stratification. This review focuses mainly on medical therapy. Induction phase is quite uniform, it consists of antracyclin and cytosin arabinosid. High-dose cytosin arabinosid is the predominant tool of postinduction therapy, especially in the favorable cytogenetic pattern cases. All-trans retinoic acid resulted in extremely good results in the promyelocytic cases, and this therapy seems to be advantageous in respect of acute DIC, too. Arsenic trioxide could be the drug of choice in relapsed promyelocytic leukemia. Some new agents are promising in refractory or relapsed cases, i.e. antibodies (Mylotarg) or farnesyltransferase inhibitors. The near future may bring about new therapeutic approaches, involving immunotherapy (dendritic cell vaccines) or gene-therapy as well.
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PMID:[Expanding possibilities, strategic considerations, and novel methods in the diagnosis and chemotherapy of adult acute myeloid leukemia]. 1457 74

Acute myeloid leukemia is the most common type of leukemia in adults, yet it continues to have the lowest survival rate of all leukemias. Prognosis for the elderly in particular continues to be dismal. This review examines the currently available literature on the epidemiology, etiology, diagnosis and management of acute myeloid leukemia. New therapies and therapeutic strategies must be found to improve survival, especially as the worldwide population ages. Gemtuzumab ozogamicin (Mylotarg) for the treatment of patients with CD33-positive acute myeloid leukemia, selective FLT3 inhibitors currently in advanced development (e.g., SU11248, PKC412, CT53518 and CEP-710) and other targeted compounds (e.g., farnesyl transferase inhibitors, BCL-2 inhibitors and interleukin-2) may present initial opportunities to achieve improved outcomes.
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PMID:Epidemiology and clinical burden of acute myeloid leukemia. 1459 92

Gemtuzumab ozogamicin (GO) is a chemotherapeutic agent that consists of a humanized anti-CD33 antibody (hP67.6) linked to N-acetyl-gamma calicheamicin 1,2-dimethyl hydrazine dichloride, a potent enediyne antitumor antibiotic. GO was approved conditionally by the Federal Drug Administration in May 2000 as single-agent therapy for first recurrence of acute myeloid leukemia (AML) in a subset of older patients. Data on studies in AML with GO-based regimens have been reported rapidly in addition to new observations on the target antigen, CD33. These data indicate promising new areas of investigation with GO, including its application as maintenance therapy in patients with AML and as an induction and/or maintenance agent in patients with acute promyelocytic leukemia;, and they also have highlighted challenges in the development of GO, particularly its association with hepatic venoocclusive disease. In vitro data on the mechanism of action of GO may be particularly helpful in the design of future clinical studies.
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PMID:Gemtuzumab ozogamicin in the treatment of acute myeloid leukemia. 1460 Oct 78

Multicenter phase II trials with Gemtuzumab Ozogamicin (GO/Mylotarg), consisting of a CD33 antibody linked to the cytotoxic drug calicheamicin, have shown a 30% overall response rate in relapsed acute myeloid leukemia patients. However, no clear correlation was observed between CD33 expression on leukemic blasts and response to GO therapy. We analyzed the CD33 specificity of GO-induced cell death and the effect of GO on CD33-negative malignancies. We demonstrate that lysis induced by clinically relevant GO concentrations is partially CD33 mediated, and that efficient non-CD33-mediated GO uptake can occur via endocytosis. In agreement with these results, we observed GO-mediated death of human CD33-negative acute lymphoblastic leukemia cells both in vitro and in vivo in an NOD/SCID mouse model. Finally, sensitivity to GO-induced cell death was at least partially determined by the activation status of leukemic cells, with cells in activated phases of the cell cycle being most effective in both CD33-specific GO internalization, renewed expression of CD33 molecules, and non-CD33-mediated GO uptake via endocytosis. In conclusion, these data provide mechanistic insight into the efficacy of GO in CD33-positive as well as in CD33-negative malignancies with endocytic capacity, and provide a rationale for the use of GO in the treatment of malignancies with endocytic capacity.
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PMID:Internalization and cell cycle-dependent killing of leukemic cells by Gemtuzumab Ozogamicin: rationale for efficacy in CD33-negative malignancies with endocytic capacity. 1461 14

Molecular targeting therapies for hematological malignant diseases such as monoclonal antibodies and small molecules have been reviewed. Imatinib mesylate (STI571) targets the tyrosine kinase activity of the BCR-ABL fusion protein in CML, and was superior to IFN-alpha plus low-dose cytarabine in newly diagnosed chronic-phase CML in a phase III randomized study. Imatinib induced apoptosis in BCR-ABL-positive cells in vitro, and activates several signaling pathways such as PI3K/Akt, STAT5 and Ras/MAPK. Combination therapies with imatinib and new strategies for downregulation of intracellular BCR-ABL protein levels have also been investigated from the phenomenon of resistance to imatinib. Anti-CD20 (rituximab) became the first monoclonal antibody approved for the treatment of a relapsed/refractory follicular/low-grade NHL and promising results were obtained from a phase III randomized study. Although antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity are likely to be the major effectors of B-cell depletion in vivo, direct cytotoxicity by CD20 monoclonal antibody on B-cell lines in vitro has been reported. Anti-CD33 (Mylotarg) and FLT3 inhibitors for AML have also been used in clinical trials and signaling pathways induced by these agents are under intensive investigation. Arsenic trioxide, like all-TRANS-retinoic acid (ATRA), downregulates promyelocytic leukemia protein/retinoic acid receptor-alpha (PML/RARalpha) fusion protein and induced apoptosis in APL cells, and promising results were obtained from ATRA-resistant APL patients. Finally we show our promising in vitro and in vivo data of R-etodolac (a non-steroidal anti-inflammatory drug lacking cyclooxygenase inhibitor activity) against chronic lymphocytic leukemia (CLL) cells.
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PMID:Apoptosis induced by molecular targeting therapy in hematological malignancies. 1464 49

Treatment options are limited for patients with relapsed acute myelogenous leukemia (AML), particularly when the disease is refractory to standard cytotoxic chemotherapy. Targeted drug therapy offers the advantage of delivering higher doses of non-cross resistant chemotherapy with potentially less systemic toxicity. Gemtuzumab ozogamicin (Mylotarg, Wyeth-Ayerst Laboratories) is an immunoconjugate that consists of humanized anti-CD 33 antibody linked to the potent anti-tumor antibiotic calicheamicin and has been an effective therapy for some patients with relapsed AML. However, the overall utility of gemtuzumab ozogamicin is not well defined. For instance, it is not known how well this antibody will target extramedullary disease. This article reports gemtuzumab treatment of refractory AML in a 32-year-old man. At the time of recurrence, his bone marrow was hypoplastic and without leukemia, but the condition progressed resulting in marked leukemic infiltration of the oral mucosa. This case history raises the possibility that leukemic sanctuary sites may exist, and that monoclonal antibody therapy may have sub-optimal activity in non-medullary sites of disease.
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PMID:Leukemic gingival infiltrate as an indicator of chemotherapeutic failure following monoclonal antibody therapy: a case report. 1465 May 59

Monoclonal antibodies have become an important treatment modality in cancer therapy. Genetically engineered chimaeric and humanised antibodies have demonstrated activity against a variety of tumours. Whereas the humanised anti-CD33 monoclonal antibody HuM195 has only modest activity against overt acute myeloid leukaemia (AML), it can eliminate minimal residual disease detectable by reverse transcription-polymerase chain reaction in acute promyelocytic leukaemia. High-dose radioimmunotherapy with beta-particle-emitting isotopes targeting CD33, CD45 and CD66 can potentially allow intensification of antileukaemic therapy before bone marrow transplantation. Conversely, alpha-particle immunotherapy with isotopes such as bismuth-213 or actinium-225 offers the possibility of selective tumour cell kill while sparing surrounding normal cells. Targeted chemotherapy with the anti-CD33-calicheamicin construct gemtuzumab ozogamicin has produced remissions as a single agent in patients with relapsed AML and appears promising when used in combination with standard chemotherapy in the treatment of newly diagnosed AML.
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PMID:Antibody-based treatment of acute myeloid leukaemia. 1468 Apr 72

A 69-yr-old male with a history of familial hemochromatosis and status after liver transplantation was found to have severe thrombocytopenia (platelet count of 8000/microL). He was also anemic and was diagnosed with acute myeloid leukemia (AML) after a bone marrow biopsy. He was started on gemtuzumab ozogamicin (Mylotarg) and developed hepatic and multiorgan failure consistent with veno-occlusive disease within 2 wk. He did not have a history of hematopoietic stem cell transplantation, which is usually the case in AML patients who develop veno-occlusive disease of the liver after treatment with Mylotarg.
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PMID:Probable veno-occlusive disease after treatment with gemtuzumab ozogamicin in a patient with acute myeloid leukemia and a history of liver transplantation for familial hemochromatosis. 1471 35

The antibody-targeted therapeutic, gemtuzumab ozogamicin (GO, Mylotarg), is approved for treatment of relapsed acute myeloid leukemia (AML). We previously showed that AML blasts from GO refractory patients frequently express the drug transporters P-glycoprotein (Pgp) and/or multidrug resistance protein (MRP). We also previously reported that inhibition of drug transport by the Pgp modulator, cyclosporine A (CSA), can increase GO sensitivity in Pgp(+) AML cells and that the peripheral benzodiazepine receptor ligand, PK11195, sensitizes AML cells to standard chemotherapeutics both by inhibiting Pgp-mediated efflux and by promoting mitochondrial apoptosis. We now show that PK11195 also can overcome multiple resistance mechanisms to increase GO sensitivity in AML cells, including resistance associated with expression of drug transporters and/or antiapoptotic proteins. PK11195 substantially increases GO cytotoxicity in AML cells from many different cell lines and primary patient samples, often more effectively than CSA. We also show that PK11195 is nontoxic in NOD/SCID mice and can sensitize xenografted human AML cells to GO. Since PK11195 is well tolerated in humans as a single agent, its further study as a multifunctional chemosensitizer for anti-AML therapies, including GO-based therapies, is warranted.
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PMID:The peripheral benzodiazepine receptor ligand PK11195 overcomes different resistance mechanisms to sensitize AML cells to gemtuzumab ozogamicin. 1496 98


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