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)

We summarize in this article the antitumor activity of newly developed drugs against non-Hodgkin's lymphoma. The Taxans (paclitaxel and docetaxel), complex polycyclic organic chemicals isolated from the yew tree, have a broad antitumor spectrum with impressive activity in solid tumors. In the SWOG Phase II study on relapsed non-Hodgkin's lymphomas, paclitaxel (Taxol), showed 30% CR and 14% PR. In the CALGB study on docetaxel, a 14.5% response rate (12.5% for low-grade lymphoma and 16.1% for intermediate-high grade lymphoma) was found. In the Japanese phase II study of docetaxel, the response rate was 29.4% for all patients (14.3% for low-grade lymphoma and 40.0% for intermediate-high grade lymphoma). Rituximab is a chimeric monoclonal antibody directed against the B-cell specific antigen CD20. A phase II trial was conducted with four weekly infusions of 375 mg/m2 in patients with relapsed low-grade or follicular lymphoma. The response rate was 46%. A clinical trial combining Rituximab with 6 cycles of CHOP chemotherapy in newly diagnosed patients has recently been completed. Early evaluation of this experience suggests that this combination resulted in a PR or CR in all patients. New purine nucleoside analogs (fludarabine, cladribine, pentostatin) are active against common and generally incurable low-grade lymphoproliferative disorders. These new drugs combined with other chemotherapeutic reagents are expected to overcome refractory or incurable non-Hodgkin's lymphoma.
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PMID:[New antitumor drugs for non-Hodgkin's lymphoma]. 988 Oct 79

Rituximab is a novel anti-CD20 monoclonal antibody used in the treatment of relapsed low-grade non-Hodgkin lymphoma. To determine the impact of this therapy on the interpretation of posttherapy specimens, we reviewed the pretherapy and posttherapy bone marrow and peripheral blood morphologic and flow cytometric findings for 20 patients who received rituximab. Nine patients had a total of 13 posttherapy bone marrow specimens; all were positive for lymphoma before therapy. After therapy, 11 of 13 posttherapy bone marrow specimens were interpreted as positive or suggestive of lymphoma based on routine H&E-stained sections. However, immunohistochemical and/or flow cytometric immunophenotyping showed that 6 of the 11 cases were negative for lymphoma; the lymphoid infiltrates were composed entirely of T cells without B cells. We report that posttherapy bone marrow specimens from patients treated with rituximab may mimic residual lymphoma if examined by morphologic features alone. Familiarity with this finding and the use of ancillary immunophenotypic studies will aid in the accurate interpretation of posttherapy specimens.
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PMID:Lymphoid aggregates in bone marrow mimic residual lymphoma after rituximab therapy for non-Hodgkin lymphoma. 1058 8

Anti-CD20 monoclonal antibodies have been successfully employed in the clinical treatment of non-Hodgkin's lymphomas in both unmodified and radio-labeled forms. Previous publications have demonstrated that the antitumor effects of unmodified anti-CD20 mAb are mediated by several mechanisms including antibody-dependent cellular cytotoxicity, complement-mediated cell lysis, and induction of apoptosis by CD20 cross-linking. In this report, we demonstrate induction of apoptosis by three anti-CD20 monoclonal antibodies [1F5, anti-B1, and C2B8 (Rituximab)]. The magnitude of apoptosis induction was greater with the chimeric Rituximab antibody than with the murine 1F5 and anti-B1 antibodies. Apoptosis could be enhanced with any of the antibodies by cross-linking with secondary antibodies (or Fc-receptor-bearing accessory cells). The signaling events involved in anti-CD20-induced apoptosis were investigated, including activation of protein tyrosine kinases, increases in intracellular Ca2+ concentrations, caspase activation, and cleavage of caspase substrates. Our results indicate that anti-CD20-induced apoptosis can be attenuated by PP1, an inhibitor of protein tyrosine kinases Lck and Fyn, chelators of extracellular or intracellular Ca2+, and inhibitors of caspases, suggesting that anti-CD20-induced apoptosis may involve modulation of these signaling molecules. We also demonstrated that varying the expression of Bc1-2 did not affect the magnitude of anti-B1-induced apoptosis, possibly because of the sequestering effects of other Bc1-2 family members, such as Bad. These studies identify several of the signal-transduction events involved in the apoptosis of malignant B cells that transpire following ligation of CD20 by anti-CD20 antibodies in the presence of Fc-receptor-expressing cells or secondary goat anti-(mouse Ig) antibodies and which may contribute to the tumor regressions observed in mouse models and clinical trials.
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PMID:Signaling events involved in anti-CD20-induced apoptosis of malignant human B cells. 1075 75

Rituxan (Rituximab) is a chimeric mAb with human IgG1 constant domains used in the therapy of non-Hodgkin's B cell lymphomas. This Ab targets B cells by binding to the cell-surface receptor, CD20. In our investigation of the mechanism of B cell depletion mediated by Rituximab, we first constructed mutants of Rituximab defective in complement activation but with all other effector functions intact. Our results demonstrate that the previously described C1q binding motif in murine IgG2b constituting residues E318, K320, and K322 is not applicable to a human IgG1 when challenged with either human, rabbit, or guinea pig complement. Alanine substitution at positions E318 and K320 in Rituximab had little or no effect on C1q binding and complement activation, whereas alanine substitution at positions D270, K322, P329, and P331 significantly reduced the ability of Rituximab to bind C1q and activate complement. We have also observed that concentrations of complement approaching physiological levels are able to rescue >60% of the activity of these mutant Abs with low affinity for C1q. These data localize the C1q binding epicenter on human IgG1 and suggest that there are species-specific differences in the C1q binding site of Igs.
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PMID:Mapping of the C1q binding site on rituxan, a chimeric antibody with a human IgG1 Fc. 1075 13

Rituximab, a chimeric antibody that targets CD20(+) B cells, produces a 48% response rate in patients with refractory low-grade non-Hodgkin lymphoma. In this phase II trial, patients with low-grade non-Hodgkin lymphoma who had previously received no systemic therapy were treated with rituximab, 375 mg/m(2), administered by IV infusion for 4 consecutive weeks. Patients with objective response or stable disease received repeat 4-week courses of rituximab at 6-month intervals. At the time of initial reevaluation at 6 weeks, 21 of 39 patients (54%) had objective response to treatment, and an additional 14 patients (36%) had stable disease or minor response. Response rates were similar in patients with follicular and small lymphocytic (CLL-type) lymphoma (52% versus 57%, respectively). At present, follow-up is short and only 13 patients have undergone a second course of rituximab treatment. However, 4 additional responses were documented either prior to the second course of rituximab (2 patients) or following the second course (2 patients) and 4 patients improved from partial to complete response. The current response rate is 64%, with 6 complete responses (15%). Treatment with rituximab was well tolerated, with only 1 patient experiencing grade 3/4 infusion-related toxicity. Rituximab is well tolerated and highly active in patients with low-grade non-Hodgkin lymphoma previously untreated with systemic therapy. Although further follow-up is required, the demonstration of minimal toxicity and considerable activity of this new biologic agent represents an important beginning of more specific, less toxic treatment for this important group of cancer patients.
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PMID:Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin lymphoma. 1080 68

The chimeric anti-CD20 MAb rituximab has recently become a treatment of choice for low-grade or follicular non-Hodgkin's lymphomas (FL) with a response rate of about 50%. In this report, we have investigated the mechanism of action of rituximab on 4 FL and 1 Burkitt's lymphoma (BL) cell lines, 3 fresh FL samples and normal B cells in vitro. Rituximab efficiently blocks the proliferation of normal B cells, but not that of the lymphoma lines. We did not detect significant apoptosis of the cell lines in response to rituximab alone. All cell lines were targets of antibody-dependent cellular cytotoxicity (ADCC). On the other hand, human complement-mediated lysis was highly variable between cell lines, ranging from 100% lysis to complete resistance. Investigation of the role of the complement inhibitors CD35, CD46, CD55, and CD59 showed that CD55, and to a lesser extent CD59, are important regulators of complement-mediated cytotoxicity (CDC) in FL cell lines as well as in fresh cases of FL: Blocking CD55 and/or CD59 function with specific antibodies significantly increased CDC in FL cells. We conclude that CDC and ADCC are major mechanisms of action of rituximab on B-cell lymphomas and that a heterogeneous susceptibility of different lymphoma cells to complement may be at least in part responsible for the heterogeneity of the response of different patients to rituximab in vivo. Furthermore, we suggest that the relative levels of CD55 and CD59 may become useful markers to predict the clinical response. (Blood. 2000;95:3900-3908)
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PMID:Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. 1084 26

Rituximab (IDEC-C2B8, Mabthera(R)) is a chimeric (human-mouse) monoclonal antibody (MoAb) against the B-cell specific CD20-antigen. It has been used for the clinical treatment of non-Hodgkin's lymphomas, but variable clinical results suggest that some lymphoma cells remain resistant. In the present study we have evaluated the relative efficiencies of humoral and cell-mediated effector mechanisms complement-dependent cytotoxicity (CDC), antibody-(ADCC), complement-(CDCC) dependent cellular cytotoxicity and apoptosis on lymphoma cell killing by rituximab. Rituximab activated the cytolytic complement (C) cascade and induced a strong CDC, but the rituximab-triggered ADCC and CDCC were relatively ineffective. The CDC was strongly enhanced by antibodies against the C inhibitor CD59 (protectin). Neutralization of CD55 (DAF) and CD46 (MCP) had a similar but weaker effect. Rituximab also induced apoptosis but in a cell line-dependent fashion. The results strongly emphasize the role of direct CDC as the major, fast and efficient effector mechanism of rituximab. In the immunotherapeutic treatment of B-cell lymphomas, it is important to consider the role of C-regulatory proteins as an escape mechanism of the malignant cells. Our results suggest that the effect of rituximab therapy could be enhanced by combining it with neutralization of CD59.
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PMID:Rituximab (anti-CD20) therapy of B-cell lymphomas: direct complement killing is superior to cellular effector mechanisms. 1084 76

The clinical activity of rituximab, a chimeric monoclonal antibody which binds to the CD20 antigen, was evaluated as a single first-line therapy for patients with follicular non-Hodgkin lymphoma (NHL). Fifty patients with follicular CD20(+) NHL and a low tumor burden were analyzed for clinical and molecular responses. They received 4 weekly infusions of rituximab at a dose of 375 mg/m(2). The response rate a month after treatment (day 50) was 36 of 49 (73%), with 10 patients in complete remission, 3 patients in complete remission/unconfirmed, and 23 patients in partial remission. Ten patients had stable disease, and the disease progressed in 3 patients. One of 13 (8%) patients in complete remission, 9 of 23 (39%) patients in partial remission, and 5 of 10 (50%) patients with stable disease exhibited disease progression during the first year. Within the study population, 32 patients were initially informative for polymerase chain reaction (PCR) data on bcl-2-J(H) rearrangement. On day 50, 17 of 30 patients (57%) were negative for bcl-2-J(H) rearrangement in peripheral blood, and 9 of 29 (31%) were negative in bone marrow; a significant association was observed between molecular and clinical responses (P <.0001). At month 12, 16 of 26 patients (62%) were PCR negative in peripheral blood. These results indicate that early molecular responses can be sustained for up to 12 months and that this response is highly correlated with progression-free survival. Rituximab has a high clinical activity and a low toxicity and induces a high complete molecular response rate in patients with follicular lymphoma and a low tumor burden.
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PMID:Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. 1113 48

Rituximab is a chimeric anti CD-20 monoclonal antibody containing human IgG1 kappa constant regions, with murine variable regions. The anti-lymphoma effects of Rituximab are probably due to complement and antibody-dependent cell-mediated cytotoxicity, and induction of apoptosis. Phase II trials have demonstrated a strong activity of rituximab alone in indolent B non-Hodgkin lymphoma, especially in patients with follicular lymphoma. The most utilized dose-schedule is 375 mg/m(2) weekly x 4. The association with chemotherapy or with interferon-alpha increases Rituximab efficacy. More recently, Rituximab have showed activity also in diffuse large cell lymphoma, mantle cell lymphoma and in other B-malignancies. Good results have also been obtained utilizing Rituximab for in vivo purging. However, we are still far from having found a definite position for Rituximab in the treatment of lymphoproliferative disorders. The aim of future studies should be to develop new strategies that will hopefully produce the most effective Rituximab-based regimens in order to find the Rituximab key position in the treatment of B-malignancies
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PMID:Treatment of B-cell non-Hodgkin's lymphoma with anti CD 20 monoclonal antibody Rituximab. 1116 15

Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA) is a monoclonal antibody that targets the CD20 antigen present in most B-cell non-Hodgkin's lymphomas. Previous studies have shown overall response rates (ORR) of approximately 50% in relapsed patients. Ibritumomab is the murine parent anti-CD20 antibody that is linked through a MX-DTPA chelator to yttrium 90 (90Y) to form the radioimmunoconjugate 90Y-ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals, San Diego, CA). A phase I study of 90Y-ibritumomab tiuxetan determined that 0.4 mCi/kg was the maximum tolerated dose, and responses were reported in 67% of all patients and in 82% of patients with low-grade non-Hodgkin's lymphoma. A separate trial randomized eligible patients to either rituximab or 90Y-ibritumomab tiuxetan. An interim analysis of the first 90 patients showed an ORR of 80% with 90Y-ibritumomab tiuxetan versus 44% with rituximab (P < .05). A subsequent trial for patients with rituximab-refractory disease showed a 46% ORR. These studies show that 90Y-ibritumomab tiuxetan is an active agent in relapsed non-Hodgkin's lymphoma and appears to have a higher ORR compared with unconjugated rituximab.
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PMID:The use of ibritumomab tiuxetan radioimmunotherapy for patients with relapsed B-cell non-Hodgkin's lymphoma. 1122 3


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