Gene/Protein Disease Symptom Drug Enzyme Compound
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Anti-CD20 antibodies may reduce or eliminate non-Hodgkin's lymphoma B cells in patients, although the mechanism of action is not clear. To explore mechanism(s), we examined the induction of signal transduction events using anti-CD20 monoclonal antibodies (mAb) in the human non-Hodgkin's lymphoma Ramos B cell line. We found that while Rituximab (a human-mouse hybrid mAb) alone induced apoptotic cell death, other murine anti-CD20 mAbs induced apoptosis of Ramos B cells only upon clustering with a secondary antibody. CD20 clustering was accompanied by activation of tyrosine protein kinase activity, PLCgamma2 phosphorylation, influx of Ca(2+), and activation of caspase 3. All signaling events, as well as the subsequent apoptosis, were blocked by PP2, a selective inhibitor of Src-family kinases. Treatment of Ramos with EGTA and BAPTA to block changes in cytoplasmic Ca(2+) likewise prevented CD20-induced apoptosis. Our findings support a model in which CD20 clustering activates members of the Src family of protein tyrosine kinases, leading to phosphorylation of PLCgamma2 and increased cytoplasmic Ca(2+). These early signal transduction events activate caspase 3 to promote apoptotic cell death of NHL B cells.
Blood Cells Mol Dis 2000 Apr
PMID:Clustered CD20 induced apoptosis: src-family kinase, the proximal regulator of tyrosine phosphorylation, calcium influx, and caspase 3-dependent apoptosis. 1075 4

Chimeric CD20 monoclonal antibody as alternative therapy in relapsed low-grade non-Hodgkin's lymphoma (NHL) has produced responses in nearly 50% of patients. Augmenting CD20 expression on tumor cells and/or inducing its expression may increase the cell kill and effectiveness of antibody therapy. Peripheral blood lymphocytes from 19 patients with B-cell chronic lymphocytic leukemia (B-CLL) were incubated in vitro in the presence of interferon-alpha (IFN-alpha) (500 U/ml and 1,000 U/ml) for 24 and 72 hours. The effect on CD20 expression was studied by flow cytometry. The differences in the percentage positivity, the mean fluorescence intensity (MFI), and the product of percentage positivity and MFI were used to assess upregulation. There was a significant upregulation of CD20 expression on B cells seen at both concentrations after 24-hour priming (p < 0.01). B-CLL cells cultured for 72 hours in the presence of IFN-alpha also showed upregulation of CD20 expression; however, the degree of upregulation was much lower than that seen at 24 hours. There was no statistically significant increase in CD20 antigen expression on normal lymphocytes following cytokine exposure. These results suggest that IFN-alpha priming may augment the effectiveness of antibody therapy by directly upregulating CD20 antigen expression in addition to its indirect action through effector cells of the host.
Cytokines Cell Mol Ther 2000 Jun
PMID:Effect of interferon-alpha on CD20 antigen expression of B-cell chronic lymphocytic leukemia. 1110 73

Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis, and it may also be found in a wide variety of benign and malignant lesions including oral hairy leukoplakia, inflammatory pseudotumor, Hodgkin's disease, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, and gastric carcinoma. Molecular testing is increasingly important in the diagnosis and monitoring of patients affected by these diseases. In biopsy tissues, molecular detection of EBV-encoded RNA transcripts by in situ hybridization remains the gold standard for proving that a histopathological lesion is EBV-related. EBV-encoded RNA hybridization and EBV LMP1 immunostains are used routinely to detect latent EBV in tissues affected by posttransplant lymphoproliferative disorder (PTLD) or in enlarged nodes from patients with infectious mononucleosis. Traditional serology is the best test for evaluating acute versus remote infection in healthy individuals. High serological titers serve as a tumor marker for some EBV-related malignancies, but titers are not a dependable tumor marker in immunocompromised hosts. EBV viral load testing by quantitative DNA amplification of blood samples is a promising new laboratory test that has proven useful for early diagnosis and monitoring patients with PTLD. Recent studies suggest a role for EBV viral load testing in nasopharyngeal carcinoma, Hodgkin's disease, and AIDS patients with brain lymphoma. Further research is needed to define more fully the clinical utility of viral load tests in the full spectrum of EBV-associated diseases. Gene expression profiling is on the horizon as a means to improve subclassification of EBV-related diseases and to predict response to therapy.
J Mol Diagn 2001 Feb
PMID:Molecular diagnosis of Epstein-Barr virus-related diseases. 1122 65

Through differential screening of mouse hematopoietic stem cell (HSC) and progenitor subtracted cDNA libraries we have identified a HSC-specific transcript that represents a novel RING finger gene, named FLRF (fetal liver ring finger). FLRF represent a novel evolutionarily highly conserved RING finger gene, present in Drosophila, zebrafish, Xenopus, mouse, and humans. Full-length cDNA clones for mouse and human gene encode an identical protein of 317 amino acids with a C3HC4 RING finger domain at the amino terminus. During embryonic hematopoiesis FLRF is abundantly transcribed in mouse fetal liver HSC (Sca-1+c-kit+AA4.1+Lin- cells), but is not expressed in progenitors (AA4.1-). In adult mice FLRF is not transcribed in a highly enriched population of bone marrow HSC (Rh-123lowSca-1+c-kit+Lin- cells). Its expression is upregulated in a more heterogeneous population of bone marrow HSC (Lin-Sca-1+ cells), downregulated as they differentiate into progenitors (Lin-Sca-1- cells), and upregulated as progenitors differentiate into mature lymphoid and myeloid cell types. The human FLRF gene that spans a region of at least 12 kb and consists of eight exons was localized to chromosome 12q13, a region with frequent chromosome aberrations associated with multiple cases of acute myeloid leukemia and non-Hodgkin's lymphoma. The analysis of the genomic sequence upstream of the first exon in the mouse and human FLRF gene has revealed that both putative promoters contain multiple putative binding sites for several hematopoietic (GATA-1, GATA-2, GATA-3, Ikaros, SCL/Tal-1, AML1, MZF-1, and Lmo2) and other transcription factors, suggesting that mouse and human FLRF expression could be regulated in a developmental and cell-specific manner during hematopoiesis. Evolutionary conservation and differential expression in fetal and adult HSC and progenitors suggest that the FLRF gene could play an important role in HSC/progenitor cell lineage commitment and differentiation and could be involved in the etiology of hematological malignancies.
Blood Cells Mol Dis
PMID:FLRF, a novel evolutionarily conserved RING finger gene, is differentially expressed in mouse fetal and adult hematopoietic stem cells and progenitors. 1135 94

G-3139 is an antisense phosphorothioate oligodeoxynucleotide (AS PS ON) which suppresses bcl-2 expression and is being developed by Genta Inc for the potential treatment of various cancers [308375]. G-3139 is in various stages of phase I/lIa trials. One study, initiated in May 1999, at the Lombardi Cancer Center at Georgetown University Medical Center, US, will examine G-3139 in conjunction with docetaxel. In a phase I/IIa dose-escalating trial to treat non-Hodgkin's lymphoma (NHL), at the Royal Marsden NHS Trust, UK, no serious, clearly drug-attributable or doselimiting adverse effects were noted and in some patients encouraging signs of potential drug activity were observed. The responses included one patient in whom cancer mass was reduced and one who developed a complete response for over 38 weeks in duration [239159,291608,325262]. A new phase II protocol using G-3139 combined with standard chemotherapies in relapsed NHL patients has also begun [325262]. Other phase I/lIa studies include: the safety and efficacy of G-3139 in the treatment of hormone-resistant, metastatic prostate cancer, when administered with mitoxantrone [305822]; the treatment of relapsed follicular NHL, when administered with cyclophosphamide [311217]; the treatment of Stage III and IV metastatic malignant melanoma in combination with dacarbazine [289755]; the treatment of hormone-resistant, metastatic prostate cancer when administered over a significantly longer duration than studied previously and in combination with an androgen-receptor blocking agent [291608]. The National Cancer Institute (NCI) funded and conducted preclinical studies of G-3139 in July 1996 and in June 1998, the NCI and Genta entered into a Cooperative Research and Development Agreement (CRADA) for the development of G-3139 [290153]. Clinical trials,focusing on colorectal cancer, small cell lung cancer and leukemia, were underway as of April 1999. The company licensed the rights for the use of bcl-2 as a target for antisense and gene therapy-based treatments from the University of Pennnsylvania. In June 1998, Genta received two patents relating to its antisense compounds [289685].
Curr Opin Mol Ther 1999 Jun
PMID:Technology evaluation: G-3139. 1171 6

In order to characterize the molecular mechanisms of lymphoma formation in HIV-infected humans, a method of two-staged substractive cloning was used, which adequately detects genes whose expression is increased in cells of one lymphoma in comparison with another. Using this method, we determined the spectrum of genes whose expression was increased in centroblastic non-Hodgkin's lymphoma in comparison with immunoblastic non-Hodgkin's lymphoma. Several gene groups were distinguished in this spectrum; their probable involvement in lymphogenesis is discussed.
Mol Gen Mikrobiol Virusol 2001
PMID:[Comparative analysis of the level of gene transcription in two types of HIV-associated lymphoma]. 1181 16

Primary central nervous system lymphoma (PCNSL) is usually a large B-cell, high grade non-Hodgkin's lymphoma (NHL) classified as a diffuse large cell lymphoma (DLCL). In rare cases, however, T cell lymphomas have been described. Although a relatively rare tumor, the incidence of PCNSL has increased dramatically over the past 15 years in both immuno-competent and immunocompromised patients. The disease is aggressive with a 5-year survival rate of less than 25 %. The cause of death is progressive and recurrent disease in the CNS, despite aggressive treatment. Approximately 20-25% of patients with PCNSL also have primary intra-ocular lymphoma (PIOL). PCNSL and PIOL are closely related and inter-connected pathologies involving two immune privileged sites. The study of PCNSL and PIOL has been limited due to the fact that viable malignant cells are rare and difficult to recognize. Moreover, the cells are difficult to culture and to date there is no good animal model for the disease. Here, we will present the current literature on the disease. In particular, we will present data suggesting that PCNSL in immuno-compromised and AIDS patients may correspond to two different pathologies. Furthermore, we will discuss how the study of these lymphomas can benefit from new advanced molecular biology techniques including single cell PCR and laser capture microdissection (LCM). PCNSL and PIOL are aggressive tumors, therefore, early diagnosis and prompt, aggressive treatment may improve prognosis. Advanced molecular biology will help delineate the oncogenesis of PCNSL and PIOL.
Curr Mol Med 2001 May
PMID:Molecular analysis of primary central nervous system and primary intraocular lymphomas. 1189 75

The usefulness and complementarity of gallium (67Ga) scintigraphy and computed tomography (CT) in the management of patients with lymphoma have been extensively demonstrated. Owing to a lack of anatomical landmarks and physiological distribution of the tracer, precise localisation of abnormalities on 67Ga scintigraphy can be difficult. As fusion imaging techniques between single-photon emission tomography (SPET) and CT have been developed recently, we investigated whether use of CT/67Ga SPET fusion imaging could help in the interpretation of 67Ga scintigraphy. From November 1999 to May 2001, 52 consecutive fusion studies were performed in 38 patients [22 patients with Hodgkin's disease (HD) and 16 patients with non-Hodgkin's lymphoma (NHL)] as part of pre-treatment staging (n=13), treatment evaluation (n=20) or evaluation of suspected recurrence (n=19). 67Ga scintigraphy was carried out 2 and 6 days following the injection of 185-220 MBq 67Ga citrate. On day 2, 67Ga SPET and CT were performed, focussing on the chest and/or the abdomen/pelvis. Data from each imaging method were co-registered using external markers. 67Ga scintigraphy and CT were initially interpreted independently by nuclear medicine physicians and radiologists. CT/67Ga SPET fusion studies were then jointly interpreted and both practitioners indicated when fusion provided additional information in comparison with CT and 67Ga SPET alone. Image fusion was considered to be of benefit in 12/52 (23%) studies which were performed for initial staging (n=4), treatment evaluation (n=4) or evaluation of suspected recurrence (n=4). In these cases, image fusion allowed either confirmation and/or localisation of pathological gallium uptake (n=10) or detection of lesions not visible on CT scan (n=2). Fusion was relevant for discrimination between osseous lesions and lymph node involvement adjacent to bone, especially in the thoracic and lumbar spine and pelvis. In the abdomen and pelvis, fusion helped to differentiate physiological bowel elimination from abnormal uptake, and assisted in precisely locating uptake in neighbouring viscera of the left hypochondrium, including the spleen, left liver lobe, coeliac area, stomach wall and even the splenic flexure. At the thoracic level, fusion also proved useful for demonstrating clearly the relationships of abnormal foci to the pleura, hepatic dome, mediastinum, ribs or thoracic spine. Clinical management was altered by fusion imaging in one patient (chemotherapy was given instead of radiotherapy) and was potentially affected in three other patients (in that, in conjunction with other factors, the results of fusion imaging had an influence on the decision regarding use of irradiation and especially the treatment volume). In conclusion, CT/67Ga SPET fusion imaging allowed precise localisation of gallium uptake and correct attribution to the involved viscera, thereby altering the diagnosis in 20%-25% of studies in comparison with CT and 67Ga SPET analyses alone. CT/67Ga SPET fusion therefore appears valuable in facilitating the interpretation of 67Ga scintigraphy and we recommend its use in patients with lymphoma when CT and 67Ga scintigraphy are planned.
Eur J Nucl Med Mol Imaging 2002 Mar
PMID:Gallium-67 scintigraphy in lymphoma: is there a benefit of image fusion with computed tomography? 1200 15

Fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGF beta R, TEL/TRKC(L), and NPM/ALK arise from reciprocal chromosomal translocations and cause acute and chronic leukemias and non-Hodgkin's lymphoma. FTK-transformed cells displayed drug resistance against the cytostatic drugs cisplatin and mitomycin C. These cells were not protected from drug-mediated DNA damage, implicating activation of the mechanisms preventing DNA damage-induced apoptosis. Various FTKs, except TEL/TRKC(L), can activate STAT5, which may be required to induce drug resistance. We show that STAT5 is essential for FTK-dependent upregulation of RAD51, which plays a central role in homology-dependent recombinational repair (HRR) of DNA double-strand breaks (DSBs). Elevated levels of Rad51 contributed to the induction of drug resistance and facilitation of the HRR in FTK-transformed cells. In addition, expression of antiapoptotic protein Bcl-xL was enhanced in cells transformed by the FTKs able to activate STAT5. Moreover, cells transformed by all examined FTKs displayed G(2)/M delay upon drug treatment. Individually, elevated levels of Rad51, Bcl-xL, or G(2)/M delay were responsible for induction of a modest drug resistance. Interestingly, combination of these three factors in nontransformed cells induced drug resistance of a magnitude similar to that observed in cells expressing FTKs activating STAT5. Thus, we postulate that RAD51-dependent facilitation of DSB repair, antiapoptotic activity of Bcl-xL, and delay in progression through the G(2)/M phase work in concert to induce drug resistance in FTK-positive leukemias and lymphomas.
Mol Cell Biol 2002 Jun
PMID:Fusion tyrosine kinases induce drug resistance by stimulation of homology-dependent recombination repair, prolongation of G(2)/M phase, and protection from apoptosis. 1202 32

Positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (FDG) is a very useful technique for the imaging of lymphomas in the adult population. It provides unique information about the behaviour of malignant cells and contributes to more accurate staging of the illness and better assessment of response to therapy. The purpose of this study was to evaluate the usefulness of FDG PET in childhood lymphoma compared with conventional imaging methods (CIMs) and clinical data. Between July 1998 and August 2001, 42 FDG PET examinations were performed using a dedicated PET system (27 examinations) or a hybrid coincidence PET system (15 examinations) for initial tumour staging ( n=7), restaging ( n=5) or assessment of response to therapy or residual masses ( n=30) in 27 children with Hodgkin's disease (HD) ( n=20) or non-Hodgkin's lymphoma (NHL) ( n=7). FDG PET results were compared with CIM findings and clinical data. Since 2000, a standardised questionnaire for evaluation of the clinical impact of FDG PET on both staging and therapy has been sent to the 16 referring physicians and 13 have replied. In all children, FDG PET was performed without any side-effects. FDG PET was found to be very sensitive (Se=12/12) for staging and restaging of the illness, showing more lesions than CIMs, with a 50% patient upstaging rate (6/12). It was very accurate for monitoring response to therapy and for characterisation of residual masses. False-positive results were observed in two NHL patients with thymic uptake and one false-negative result was obtained in a patient whose NHL relapsed 1 month after a negative FDG PET. The questionnaire emphasised the impact of FDG PET on clinical management, which was modified on the basis of the FDG PET results in 23% of patients. As previously demonstrated in the adult population, FDG PET appeared to be a very sensitive imaging technique for staging and restaging of lymphoma in children and was very useful for monitoring the response to therapy.
Eur J Nucl Med Mol Imaging 2002 Sep
PMID:[(18)F]FDG in childhood lymphoma: clinical utility and impact on management. 1219 60


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