Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty cases of patients with relapsed acute promyelocytic leukemia (APL) were entered into this study for evaluating the clinical efficacy and pharmacokinetics of low-dose arsenic trioxide (As2O3). As2O3 was given at a daily dose of 0.08 mg/kg intravenously for 28 days. Pharmacokinetic study was carried out in eight patients. 16/20 (80%) patients achieved CR. The occurrence of some toxic events including gastrointestinal disturbance, facial edema and cardiac toxicity seemed reduced in the low-dose group than those in the standard-dose group. Differentiation changes were observed in peripheral blood, as well as in bone marrow (BM). Pharmacokinetic study showed that the plasma concentration increased soon after administration of As2O3 with the peak values of 1.535-3.424 micromol/l. After infusion, the plasma concentration was around 0.1-0.5 micromol/l. The arsenic concentration of the plasma of BM aspirates 24 h after administration in five patients was close to the level needed for differentiation-inducing effect. The estimated 2-year OS and RFS were 61.55+/-15.79% and 49.11+/-15.09% respectively, with no difference as compared with those in patients treated with conventional dose (P = 0.2865 and 0.7146, respectively). In conclusion, we demonstrated that low-dose As2O3 had the same effect as the conventional dosage and the mechanism of low-dose arsenic seemed to primarily induce differentiation of APL cells.
Leukemia 2001 May
PMID:Studies on the clinical efficacy and pharmacokinetics of low-dose arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia: a comparison with conventional dosage. 1136 33

Fanconi anemia (FA) is an autosomal recessive disease characterized by congenital anomalies, bone marrow failure, and leukemia susceptibility. FA cells show chromosome instability and hypersensitivity to DNA cross-linking agents such as mitomycin C. Recent studies indicate that there are at least 8 genetically distinct FA groups (A, B, C, D1, D2, E, F, G). To date, 6 genes (for A, C, D2, E, F, and G) have been cloned. In this review, we describe the structures and functions of FA proteins. Increasing evidence indicates that the multiple FA proteins cooperate in a biochemical pathway and/or a multimer complex. FANCD2, a downstream component of the FA pathway, has recently been shown to be ubiquitinated in response to DNA damage and to translocate to nuclear foci containing BRCA1, a breast cancer susceptibility gene product, suggesting a role for this protein in DNA repair functions. We also describe 2 emerging issues: genotype-phenotype relationships and mosaicism. The FA pathway is likely to play a critical role as a caretaker of genomic integrity in hematopoietic stem cells. Clarifying the molecular basis of this disease may provide new insights into the pathogenesis of bone marrow failure syndromes and myeloid malignancies.
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PMID:Current knowledge on the pathophysiology of Fanconi anemia: from genes to phenotypes. 1153 Aug 3

Fanconi anemia (FA) is an autosomal recessive disease with congenital anomalies, bone marrow failure, and susceptibility to leukemia. Patient cells show chromosome instability and hypersensitivity to DNA cross-linking agents. At least 8 complementation groups (A-G) have been identified and 6 FA genes (for subtypes A, C, D2, E, F, and G) have been cloned. Increasing evidence indicates that a protein complex assembly of multiple FA proteins, including FANCA and FANCG, plays a crucial role in the FA pathway. Previously, it was reported that FANCA was phosphorylated in lymphoblasts from normal controls, whereas the phosphorylation was defective in those derived from patients with FA of multiple complementation groups. The present study examined phosphorylation of FANCA ectopically expressed in FANCA(-) cells. Several patient-derived mutations abrogated in vivo phosphorylation of FANCA in this system, suggesting that FANCA phosphorylation is associated with its function. In vitro phosphorylation studies indicated that a physiologic protein kinase for FANCA (FANCA-PK) forms a complex with the substrate. Furthermore, at least a part of FANCA-PK as well as phosphorylated FANCA were included in the FANCA/FANCG complex. Thus, FANCA-PK appears to be another component of the FA protein complex and may regulate function of FANCA. FANCA-PK was characterized as a cytoplasmic serine kinase sensitive to wortmannin. Identification of the protein kinase is expected to elucidate regulatory mechanisms that control the FA pathway.
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PMID:A cytoplasmic serine protein kinase binds and may regulate the Fanconi anemia protein FANCA. 1173 69

Fanconi anaemia (FA) comprises a group of autosomal recessive disorders resulting from mutations in one of eight genes (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF and FANCG). Although caused by relatively simple mutations, the disease shows a complex phenotype, with a variety of features including developmental abnormalities and ultimately severe anaemia and/or leukemia leading to death in the mid teens. Since 1992 all but two of the genes have been identified, and molecular analysis of their products has revealed a complex mode of action. Many of the proteins form a nuclear multisubunit complex that appears to be involved in the repair of double-strand DNA breaks. Additionally, at least one of the proteins, FANCC, influences apoptotic pathways in response to oxidative damage. Further analysis of the FANC proteins will provide vital information on normal cell responses to damage and allow therapeutic strategies to be developed that will hopefully supplant bone marrow transplantation.
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PMID:Molecular biology of Fanconi anaemia--an old problem, a new insight. 1200 Dec 67

Twenty-one paediatric patients (11 males and 10 females) received a CD34-selected partially matched related donor transplant for malignant (16 cases) and non-malignant conditions (five cases). The average cell dose was 11.13 x 10(6)/kg. Fifteen of 16 patients with malignant conditions and one with non-malignant disease received total body irradiation plus cyclophosphamide. Three of 5 patients with non-malignant conditions and one with leukaemia, received busulphan plus cyclophosphamide. One patient with Fanconi anaemia received 100 mg/kg of cyclophosphamide. Fludarabine (25 mg/m(2)/day for 5 days) was administered prior to all these regimens. Additionally, anti-lymphocyte gamma-globulin (12.5 mg/kg/day) was administered from day -2 to day +2. Three (15%) patients failed to achieve complete chimaerism (CC). These patients received a second cell infusion. Two of them achieved CC. In the third patient, the percentage of donor cells was increased. The likelihood for engraftment was not related to the cell dose received. Acute graft-versus-host disease (GVHD) occurred in nine patients but only one developed GVHD >grade II. Eight patients developed active viral infections, which resolved after treatment. Patients receiving cell doses higher than our average had a significantly faster CD3 and CD4 cell recovery and experienced a lower incidence of viral infections. After 480 +/- 255 days of median follow-up, 16/21 patients are alive and well and have CC. Three patients died of leukaemic relapse and a fourth from progression of his disease (adreno-leuko-dystrophy). We conclude that partially matched related donors are a feasible source of haemopoietic progenitor cells for transplantation for patients without matched familial or unrelated donors.
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PMID:Partially matched related donor peripheral blood progenitor cell transplantation in paediatric patients adding fludarabine and anti-lymphocyte gamma-globulin. 1223 20

Fanconi anemia (FA) is a rare autosomal recessive disease characterized by skeletal defects, anemia, chromosomal instability and increased risk of leukemia. At the cellular level FA is characterized by increased sensitivity to agents forming interstrand crosslinks (ICL) in DNA. Six FA genes have been cloned and interactions among individual FANC proteins have been found. The FANCD2 protein co-localizes in nuclear foci with the BRCA1 protein following DNA damage and during S-phase, requiring the FANCA, C, E and G proteins to do so. This finding may reflect a direct role for the BRCA1 protein in double strand break (DSB) repair and interaction with the FANC proteins. Therefore interactions between BRCA1 and the FANC proteins were investigated. Among the known FANC proteins, we find evidence for direct interaction only between the FANCA protein and BRCA1. The evidence rests on three different tests: yeast two-hybrid analysis, coimmunoprecipitation from in vitro synthesis, and coimmunoprecipitation from cell extracts. The amino terminal portion of FANCA and the central part (aa 740-1083) of BRCA1 contain the sites of interaction. The interaction does not depend on DNA damage, thus FANCA and BRCA1 are constitutively interacting. The demonstrated interaction directly connects BRCA1 to the FA pathway of DNA repair.
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PMID:BRCA1 interacts directly with the Fanconi anemia protein FANCA. 1235 84

Fanconi anemia (FA) is an autosomal recessive condition associated with congenital abnormalities, progressive pancytopenia, and a predisposition to leukemia and solid tumors. We studied a retrospective cohort of North American patients with FA. We calculated relative risks of cancer compared to the general population and cause-specific hazards of the first major adverse outcomes of FA: bone marrow transplantation (BMT) for marrow complications, acute myeloid leukemia (AML), solid tumors, or death from bone marrow failure. We also estimated the cumulative incidence of each adverse event in the presence of the competing risks. Among 145 patients with FA, 9 developed leukemia and 14 developed a total of 18 solid tumors. The ratio of observed to expected cancers (O/E ratio) was 50 for all cancers, 48 for all solid tumors, and 785 for leukemia; these increased risks were statistically significant. The highest solid tumor O/E ratios were 4317 for vulvar cancer, 2362 for esophageal cancer, and 706 for head and neck cancer. Cause-specific hazards of both death and AML peaked at 1%/y in teenage years; the hazard of BMT peaked at 4%/y at age 7. In contrast, the hazard of a solid tumor approached 8%/y by age 40 years. The cumulative incidence to age 48 was 10% for leukemia, 11% for death from marrow failure, 29% for a solid tumor, and 43% for BMT. The risk of a solid tumor may become even higher as death from aplastic anemia is reduced and as patients survive longer after BMT.
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PMID:Cancer incidence in persons with Fanconi anemia. 1258 46

We studied the graft-versus-leukaemia (GVL) effect in 185 patients with haematological malignancies who underwent unrelated donor haematopoietic stem cell transplantation (HSCT) at Huddinge University Hospital between May 1991 and June 2001. Ninety-five were in first CR/CP and 90 in later stages. Most (86%) of them had a HLA-A, -B and -DRbeta1 matched donor. Conditioning usually consisted of total body irradiation and cyclophosphamide, and GVHD prophylaxis of cyclosporine and methotrexate. In the multivariate risk-factor analysis of relapse, we found that disease stage beyond CR1/CP1 (P = 0.02), acute GVHD 0-I (P = 0.02), absence of chronic GVHD (P = 0.02) and ALL (P = 0.02) were independent risk factors for relapse. The incidence of relapse in those with acute GVHD grade II was 18% vs 46% in those with no or grade I (P = 0.04). In patients with or without chronic GVHD, the incidences of relapse were 32% and 48%, respectively (P < 0.01). The best RFS was seen in patients with chronic GVHD. No difference in RFS was seen in patients with no, mild or moderate acute GVHD. Risk factors for relapse after HSCT with unrelated donors were: acute lymphoblastic leukaemia, disease stage beyond CR1/CP1, absence of chronic GVHD and no, or mild acute GVHD. Overall and relapse-free survival were not improved by the occurrence of acute GVHD.
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PMID:The graft-versus-leukaemia effect in haematopoietic stem cell transplantation using unrelated donors. 1243 99

Fanconi anemia (FA) is a condition that induces susceptibility to bone marrow failure, myelodysplastic syndrome (MDS), and leukemia. We report on a high incidence of expanding clonal aberrations with partial trisomies and tetrasomies of chromosome 3q in bone marrow cells of 18 of 53 FA patients analyzed, detected by conventional and molecular cytogenetics. To determine the clinical relevance of these findings, we compared the cytogenetic data, the morphologic features of the bone marrow, and the clinical course of these patients with those of 35 FA patients without clonal aberrations of 3q. The 2 groups did not differ significantly with respect to age, sex, or complementation group. There was a significant survival advantage of patients without abnormalities of chromosome 3q. Even more pronounced was the risk assessment of patients with gains of 3q material with respect to the development of morphologic MDS and acute myeloid leukemia (AML). Thus, our data from 18 patients with 3q aberrations reveal that gains of 3q are strongly associated with a poor prognosis and represent an adverse risk factor in FA.
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PMID:Clonal chromosomal aberrations in bone marrow cells of Fanconi anemia patients: gains of the chromosomal segment 3q26q29 as an adverse risk factor. 1251 6

Fanconi anemia or pancytopenia is an autosomal recessive condition presenting with a combination of pancytopenia with a mean age of onset of about eight years, a tendency to leukemia, and congenital anomalies. Although ocular abnormalities have been described, cataracts have not been previously reported. We present a patient with proven Fanconi anemia and cataracts.
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PMID:Fanconi anemia and primary cataracts: first case. 1256 68


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