Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The occurrence of Myelodysplastic Syndrome (MDS) and Acute Myeloblastic Leukaemia (AML) following cytotoxic therapy for neoplastic disease is well recognised. RAS mutations are common in patients with MDS and AML. To determine whether these lesions are found as early markers of secondary disease, we have studied the incidence of RAS mutations in the peripheral blood of 70 patients in complete remission from lymphoma. Patients were treated by standard chemotherapy regimes and/or localised radiotherapy. Treatment had been given 6 months to 14 1/2 years previously and no patient showed any sign of residual disease. Genomic DNA from peripheral blood leukocytes was amplified in vitro at target codons of N, K and H RAS genes, and mutations detected by hybridisation with oligonucleotide probes. RAS mutations were detected in 9 subjects. One patient with an N12 valine (Val) substitution had been in complete remission from Hodgkin's disease (HD) for 9 years. DNA from this patient registered in a nude mouse tumorigenicity assay (NMT). The N12 Val mutation was not detected in the original tumour tissue from the same patient. A second patient in remission from HD showed evidence of co-existent N12 cysteine (Cys) and N13 valine (Val) substitutions which were not detected in presentation material or unaffected tissues. All patients are currently haematologically normal, indicating that clones of mutant RAS bearing cells may be detected prior to any overt sign of disease.
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PMID:RAS mutations in patients following cytotoxic therapy for lymphoma. 217 19

We have previously shown that the LAZ3/BCL6 gene encoding a potential transcription factor, is disrupted in B-diffuse large cell non-Hodgkin's lymphomas (NHL) with 3q27 chromosomal abnormalities involving the immunoglobulin (IG) genes. However, LAZ3 rearrangement also occurs in NHL bearing 3q27 translocations without involvement of the IG genes: for example the VAl cell line exhibits t(3;4)(q27;p11). In the present work we have used a RT-PCR method to detect and to sequence the LAZ3 mRNA products from the VAL cell line. We report that the consequence of the t(3;4) is the expression of a chimeric transcript of LAZ3 with a new gene encoding a small G-like protein, termed TTF (Translocation Three Four). Nucleotide sequence analysis of a 1.4 kb cDNA predicts that the TTF gene encodes a protein of 191 amino-acids similar to members of the RAS superfamily including HRAS (27% identical), RAB1A (30% identical) and RHO proteins: the human RAC1, RHOB and CDC42Hs proteins (respectively 43, 44 and 45% identical) and the yeast RHO2 protein (44% identical). Unlike most other small G proteins which are expressed ubiquitously, TTF was transcribed only in hemopoietic cells as a 2.2 kb transcript. TTF may define a new subgroup of RHO-like proteins.
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PMID:TTF, a gene encoding a novel small G protein, fuses to the lymphoma-associated LAZ3 gene by t(3;4) chromosomal translocation. 778 61

Peptides from 10 to 22 amino acids containing sequences encompassed by Staphylococcus aureus protein A were synthesized. Some of these peptides, when present in cultures of lymphomononuclear cells from healthy donors or from cancer patients (melanoma, breast carcinoma, non-Hodgkin lymphoma and renal cell carcinoma) promoted: (i) changes in the phenotype of the lymphomononuclear population, (ii) stimulation of monocytes (release of IL-1 and TNF-alpha), and (iii) an increase in cytotoxicity against K562, Daudi and HT-29 cells. Isolated monocytes responded also to those peptides with a release of IL-1 and TNF alpha and an increase of cytotoxicity against HT-29 cells. It was found that the active peptides had the following structural pattern: a length of at least 15 amino-acid residues with a proline at position 6, valine, leucine, isoleucine, glycine, alanine or lysine at position 2, and glutamic or aspartic acid at position 11. Replacement of Pro at position 6 with any other residue turned the peptide inactive. Replacement of residues at positions 2 and 11 with amino-acid residues other than those required for activity resulted in compounds with a marked decrease in the immunomodulating properties described, or lacking these properties altogether.
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PMID:Immunomodulation induced by synthetic peptides derived from Staphylococcus aureus protein A. 814 92

Concurrent activation of BCL2 and MYC usually occurs in B cell non-Hodgkin lymphoma (B-NHL) by translocation of both oncogenes to both immunoglobulin heavy chain (IGH) alleles: this abrogates immunoglobulin synthesis. We have studied three B-NHL cell lines (DoHH2, VAL and ROS 50) and show that concurrent activation of BCL2 and MYC may follow translocation of both oncogenes to the same IGH allele. Conventional cytogenetics of DoHH2 suggested the presence of a t(14;18)(q32;q21) translocation. However, fluorescent in situ hybridization (FISH) studies using whole chromosome paints, alpha satellite probes and flow-sorted chromosomes as probes revealed an unexpected complexity of rearrangements involving chromosomes 8, 14 and 18, namely t(8;14;18)(q24;q32;q21). DNA blot and previous PCR analysis confirmed the juxtaposition of BCL2 major breakpoint region (mbr) with IGJH6, but also demonstrated a rearrangement within the first exon of MYC. The centromeric (5') MYC rearranged fragment comigrated with the BCL2-JH6 rearranged fragment in BamHI, EcoRI and Bg/II restriction digests. The der(8)t(8;14;18) therefore comprised 5' MYC (exon I)-Sgamma4-JH6-BCL2 mbr. Similar rearrangements were observed in both ROS 50 and VAL cell lines which contained two and three copies of the der(8)t(8;14;18) respectively. Quantitative flow cytometry for BCL2 and MYC expression showed abundant expression of both proteins in all three lines. These data indicate the der(14)t(14;18)(q32;q21) may itself be the target for any second translocation. The presence of the intact BCL2-JH fusion gene on the der(8)t(8;14;18) allowed concurrent activation of both BCL2 and MYC with no loss of immunoglobulin expression.
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PMID:Concurrent activation of MYC and BCL2 in B cell non-Hodgkin lymphoma cell lines by translocation of both oncogenes to the same immunoglobulin heavy chain locus. 868 2

The LAZ3/BCL6 gene encoding a Zinc-finger nuclear protein is altered in Non-Hodgkin's Lymphomas (NHLs) by translocations, mutations and/or deletions clustered in its 5' non coding region, in a 3.3 Kbp EcoRI fragment which thus defines the Major Translocation Cluster (MTC). In the present study, we describe at the molecular level the deletions found in the MTC of two (NHL) cases using, (i) DNA obtained from a patient (GUI) with a monosomy 3 and three microdeletions of 101, 22, 25 bp in its unique untranslocated 3q27 allele; (ii) a cell line derived from a patient (VAL) carrying a t(3;4) (q27;p11) translocation and a 2.4 Kbp deletion in the untranslocated allele. As the MTC is recurrently subject to alterations, we have cloned and sequenced the murine equivalent of the human MTC and promoter region in an attempt to identify sequences well conserved in mammals that may be thus important for the LAZ3/BCL6 gene regulation. We show that the human and mouse 5' upstream regions of the LAZ3/BCL6 gene although mainly intronic share a particularly high homology of 79% on the overall sequence. Strikingly, the small sequences which are deleted in patient (GUI) are highly conserved (81%, 100% and 92% respectively). Furthermore, they may play a role in the pathogenesis since proteins prepared from B cell lines and HeLa nuclear extracts bind to these sequences in gel retardation assays. Although a large part of this region is intronic, the high conservation of its sequence and the frequency of alterations in NHLs suggest that they are likely to be significant for the regulation of the LAZ3/BCL6 gene.
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PMID:Small deletions occur in highly conserved regions of the LAZ3/BCL6 major translocation cluster in one case of non-Hodgkin's lymphoma without 3q27 translocation. 904 92

The chimeric monoclonal antibody cAC10, directed against CD30, induces growth arrest of CD30+ cell lines in vitro and has pronounced antitumor activity in severe combined immunodeficiency (SCID) mouse xenograft models of Hodgkin disease. We have significantly enhanced these activities by conjugating to cAC10 the cytotoxic agent monomethyl auristatin E (MMAE) to create the antibody-drug conjugate cAC10-vcMMAE. MMAE, a derivative of the cytotoxic tubulin modifier auristatin E, was covalently coupled to cAC10 through a valine-citrulline peptide linker. The drug was stably attached to the antibody, showing only a 2% release of MMAE following 10-day incubation in human plasma, but it was readily cleaved by lysosomal proteases after receptor-mediated internalization. Release of MMAE into the cytosol induced G2/M-phase growth arrest and cell death through the induction of apoptosis. In vitro, cAC10-vcMMAE was highly potent and selective against CD30+ tumor lines (IC50 less than 10 ng/mL) but was more than 300-fold less active on antigen-negative cells. In SCID mouse xenograft models of anaplastic large cell lymphoma or Hodgkin disease, cAC10-vcMMAE was efficacious at doses as low as 1 mg/kg. Mice treated at 30 mg/kg cAC10-vcMMAE showed no signs of toxicity. These data indicate that cAC10-vcMMAE may be a highly effective and selective therapy for the treatment of CD30+ neoplasias.
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PMID:cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. 1271 94

Effective antibody-drug conjugates (ADC) combine high drug-linker stability in circulation and efficient intratumoral release of drug. Conjugation of monomethyl auristatin E (MMAE) to the anti-CD30 monoclonal antibody (mAb), cAC10, produced a selective and potent ADC against CD30(+) anaplastic large cell lymphoma and Hodgkin's disease models. This ADC, cAC10-valine-citrulline-MMAE, uses a protease-sensitive dipeptide linker designed to release MMAE by lysosomal cathepsin B in target cells but maintain a stable linkage and attenuate drug potency in circulation. To evaluate ADC stability in vivo, we developed methods for measuring drug/mAb ratios at progressive times in plasma from ADC-treated mice and nonhuman primates. Anti-idiotype mAb permitted the capture and quantitation of mAb cAC10, whereas antidrug mAb and MMAE-conjugated horseradish peroxidase reporter provided quantitative detection of conjugated drug following its in vitro release by cathepsin B. These data were validated by an alternative ELISA using anti-idiotype and anti-MMAE mAbs for capture and detection, respectively. Both methods differentiated ADC with variable levels of drug loading and were subsequently applied to stability studies in severe combined immunodeficient mice and cynomolgus monkeys. Evaluation of ADC from mouse circulation showed the linker half-life to be approximately 144 hours (6.0 days), significantly greater than that reported for disulfide- or hydrazone-linked ADCs in mice or human trials. In cynomolgus monkey, the apparent linker half-life was approximately 230 hours (9.6 days), suggesting that the drug-linker will be highly stable in humans. These data represent the longest reported drug-linker half-life to date and provide the basis for the pronounced specificity and antitumor activity of cAC10-valine-citrulline-MMAE.
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PMID:In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate. 1570 75

The presence of valine (V) at position 158 of FcgammaRllla (CD16) is known to improve clinical response to rituximab in indolent non-Hodgkin lymphoma (NHL). Little is known about the basic mechanisms for this observation. We examined natural killer (NK) cells from healthy donors representing the FcgammaRIIIa-158 polymorphic subgroups (V/V, V/F, and F/F) for gene transcript and cell surface CD16 expression, rituximab binding, and rituximab-dependent NK cell-mediated cytotoxicity. We observed higher levels of FcgammaRIIIa transcripts among individuals with the FcgammaRIIIa-158 V/V versus V/F or F/F genotype (P < .001); increased cell surface CD16 expression by quantitative flow cytometry on NK cells from individuals expressing at least one valine at FcgammaRIIIa-158 versus F/F (P = .029); as well as augmented rituximab binding and rituximab-mediated, antibody-dependent cellular cytotoxicity (ADCC). These results suggest that individuals expressing at least one valine at FcgammaRIIIa-158 might, in part, have better clinical outcomes due to increased CD16 expression, rituximab binding, and rituximab-mediated ADCC.
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PMID:Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the Fc{gamma}RIIIa-158 V/V and V/F polymorphism. 1747 6

Despite major advances in the treatment of non-Hodgkin lymphoma (NHL), including the use of chemotherapeutic agents and the anti-CD20 antibody rituximab, the majority of patients eventually relapse, and salvage treatments with non-cross-resistant compounds are needed to further improve patient survival. Here, we evaluated the antitumor effects of the microtubule destabilizing agent monomethyl auristatin E (MMAE) conjugated to the humanized anti-CD19 antibody hBU12 via a protease-sensitive valine-citrulline (vc) dipeptide linker. hBU12-vcMMAE induced potent tumor cell killing against rituximab-sensitive and -resistant NHL cell lines. CD19 can form heterodimers with CD21, and high levels of CD21 were reported to interfere negatively with the activity of CD19-targeted therapeutics. However, we observed comparable internalization, intracellular trafficking, and drug release in CD21(low) and CD21(high), rituximab-sensitive and -refractory lymphomas treated with hBU12-vcMMAE. Furthermore, high rates of durable regressions in mice implanted with these tumors were observed, suggesting that both rituximab resistance and CD21 expression levels do not impact on the activity of hBU12-vcMMAE. Combined, our data suggest that hBU12-vcMMAE may represent a promising addition to the treatment options for rituximab refractory NHL and other hematologic malignancies, including acute lymphoblastic leukemia.
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PMID:Potent antitumor activity of the anti-CD19 auristatin antibody drug conjugate hBU12-vcMMAE against rituximab-sensitive and -resistant lymphomas. 1914 85

Cytotoxic agents streptonigrin and 17-amino-geldanamycin were linked to monoclonal antibodies (mAbs), forming antibody-drug conjugates (ADCs) for antigen-mediated targeting to cancer cells. The drugs were conjugated with a linker construct that is labile to lysosomal proteases and incorporates a valine-alanine-p-aminobenzyl (PAB)-amino linkage for direct attachment to the electron-deficient amine functional groups present in both drugs. The resulting ADCs release drug following internalization into antigen-positive cancer cells. The drug linkers were conjugated to mAbs cAC10 (anti-CD30) and h1F6 (anti-CD70) via alkylation of reduced interchain disulfides to give ADCs loaded with 4 drugs/mAb. The streptonigrin ADCs were potent and immunologically specific on a panel of cancer cell lines in vitro and in a Hodgkin lymphoma xenograft model. We conclude that streptonigrin ADCs are candidates for further research, and that the novel linker system used to make them is well-suited for the conjugation of cytotoxic agents containing electron-deficient amine functional groups.
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PMID:Novel immunoconjugates comprised of streptonigrin and 17-amino-geldanamycin attached via a dipeptide-p-aminobenzyl-amine linker system. 1938 99


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