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)

To demonstrate that the effect of 1-beta-D-arabinofuranosylcytosine can be increased when the leukemic cell growth fraction is augmented by induced humoral factors, bone marrow cells from 14 patients with acute myeloblastic leukemia were studied in vitro. Cells were cultured in either pooled stimulatory serum, obtained from leukemic patients undergoing chemotherapy, or autologous leukemic pre-treatment serum. After 2 days in culture, serum containing 1-beta-D-arabinofuranosylcytosine was added. Cells cultured in stimulatory serum proliferated markedly when compared with cells cultured in pretreatment serum, as measured by tritiated thymidine incorporation into an acid-insoluble precipitate, tritiated thymidine labeling indices, and viable tumor cell counts. The cytotoxic effect of 1-beta-D-arabinofuranosylcytosine was enhanced in those cells initially cultured in stimulatory serum relative to cells initially cultured in pretreatment serum. These studies are consistent with the hypothesis that induced humoral stimulation of acute myeloblastic leukemic cells in vitro recruits a greater tumor growth fraction and thereby increases the cytotoxicity of cycle-dependent drugs.
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PMID:Enhancement of drug cytotoxicity by recruitment of leukemic myeloblasts with humoral stimulation. 106 83

The hazards and complications of BCG immunotherapy, as well as the potential for enhanced tumor growth, make it imperative that the clinician know the clinical setting in which BCG can offer therapeutic benefit. This would include the intratumor injection of localized intradermal tumor deposits of melanoma and breast cancer, chemoimmunotherapy with BCG to prolong remission in acute myelogenous leukemia, and possibly the use of BCG as an adjuvant to control minimal residual disease. Aside from these situations, it is advisable to treat patients only on clearly defined experimental protocols.
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PMID:Hazards and complications of BCG immunotherapy. 127 90

Interferons (IFNs) are a family of polypeptides originally identified as antiviral substances. Subsequently, other properties of interferons were recognized, including inhibition of cell proliferation, and effects on the immune response and on expression of surface antigens. In this paper we present evidence that interferons, even the highly purified cloned IFNs, can stimulate clonogenic tumor growth in vitro. Of 225 human tumor (HT) samples tested with IFN in a clonogenic assay (HTCA), 30 (13.3%) showed growth stimulation (greater than 2 S.E. above control). The phenomenon was observed most frequently with acute myeloid leukemia (6/22 samples, 27.3%), and renal (2/10, 20%) and breast cancer (4/21, 19%), but significantly less frequent in melanomas (2/34, 5.9%). As an independent assessment of proliferation, tritiated thymidine uptake by tumor cells was measured autoradiographically in 21 patients with multiple myeloma. A significant increase of the thymidine labeling index was seen in 4 (19%) of the samples. Since this growth stimulatory effect was also observed with cell lines which lack any contaminating immunoreactive cells, there is strong evidence that interferons can directly stimulate the proliferation of clonogenic tumor cells in vitro. Growth stimulation by interferons occurred preferentially with lower dosages. It is important to be cognizant of potential clinical implications of tumor growth stimulation by interferons.
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PMID:Tumor growth stimulation in vitro by interferons. 658 Jan 72

An animal model has been developed that utilizes antibody and complement to eliminate a transplantable cloned line of Wistar/Furth acute nonlymphocytic leukemia (CI-3) from syngeneic Wistar/Furth bone marrow. The CI-3 leukemia grows progressively from an i.v. inoculum of 10(1) to 10(2) cells. Antiserum has been raised in rabbits following multiple injections of CI-3. Using optimal concentrations of absorbed antibody and complement, approximately 3 logs of tumor could be destroyed in vitro, judged by the number of cells required to produce progressive growth in vivo. Similar incubation with antibody and complement did not affect the ability of Wistar-Furth marrow to reconstitute rats that had received lethal total-body irradiation (950 R). Each of the 33 irradiated rats that received mixtures of 10(4) CI-3 and 1.6 X 10(8) nucleated bone marrow cells succumbed to leukemia within 65 days, whereas 16 of 33 rats (48%) receiving similar inocula that had been treated with antibody and complement survived greater than 180 days without evidence of tumor growth. Repeated treatment of contaminated marrow with antibody and complement following removal of mature granulocytes and erythrocytes on density gradients permitted elimination of 10(5) CI-3.
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PMID:Elimination of leukemic cells from rat bone marrow using antibody and complement. 694 13

Studies were conducted in the leukemic mouse and rat to test the hypothesis that enhanced effects of drugs given in sequence relate to a predictable increase in tumor growth and sensitivity to cycle-active agents. The rationale is based on a) evidence that, following drug-induced aplasia, resultant bone marrow proliferation in vivo corresponds temporally with induced humoral stimulatory activity, and on b) models that demonstrate increased cytotoxicity of beta-cytosine arabinoside (Ara-C) to myeloblasts cultured in humoral stimulatory activity (HSA). CD2F1 mice bearing L-1210 leukemia received a course of 60 mg Ara-C/kg every 8th hour (q.8 h) three times on day 0 and on another day in sequence (0,1 through 0,7). The longest survival (250% of controls) was in animals whose second course began on day 3, the time of peak HSA as measured by DNA synthesis induced in L-1210 cells in culture. LBN rats bearing acute myelocytic leukemia (AML) were treated with 100 mg Ara-C/kg q.8 h six times beginning on day 0 and on other days in sequence (0,1 through 0,12). The longest survival was in those treated on day 0,6 (760% of controls), the time of peak serum stimulation, and tumor labeling index (LI). Thirty-seven patients with AML received a single course of therapy with 45 mg Ara-C/kg by a 72-hour infusion and 1.0 mg daunorubicin/kg every day three times. On day 8, the time of peak HSA and tumor LI, Ara-C was again infused. Complete remission was achieved in 56% (65% of all patients less than 60 yr old) with a single cycle of therapy. Median duration of chemotherapy-free remission was 10 months. Of 11 relapsing patients, 8 achieved a second remission with the same regimen. These studies demonstrated that the amount of proliferation of residual tumor and thereby sensitivity to cycle-active drugs given in sequence relates to the initial drug effect on tumor proliferation and the induction of humoral stimulation.
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PMID:Chemotherapy of leukemia in mice, rats, and humans relating time of humoral stimulation, tumor growth, and clinical response. 694 25

An unusual case of granulocytic sarcoma developing at the site of a previous cerebral hemorrhage in a patient with acute myelogenous leukemia in complete hematological remission is presented. The pathogenesis of the tumor growth at this site and its relevance to the antecedent hemorrhage are discussed.
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PMID:Brain granulocytic sarcoma at the site of previous cerebral hemorrhage in a patient with acute myelogenous leukemia. 821 8

We report a patient who at the time of kidney transplantation for polycystic kidney disease was found to have an enlarged inguinal lymph node which later demonstrated evidence of extra medullary granulopoiesis. During the first two weeks following kidney transplantation, a striking leukemoid pattern developed and 2 months after transplant the patient was diagnosed with acute myelogenous leukemia (AML). Retrospective analysis of peripheral blood cytokines over this time revealed elevated levels of GMCSF and gamma IFN at the time of peak peripheral blood WBC with subsequent peaks in IL-4, IL-6 and IL-2 as the peripheral blood WBC fell. A rise in levels of TNF alpha also preceded the peripheral blood WBC rise (although these concentrations were at or below those following uncomplicated kidney transplants). The clinical course of AML in this patient was marked by relentless relapse despite chemotherapy. The possibility of cytokine facilitated tumor growth is discussed.
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PMID:Early development of acute myelogenous leukemia following kidney transplantation: possible role of multiple serum cytokines. 857 65

The (3;21)(q26;q22) translocation associated with treatment-related myelodysplastic syndrome, treatment-related acute myeloid leukemia, and blast crisis of chronic myeloid leukemia results in the expression of the chimeric genes AML1/EAP, AML1/MDS1, and AML1/EVI1. AML1 (CBFA2), which codes for the alpha subunit of the heterodimeric transcription factor CBF, is also involved in the t(8;21), and the gene coding for the beta subunit (CBFB) is involved in the inv(16). These are two of the most common recurring chromosomal rearrangements in acute myeloid leukemia. CBF corresponds to the murine Pebp2 factor, and CBF binding sites are found in a number of eukaryotic and viral enhancers and promoters. We studied the effects of AML1/EAP and AML1/MDS1 at the AML1 binding site of the CSF1R (macrophage-colony-stimulating factor receptor gene) promoter by using reporter gene assays, and we analyzed the consequences of the expression of both chimeric proteins in an embryonic rat fibroblast cell line (Rat1A) in culture and after injection into athymic nude mice. Unlike AML1, which is an activator of the CSF1R promoter, the chimeric proteins did not transactivate the CSF1R promoter site but acted as inhibitors of AML1 (CBFA2). AML1/EAP and AML1/MDS1 expressed in adherent Rat1A cells decreased contact inhibition of growth, and expression of AML1/MDS1 was associated with acquisition of the ability to grow in suspension culture. Expression of AML1/MDS1 increased the tumorigenicity of Rat1A cells injected into athymic nude mice, whereas AML1/EAP expression prevented tumor growth. These results suggest that expression of AML1/EAP and AML1/MDS1 can interfere with normal AML1 function, and that AML1/MDS1 has tumor-promoting properties in an embryonic rat fibroblast cell line.
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PMID:The chimeric genes AML1/MDS1 and AML1/EAP inhibit AML1B activation at the CSF1R promoter, but only AML1/MDS1 has tumor-promoter properties. 857 11

Several recurring chromosomal translocations involve the AML1 gene at 21q22 in myeloid leukemias resulting in fusion mRNAs and chimeric proteins between AML1 and a gene on the partner chromosome. AML1 corresponds to CBFA2, one of the DNA-binding subunits of the enhancer core binding factor CBF. Other CBF DNA-binding subunits are CBFA1 and CBFA3, also known as AML3 and AML2. AML1, AML2 and AML3 are each characterized by a conserved domain at the amino end, the runt domain, that is necessary for DNA-binding and protein dimerization, and by a transactivation domain at the carboxyl end. AML1 was first identified as the gene located at the breakpoint junction of the 8;21 translocation associated with acute myeloid leukemia. The t(8;21)(q22;q22) interrupts AML1 after the runt homology domain, and fuses the 5' part of AML1 to almost all of ETO, the partner gene on chromosome 8. AML1 is an activator of several myeloid promoters; however, the chimeric AML1/ETO is a strong repressor of some AML1-dependent promoters. AML1 is also involved in the t(3;21)(q26;q22), that occurs in myeloid leukemias primarily following treatment with topoisomerase II inhibitors. We have studied five patients with a 3;21 translocation. In all cases, AML1 is interrupted after the runt domain, and is translocated to chromosome band 3q26. As a result of the t(3;21), AML1 is consistently fused to two separate genes located at 3q26. The two genes are EAP, which codes for the abundant ribosomal protein L22, and MDS1, which encodes a small polypeptide of unknown function. In one of our patients, a third gene EVI1 is also involved. EAP is the closest to the breakpoint junction with AML1, and EVI1 is the furthest away. The fusion of EAP to AML1 is not in frame, and leads to a protein that is terminated shortly after the fusion junction by introduction of a stop codon. The fusion of AML1 to MDS1 is in frame, and adds 127 codons to the interrupted AML1. Thus, in the five cases that we studied, the 3;21 translocation results in expression of two coexisting chimeric mRNAs which contain the identical runt domain at the 5' region, but differ in the 3' region. In addition, the chimeric transcript AML1/MDS1/EVI1 has also been detected in cells from one patient with the 3;21 translocation as well as in one of our patients. Several genes necessary for myeloid lineage differentiation contain the target sequence for AML1 in their regulatory regions. One of them is the CSF1R gene. We have compared the normal AML1 to AML1/MDS1, AML1/EAP and AML1/MDS1/EVI1 as transcriptional regulators of the CSF1R promoter. Our results indicate that AML1 can activate the promoter, and that the chimeric proteins compete with the normal AML1 and repress expression from the CSF1R promoter. AML1/MDS1 and AML1/EAP affect cell growth and phenotype when expressed in rat fibroblasts. However, the pattern of tumor growth of cells expressing the different chimeric genes in nude mice is different. We show that when either fusion gene is expressed, the cells lose contact inhibition and form foci over the monolayer. In addition, cells expressing AML1/MDS1 grow larger tumors in nude mice, whereas cells expressing only AML1/EAP do not form tumors, and cells expressing both chimeric genes induce tumors of intermediate size. Thus, although both chimeric genes have similar effects in transactivation assays of the CSF1R promoter, they affect cell growth differently in culture and have opposite effects as tumor promoters in vivo. Because of the results obtained with cells expressing one or both genes, we conclude that MDS1 seems to have tumorigenic properties, but that AML1/EAP seems to repress the oncogenic property of AML1/MDS1.
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PMID:Rearrangement of the AML1/CBFA2 gene in myeloid leukemia with the 3;21 translocation: expression of co-existing multiple chimeric genes with similar functions as transcriptional repressors, but with opposite tumorigenic properties. 858 55

We examined the ability of patient-derived human leukemic blasts to generate leukemic growth and dissemination in severe combined immunodeficiency (SCID) mice by subcutaneous inoculation without conditioning treatment or administration of growth-promoting cytokines. Additionally, we correlated the growth pattern with the clinical outcome of patients from whom the leukemic cells were derived. The leukemias displayed three distinct growth patterns, ie, either aggressive, indolent, or no tumor growth. Leukemic cells from 6 of 13 patients with acute myeloid leukemia (AML), 4 of 7 T-cell acute lymphoblastic leukemia (T-ALL), and 11 of 16 patients with B-lineage ALL grew as subcutaneous tumors, with a significant number subsequently disseminating into distant organs in SCID mice. Patients whose leukemic blasts displayed an aggressive growth and dissemination pattern in SCID mice had a relatively poor clinical outcome, whereas patients with AML and T- or B-lineage ALL whose leukemic blasts grew indolently or whose cells failed to induce growth had a more favorable clinical course. Our study has shown that the subcutaneous inoculation of patient-derived human leukemic cells in SCID mice can engraft and grow as subcutaneous tumors with subsequent dissemination to distant organs in a manner analogous to their pattern of growth in humans. Additionally, these data suggest a clinical correlation to the growth and dissemination of some leukemic subtypes that may represent not only an additional prognosticator for patient outcome, but also a vehicle for the study of the biologic behavior of human leukemias and the development of novel therapeutic strategies.
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PMID:Growth pattern and clinical correlation of subcutaneously inoculated human primary acute leukemias in severe combined immunodeficiency mice. 887 14


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