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)

Conventional chemotherapeutic treatments of acute leukemias are often associated with life-threatening toxic effects due to a lack of specificity for hematopoietic cells. Monoclonal antibodies and fusion proteins that target antigens on leukemic blasts are being explored for their antileukemic effects and as a means of delivering chemotherapy or radiation directly to malignant cells. This approach might be safer and more effective than current non-specific chemotherapeutic agents. The cell surface antigens CD33 and CD45 are attractive targets. Although CD33 is expressed on acute myelocytic leukemic blast cells from about 90% of patients, normal hematopoietic stem cells lack this antigen, as do essentially all non-hematopoietic tissues. Anti-CD33 antibodies have been engineered to selectively target malignant myeloid and immature normal cells while sparing normal stem cells. Recently, anti-CD33 antibodies have also been used to deliver radiation or a cytotoxic agent directly to leukemic cells. The strategy for using CD45 as a target differs from CD33 in that it is expressed not only by the vast majority of leukemias, but also by normal stem cells. Therefore, 131I-labeled anti-CD45 antibody has been used in combination with conventional preparative regimens for patients receiving marrow transplantation for acute leukemia. Because the receptor for granulocyte-macrophage colony-stimulating factor is expressed by most myeloid leukemias, fusion proteins consisting of granulocyte-macrophage colony-stimulating factor ligand associated with diphtheria toxin have been proposed as a means of delivering a toxic agent directly to leukemic cells. Both unconjugated and conjugated antibodies show significant promise in the treatment of acute myelocytic leukemia.
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PMID:Clinical studies of new "biologic" approaches to therapy of acute myeloid leukemia with monoclonal antibodies and immunoconjugates. 1068 26

There are several competing models of stem cell involvement in acute myeloid leukemia (AML). At issue is whether the disease origin is in the pluripotent stem cell or whether it arises later in a more mature progenitor cell. The observation that the CD33 antigen is present on AML cells, and on normal and leukemic progenitors, suggested that one might be able to target these cells while sparing the normal stem cells. Response rates of acute myelogenous leukemia patients treated with the newly developed anti-CD33 antibody-calicheamicin conjugate suggest that at least for a proportion of patients early precursors responsible for re-establishing hematopoiesis are likely to be predominantly normal in origin.
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PMID:Monoclonal antibodies to the myeloid stem cells: therapeutic implications of CMA-676, a humanized anti-CD33 antibody calicheamicin conjugate. 1072 Jan 44

Calicheamicin-conjugated humanized anti-CD33 mouse monoclonal antibody, CMA-676, has recently been introduced to clinics as a promising drug to treat patients with acute myeloid leukemia (AML) in relapse. However, the mechanism of action of CMA-676 has not been well elucidated. The cytotoxic effect of CMA-676 on HL60, NOMO-1, NB4, NKM-1, K562, Daudi, and the multidrug-resistant sublines, NOMO-1/ADR and NB4/MDR, was investigated by cell cycle distribution and morphology. These studies were done by a video-microscopic system, DNA fragmentation, dye exclusion and 3H-thymidine uptake after analysis of CD33, CD34, P-glycoprotein (P-gp), multidrug resistance (MDR)-associated protein and lung-related protein on these cells. A dose-dependent, selective cytotoxic effect of CMA-676 was observed in cell lines that expressed CD33, and was dependent on the amount of CD33 and the proliferative speed of the cells. Sensitive cells were temporally arrested at the G2/M phase before undergoing morphological changes. CMA-676 is not effective on P-gp-expressing multidrug-resistant sublines compared with parental cell lines. MDR modifiers, MS209 and PSC833, restored the cytotoxic effect of CMA-676 in P-gp-expressing sublines. CMA-676 is a promising agent in the treatment of patients with AML that expresses CD33. The combined use of CMA-676 and MDR modifiers may increase the selective cytotoxic effect in multidrug-resistant AML.
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PMID:Calicheamicin-conjugated humanized anti-CD33 monoclonal antibody (gemtuzumab zogamicin, CMA-676) shows cytocidal effect on CD33-positive leukemia cell lines, but is inactive on P-glycoprotein-expressing sublines. 1094 40

Traditional chemotherapy for acute leukemia often causes life-threatening toxic effects due to a lack of specificity for hematopoietic cells. Monoclonal antibodies and fusion proteins that target cell surface antigens on leukemic blasts are being evaluated for their cytotoxic effects and as a means of delivering chemotherapeutic agents or radiation directly to malignant cells. It is hoped that this strategy might selectively ablate malignant cells without many of the toxic effects commonly associated with conventional chemotherapy. In acute myeloid leukemia (AML), the cell surface antigens CD33 and CD45 are especially suitable targets. Although CD33 is expressed on AML blast cells from about 90% of patients, normal hematopoietic stem cells lack this antigen, as do essentially all nonhematopoietic tissues. For that reason, anti-CD33 antibodies have been created to target malignant myeloid and immature normal cells selectively while sparing normal stem cells. Anti-CD33 antibodies have also been used to deliver radiation or a cytotoxic agent directly to leukemic cells. Since the vast majority of leukemias and normal stem cells express the cell surface antigen CD45, another targeting approach allows the delivery of myeloablative radiation to bone marrow and spleen, common sites of leukemic involvement. Consequently, 131I-labeled anti-CD45 antibody has been combined with traditional preparative regimens for patients receiving bone marrow transplantation for acute leukemia. Finally, fusion proteins such as those combining diphtheria toxin with granulocyte-macrophage colony-stimulating factor (GM-CSF) to target the GM-CSF receptor are now being evaluated in clinical trials. Both unconjugated and conjugated antibodies have shown promise in early clinical trials, and may represent appealing therapeutic alternatives for patients with AML.
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PMID:Targeted therapy of acute myeloid leukemia with monoclonal antibodies and immunoconjugates. 1095 Jan 42

Monoclonal antibodies (mAbs) have become an important modality for cancer therapy. A genetically engineered, humanized anti-CD33 antibody HuM195 has demonstrated activity against over relapsed acute myelogenous leukemia (AML) and against minimal residual disease in acute promyelocytic leukemia (APL). Radioimmunotherapy with beta (beta) particle-emitting isotopes has produced significant responses while minimizing radiation exposure to normal tissues in both nonmyeloablative and myeloablative regimens. Targeted alpha (alpha) particle therapy with 213Bi-labeled HuM195 offers the possibility of more selective tumor cell kill. Additionally, directed chemotherapy using an anti-CD33-calicheamicin conjugate (CMA-676) has produced remissions in patients with relapsed AML.
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PMID:Antibody therapy of acute myelogenous leukemia. 1104 Oct 16

The anti-CD33 monoclonal antibody linked to NAc-gamma calicheamicin gemtuzumab ozogamicin (CMA-676) was used to treat a patient with Philadelphia/bcr-abl-positive acute myeloid leukaemia. We report a morphological and cytogenetic complete remission after treatment with two doses of gemtuzumab ozogamicin as a single agent. Using real-time polymerase chain reaction (PCR), gemtuzumab ozogamicin treatment resulted in a 3-log tumour mass reduction in bone marrow.
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PMID:Molecular remission of Philadelphia/bcr-abl-positive acute myeloid leukaemia after treatment with anti-CD33 calicheamicin conjugate (gemtuzumab ozogamicin, CMA-676). 1109 Dec 12

A promising new development in cancer treatment is antibody-targeted chemotherapy (ATC), a strategy that allows antineoplastic drugs to be delivered to malignant cells but not most normal ones, possibly resulting in fewer side effects. A new drug, gemtuzumab ozogamicin (Mylotarg), employs the ATC strategy and has been approved by the Food and Drug Administration for the treatment of CD33+ acute myeloid leukemia (AML) in patients who are 60 years of age and older, are in their first relapse, and are not considered candidates for cytotoxic chemotherapy. AML is the second most frequent type of leukemia in adults and is associated with a poor prognosis. If untreated, death usually occurs within a few months of diagnosis.
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PMID:Antibody-targeted chemotherapy for the treatment of relapsed acute myeloid leukemia. 1118 67

Curative therapy for acute myeloid leukemia (AML) remains unsatisfactory. However, three recent advances may play an important role in determining how AML is treated in the near future. First, the development of targeted antibody therapy using the anti-CD33-calicheamicin conjugate (gemtuzumab ozogamicin, Mylotarg) represents a novel targeted approach to the killing of leukemia cells. Second, modern molecular methods have improved our ability to identify minimal residual disease (MRD) in patients who appear to be in remission. These methods will allow physicians to tailor therapy, offering, for example, more intensive therapy to patients who harbor MRD. Lastly, the development of microarray gene expression technology allows for the simultaneous study of thousands of genes. With this technology, we may determine the genes responsible for the biological properties of treatment response and relapse in leukemia patients.
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PMID:New developments in the treatment of acute myeloid leukemia. 1119 6

Gemtuzumab ozogamicin (CMA-676) is a cytotoxic drug (calichaemicin) linked to a human monoclonal antibody that targets CD33, and which has been jointly developed and launched by Celltech Group and the Wyeth-Ayerst Research division of American Home Products as a treatment for acute myeloid leukemia (AML). Wyeth-Ayerst submitted an NDA to the US FDA in October 1999 for approval to treat AML patients who have relapsed after initial chemotherapy [346494]. In January 2000, the FDA assigned CMA-676 Priority Review status [351745], and in March 2000, the US FDA's Oncologic Drugs Advisory Committee voted that there was sufficient evidence of improved safety and acceptable efficacy to support accelerated approval for the treatment of AML in patients who have relapsed following initial chemotherapy [360113], [361883]. In May 2000, the FDA gave final approval for CMA-676 for the treatment of patients of 60 years and over in first relapse with CD33+ AML who are not considered candidates for cytotoxic chemotherapy [367212], [367215]. CMA-676 was launched (as Mylotarg) in the US on 1 June 2000 by AHP. An EMAA is in preparation and is expected to be submitted by the end of 2000 [382163]. In September 2000, Merill Lynch predicted sales of 2.9 million Pounds in 2002, rising to 17.9 million Pounds in 2004 [383742], while in January 2000, Lehman Brothers predicted peak sales in excess of US$200 million [360128]. In December 1999, Lehman Brothers predicted peak sales of US$150 million, with Celltech receiving royalties from AHP. Possible first-line therapy could follow depending on further studies, creating a potential market of US$300 million [352078].
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PMID:Technology evaluation: gemtuzumab ozogamicin, Celltech Group. 1124 47

The elimination of minimal residual disease remains one of the most promising applications of monoclonal antibody (mAb)-based therapies. An early study showed that treatment with iodine-131 (131I)-labeled anti-CD33 mAb M195 had antileukemic effects when given as postremission therapy to patients with acute promyelocytic leukemia (APL) in second remission. This treatment, however, was limited by significant myelosuppression and by the development of neutralizing human antimouse antibodies. Treatment with native HuM195, a humanized version of murine M195, eliminated minimal residual disease detectable by reverse transcription-polymerase chain reaction (RT-PCR) in 50% of patients. Patients with newly diagnosed APL treated with all-trans retinoic acid followed by HuM195 and consolidation chemotherapy had an 87% 3-year disease-free survival. Radioimmunotherapy with short-ranged, high-energy alpha particle-emitting isotopes may increase the potency of native mAbs while avoiding the nonspecific cytotoxicity of beta-emitting constructs. Targeted alpha particle therapy with bismuth-213-HuM195 showed significant antileukemic activity in patients with relapsed or refractory acute myelogenous leukemia. Antibody-drug conjugates, such as gemtuzumab ozogamicin, composed of a humanized anti-CD33 mAb and calicheamicin, have produced complete remissions in patients with relapsed AML and are likely to be active in the postremission setting.
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PMID:Antibody therapy for residual disease in acute myelogenous leukemia. 1125 80


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