Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The anti-CD20 chimeric monoclonal antibody rituximab (Rituxan) is used to treat patients with various B-cell tumors, including patients with plasma cell dyscrasias who have CD20+ disease. Many patients with CD20+ disease have either primary unresponsive disease or progress after initially responding to rituximab; therefore, understanding how tumor cells are, or become, resistant to rituximab is of clinical relevance. In this report, we determined whether tumor cells express antigens that block complement-mediated lysis or antibody-dependent cell-mediated cytotoxicity (ADCC) and thereby contribute to rituximab resistance. We demonstrate that expression of the complement regulator CD59 is associated with resistance to rituximab-mediated complement lysis of multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) cell lines. Moreover, neutralization of CD59 using a blocking monoclonal antibody reversed resistance to rituximab-mediated complement lysis of CD20++ CD59++ ARH-77 MM cells. In addition, we demonstrate the presence of CD59 and rituximab binding on viable tumor cells from patients with MM and Waldenstrom's macroglobulinemia with progressive disease despite rituximab therapy. Last, we also examined MM and NHL B-cell lines, as well as patient tumor cells, for the expression of other antigens that may have a role in blocking ADCC activity, such as Fas ligand (FasL), MUCI, or TRAIL. FasL, MUC1, and/or TRAIL were coexpressed with complement regulators on many of these cells. These studies therefore show that complement regulators, particularly CD59 and antigens that may block ADCC, are present on various B-cell tumors and associated with rituximab resistance in patients. A prospective, clinical study is assessing the role of these antigens in mediating rituximab resistance.
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PMID:Tumor cell expression of CD59 is associated with resistance to CD20 serotherapy in patients with B-cell malignancies. 1139 5

Waldenstrom's macroglobulinemia (WM, lymphoplasmacytic lymphoma) is a B-cell lymphoproliferative disorder in which CD20 is expressed on tumor cells from most patients. Several small studies have suggested a benefit from the anti-CD20 monoclonal antibody rituximab (Rituxan, MabThera) in patients with WM. In this retrospective study, we examined the outcome of 30 previously unreported patients with WM who received treatment with single-agent rituximab (median age 60; range 32-83 years old). The median number of prior treatments for these patients was 1 (range 0-6), and 14 patients (47%) received a nucleoside analogue before rituximab therapy. Patients received a median of 4.0 (1-11.3) infusions of rituximab (375 mg/m2). Three patients received steroids with their infusions for prophylaxis of rituximab-related infusion syndrome. Overall, treatment was well tolerated. Median immunoglobulin M (IgM) levels for all patients declined from 2,403 mg/dL (range 720-7639 mg/dL) to 1,525 mg/dL (range 177-5,063 mg/dL) after rituximab therapy (p = 0.001), with 8 of 30 (27%) and 18 of 30 (60%) patients demonstrating >50% and >25% decline in IgM, respectively. Median bone marrow lymphoplasmacytic (BM LPC) cell involvement declined from 60% (range 5-90%) to 15% (range 0-80%) for 17 patients for whom pre- and post-BM biopsies were performed (p < 0.001). Moreover, 19 of 30 (63%) and 15 of 30 (50%) patients had an increase in their hematocrit (HCT) and platelet (PLT) counts, respectively. Before rituximab therapy, 7 of 30 (23.3%) patients were either transfusion or erythropoietin dependent, whereas only 1/30 (3.3%) patients required transfusions (no erythropoietin) after rituximab. Overall responses after treatment with rituximab were as follows: 8 (27%) and 10 (33%) of the patients achieved a partial (PR) and a minor (MR) response, respectively, and an additional 9 (30%) of patients demonstrated stable disease (SD). No patients attained a complete response. The median time to treatment failure for responding (PR and MR) patients was 8.0 months (mean 8.4: range 3-20+ months), and 5.0 months (mean 6.1; range 3-12+ months) for patients with SD. These studies therefore demonstrate that rituximab is an active agent in WM. Marked increases in HCT and PLT counts were noted for most patients, including patients with WM who had MR or SD. A prospective clinical trial to more completely define the benefit of single-agent rituximab in patients with WM has been initiated by many of our centers.
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PMID:CD20-directed antibody-mediated immunotherapy induces responses and facilitates hematologic recovery in patients with Waldenstrom's macroglobulinemia. 1139 6

SUMMARY: The anti-CD20 chimeric monoclonal antibody rituximab (Rituxan) is used to treat patients with various B-cell tumors, including patients with plasma cell dyscrasias who have CD20+ disease. Many patients with CD20+ disease have either primary unresponsive disease or progress after initially responding to rituximab; therefore, understanding how tumor cells are, or become, resistant to rituximab is of clinical relevance. In this report, we determined whether tumor cells express antigens that block complement-mediated lysis or antibody-dependent cell-mediated cytotoxicity (ADCC) and thereby contribute to rituximab resistance. We demonstrate that expression of the complement regulator CD59 is associated with resistance to rituximab-mediated complement lysis of multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) cell lines. Moreover, neutralization of CD59 using a blocking monoclonal antibody reversed resistance to rituximab-mediated complement lysis of CD20++ CD59++ ARH-77 MM cells. In addition, we demonstrate the presence of CD59 and rituximab binding on viable tumor cells from patients with MM and Waldenstrom's macroglobulinemia with progressive disease despite rituximab therapy. Last, we also examined MM and NHL B-cell lines, as well as patient tumor cells, for the expression of other antigens that may have a role in blocking ADCC activity, such as Fas ligand (FasL), MUC1, or TRAIL. FasL, MUC1, and/or TRAIL were coexpressed with complement regulators on many of these cells. These studies therefore show that complement regulators, particularly CD59 and antigens that may block ADCC, are present on various B-cell tumors and associated with rituximab resistance in patients. A prospective, clinical study is assessing the role of these antigens in mediating rituximab resistance.
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PMID:Tumor Cell Expression of CD59 Is Associated With Resistance to CD20 Serotherapy in Patients With B-Cell Malignancies. 1139 43

SUMMARY: Waldenstrom's macroglobulinemia (WM, lymphoplasmacytic lymphoma) is a B-cell lymphoproliferative disorder in which CD20 is expressed on tumor cells from most patients. Several small studies have suggested a benefit from the anti-CD20 monoclonal antibody rituximab (Rituxan, MabThera) in patients with WM. In this retrospective study, we examined the outcome of 30 previously unreported patients with WM who received treatment with single-agent rituximab (median age 60; range 32-83 years old). The median number of prior treatments for these patients was 1 (range 0-6), and 14 patients (47%) received a nucleoside analogue before rituximab therapy. Patients received a median of 4.0 (1-11.3) infusions of rituximab (375 mg/m2). Three patients received steroids with their infusions for prophylaxis of rituximab-related infusion syndrome. Overall, treatment was well tolerated. Median immunoglobulin M (IgM) levels for all patients declined from 2,403 mg/dL (range 720-7639 mg/dL) to 1,525 mg/dL (range 177-5,063 mg/dL) after rituximab therapy (p = 0.001), with 8 of 30 (27%) and 18 of 30 (60%) patients demonstrating >50% and >25% decline in IgM, respectively. Median bone marrow lymphoplasmacytic (BM LPC) cell involvement declined from 60% (range 5-90%) to 15% (range 0-80%) for 17 patients for whom pre-and post-BM biopsies were performed (p < 0.001). Moreover, 19 of 30 (63%) and 15 of 30 (50%) patients had an increase in their hematocrit (HCT) and platelet (PLT) counts, respectively. Before rituximab therapy, 7 of 30 (23.3%) patients were either transfusion or erythropoietin dependent, whereas only 1/30 (3.3%) patients required transfusions (no erythropoietin) after rituximab. Overall responses after treatment with rituximab were as follows: 8 (27%) and 10 (33%) of the patients achieved a partial (PR) and a minor (MR) response, respectively, and an additional 9 (30%) of patients demonstrated stable disease (SD). No patients attained a complete response. The median time to treatment failure for responding (PR and MR) patients was 8.0 months (mean 8.4; range 3-20+ months), and 5.0 months (mean 6.1; range 3-12+ months) for patients with SD. These studies therefore demonstrate that rituximab is an active agent in WM. Marked increases in HCT and PLT counts were noted for most patients, including patients with WM who had MR or SD. A prospective clinical trial to more completely define the benefit of single-agent rituximab in patients with WM has been initiated by many of our centers.
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PMID:CD20-Directed Antibody-Mediated Immunotherapy Induces Responses and Facilitates Hematologic Recovery in Patients With Waldenstrom's Macroglobulinemia. 1139 44

Development of the chimeric mouse antihuman CD20 antibody, Rituximab, presented a notable advance in the treatment of patients with non-Hodgkin's lymphoma (NHL). Its use allowed the specific targeting of tumor B cells without the systemic toxicity of traditional therapies. The mechanisms by which Rituximab induces its antitumor activity are not fully understood. We have shown previously that Rituximab down-regulates Bcl-2 expression in some B-NHL cell lymphoma lines through an interleukin 10 (IL-10)-dependent autocrine loop, an effect that renders the resistant cells susceptible to chemotherapeutic drugs. The objective of this study was to delineate the signaling pathway by which Bcl-2 is controlled by Rituximab and IL-10. We hypothesized that the down-regulation of IL-10 by Rituximab decreases activation of the signal transducer and activator of transcription 3 (STAT3) protein, which in turn, is responsible for decreased levels of Bcl-2. We demonstrate by phosphoprotein immunoblotting and gel shift analyses that endogenous IL-10 induces activation of STAT3 in the 2F7 cell line. Furthermore, we show that Rituximab and anti-IL-10 antibody treatment decreases the ability of STAT3 to bind to its DNA binding site. The decrease in STAT3 activation by these treatments correlates with a decrease in Bcl-2 expression. Additionally, piceatannol, an inhibitor of STAT3 activation, down-regulates the expression of Bcl-2. Altogether, these results demonstrate that Bcl-2 expression is under the regulation of the STAT3 signaling pathway, which is regulated by endogenously secreted IL-10. Hence, Rituximab-induced down-regulation of IL-10 expression is responsible for the down-regulation of Bcl-2 and sensitization of NHL cells by therapeutic drugs. Furthermore, these findings support the notion that circulating IL-10 in vivo may control the resistance of NHL to drug-mediated cytotoxicity.
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PMID:Rituximab inactivates signal transducer and activation of transcription 3 (STAT3) activity in B-non-Hodgkin's lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs. 1143 52

The treatment options for chronic lymphocytic leukemia (CLL) beside standard therapy with chlorambucil or other alkylating agents have dramatically increased in the last few years. Promising results have been reported with new cytotoxic agents such as the purine analogues fludarabine and 2-chlordeoxyadenosine, either at first diagnosis or at relapse. Nevertheless, all patients with CLL relapse after initial response. Since residual lymphoma cells are very likely to be the origin of the clinical relapse, there is a need for new therapeutic approaches with different mechanism of action to eliminate these residual cells. These approaches include allogeneic or autologous stem cell transplantation as well as immunotherapeutic strategies. Monoclonal antibodies, either alone or conjugated to toxins or radioisotopes, are thus being actively investigated. In clinical trials the genetically engineered chimeric unconjugated anti-CD20 antibody Rituximab and the humanized unconjugated anti-CD52 antibody Campath-1H achieved the most promising results in the treatment of patients with relapsed or refractory low-grade non-Hodgkin's lymphoma. Thus far there is only little clinical experience with Rituximab in patients with CLL, and the exact role of these agent in the treatment of CLL has still to be determined in ongoing and future trials. As a single agent Campath-1H showed more clinical activity in previously treated CLL patients than Rituximab, with response rates of up to 33% in a multicenter pivotal study. Furthermore, the potential risks of tumor lysis and anaphylaxia for both antibodies and immunosuppression particularly for Campath-1H must be taken into account. The present review will compare the development and the basic principles of these unconjugated monoclonal antibodies and consider their present and potential role in the treatment of patients with CLL. Copyright 2000 S. Karger GmbH, Freiburg
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PMID:The Monoclonal Antibodies Campath-1H and Rituximab in theTherapy of Chronic Lymphocytic Leukemia. 1144 Dec 56

The CD20 antigen is strongly and stably expressed on cells of the B-cell lineage, but not on stem cells, and is thus an ideal target antigen for antibody therapy of B-cell malignancies. Rituximab is a human-mouse chimeric monoclonal antibody to the CD20 antigen that kills B-cells by a number of different effector mechanisms. The human IgG component of the antibody is able to bind human complement and also interact with effector cells to kill cells by antibody-dependent cell-mediated cytotoxicity. Some investigators have also shown direct effects of the antibody on human tumor cell lines expressing CD20. These effects include inhibition of proliferation, induction of apoptosis and increased sensitivity to chemotherapeutic agents, although the extent to which each of these mechanisms may contribute to the anti-tumor action of rituximab remains to be determined. Rituximab thus acts by additional mechanisms compared to conventional chemotherapeutic agents. The chimeric nature of the antibody results in minimal immunogenicity and allows repeat use. The antibody may be combined with conventional chemotherapy, with potential for increased efficacy with minimal added toxicity.
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PMID:Mechanism of action of rituximab. 1150 30

Patients with follicular lymphoma and a low tumor burden have a median overall survival of more than 10 years. Toxic conventional chemotherapy regimens are inappropriate in these patients, as they do not improve overall survival and the patients do not require palliation of symptoms. However, as most of these patients will ultimately die of their lymphoma, new therapies, with curative intent, are required. Rituximab is a human-mouse chimeric monoclonal antibody that has shown efficacy in patients with non-Hodgkin's lymphoma (NHL). The benign tolerability profile of rituximab makes it a suitable candidate for first-line treatment of follicular NHL patients with a low tumor burden. In a trial of 49 patients, 73% achieved a clinical response (26% complete response) with rituximab treatment. Molecular studies showed that 57% of patients achieved molecular remission (clearance of the bcl-2 molecular translocation from the blood, evaluated by polymerase chain reaction), 62% of these remaining bcl-2- for at least 1 year. There was a good correlation between molecular and clinical responses, with patients failing to achieve a molecular response at higher risk of disease progression. Rituximab monotherapy is therefore an effective and well-tolerated treatment for patients with low-grade lymphoma and a low tumor burden.
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PMID:Rituximab as first-line monotherapy in low-grade follicular lymphoma with a low tumor burden. 1150 31

Rituximab is a human-mouse chimeric monoclonal antibody that has demonstrated efficacy against non-Hodgkin's lymphoma (NHL). There is a powerful rationale for combining rituximab treatment with chemotherapeutic agents that have also shown efficacy in NHL, since the mechanisms of action are distinct and there is also evidence that rituximab may sensitize chemoresistant tumor cells to the actions of cytotoxic drugs. A study of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemoimmunotherapy has been carried out in 40 patients with low-grade NHL. In the 35 patients who completed the study, the overall response rate was 100%, with 63% achieving a complete response. Median time to progression has not yet been reached at 47.2+ months. Molecular analysis (polymerase chain reaction) showed that CHOP plus rituximab (unlike CHOP alone) could completely clear blood and bone marrow of cells containing the bcl-2 gene translocation, a molecular marker of NHL cells. Rituximab can therefore add to the efficacy of CHOP without significantly increasing toxicity. A further study is underway to determine whether similar efficacy with less overall toxicity can be achieved using rituximab in combination with fludarabine.
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PMID:Combination chemotherapy and rituximab. 1150 32

Rituximab (IDEC-C2B8) is a chimeric antibody that binds to the B-cell surface antigen CD20. Rituximab has significant activity in follicular non-Hodgkin lymphomas. Much less is known about the effects in chronic lymphocytic leukemia (CLL). We have initiated a phase II trial to evaluate the efficacy and safety of rituximab in patients with CD20+ pretreated CLL. To avoid the rituximab-associated toxicity, we restricted the tumor cell load, as measured by the number of circulating lymphocytes and the spleen size, in the first 2 cohorts of patients included in the study. Patients received 4 intravenous infusions of 375 mg/m2 once a week over a period of 1 month. Of the 28 patients evaluable for response, 7 patients showed a partial remission (National Cancer Institute criteria) lasting for a median of 20 weeks, with 1 patient still in remission after 71 weeks. Based on lymphocyte counts only, we found at least a 50% reduction of lymphocyte counts lasting for at least 4 weeks in 13 (45%) of 29 patients. Fifteen patients from 3 institutions were monitored for the immunophenotype profile of lymphocyte subsets. The number of CD5+CD20+ cells decreased significantly and remained low until day 28 after therapy. T-cell counts were not affected. With the exception of one rituximab-related death, adverse events in the remaining patients were mild. The results suggest that rituximab has clinical activity in pretreated patients with B-CLL. Toxicity is tolerable. Response duration after withdrawal of rituximab is rather short. Therefore, other modes of application and the combination with other agents need to be tested.
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PMID:Rituximab therapy of patients with B-cell chronic lymphocytic leukemia. 1182 61


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