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)

Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA)-mediated killing of CD20-positive tumor cells is likely caused by a combination of immune-mediated effects including complement-mediated lysis and antibody-dependent cell-mediated cytotoxicity and direct effects induced by CD20 ligation. In vivo, the clearance of damaged or preapoptotic cells through specific receptors for phosphatidylserine translocated to the outer cell membrane may also be important. Direct effects, including growth inhibition and apoptosis, have been shown in vitro; however, their contribution to the clinical effect is not known. Currently, most data suggest that the predominant effector mechanism is antibody-dependent cell-mediated cytotoxicity, with a minor role of complement. With treatment, resistance to rituximab-mediated killing may emerge. Little is known regarding the molecular pathogenesis of this resistance. In rare cases, the CD20 antigen may be lost. Complement-resistance proteins may also increase, but it is not clear that this is the reason for loss of sensitivity. A better understanding of these mechanisms should allow combination therapy with agents capable of augmenting antibody-based killing.
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PMID:Rituximab: mechanism of action and resistance. 1184 83

Collectively, low-grade B-cell malignancies constitute the fifth most common form of potentially lethal cancer in North America and Europe, with chronic lymphocytic leukemia (CLL) and follicular non-Hodgkin's lymphoma (FL) representing the most prevalent of these disorders. Chronic lymphocytic leukemia and FL represent quintessential examples of human malignancies that are caused primarily by defects in programmed cell death (apoptosis). During the early stages of disease, the mature B lymphocytes that comprise most CLLs and FLs are largely quiescent G(0) phase cells, which accumulate not because they are dividing more rapidly than normal but because they survive longer than their normal counterparts because of defects in the normal pathways for apoptosis. Defects in apoptosis pathways contribute to chemoresistance, rendering tumor cells less sensitive to the cytotoxic actions of currently available anticancer drugs, and can also promote resistance to cellular immune responses. Several biological agents or their synthetic derivatives show promise as apoptosis modulators, having the potential to place neoplastic cells into a more susceptible state or activating latent programs for cell suicide. These biological response modifiers include monoclonal antibodies such as rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) that alter signal transduction pathways, cytokines such as TRAIL (Apo2 ligand), ligands for retinoid/steroid family nuclear receptors, and small-molecule compounds that bind and inhibit protein kinases. Knowledge about the mechanisms by which these agents influence apoptosis pathways in neoplastic diseases may suggest strategies for more effective and less toxic therapies for patients suffering from CLL, FL, and other malignancies.
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PMID:Modulating apoptosis pathways in low-grade B-cell malignancies using biological response modifiers. 1184 84

Advanced-stage mantle cell lymphoma (MCL) is a disease for which no curative treatment strategy exists. Results with standard combination chemotherapy, with or without an anthracycline, are disappointing, and new and better therapies are needed. High-dose therapy and autologous stem-cell transplantation (ASCT) have been performed in patients with MCL both up front and at relapse with varying degrees of success. Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) has shown moderate response rates in patients with MCL. It has also been used safely and effectively as an in vivo purge during ASCT for patients with lymphoma. We are currently investigating an aggressive protocol in patients with newly diagnosed, untreated MCL using a combination of two promising therapeutic modalities, high-dose therapy-ASCT and rituximab. Since 1999, 13 patients with newly diagnosed MCL have been enrolled in this phase II clinical trial. CHOP (cyclophosphamide/prednisone/vincristine/doxorubicin) is used as debulking chemotherapy. Stem cells are mobilized with 5 days of granulocyte colony-stimulating factor 10 microg/kg/d, with a single infusion of rituximab 375 mg/m(2) used as an in vivo purge before stem-cell collection by large-volume leukapheresis. The transplant conditioning regimen is cyclophosphamide/carmustine/etoposide. Post-transplant consolidative immunotherapy consists of rituximab 375 mg/m(2), administered as two 4-week cycles at 2 and 6 months post-transplant. So far, 12 patients (7 men/5 women) with a median age of 55 years (range, 41 to 65 years) have been transplanted. Patients were first assessed and then transplanted a median of 40 and 201 days, respectively, from diagnosis. International Prognostic Index at diagnosis was low (n = 3), low-intermediate (n = 8), and high-intermediate (n = 1). A median of six cycles of CHOP was required to debulk tumor sufficiently for transplant. Response to CHOP was 100% with six complete responses, one complete response unconfirmed, and five partial responses. Transplantation was well tolerated. Patients engrafted quickly, with a median of 11.5 days to neutrophil engraftment and 10 days to platelet independence. Patients had modest transfusion requirements, requiring a median of four units of packed red blood cells and two and a half platelet transfusions. Six to 8 weeks post-transplant, six patients were in complete response, four in complete response unconfirmed, and two in partial response. Eight patients have received all eight maintenance rituximab treatments, and four have received only their first cycle. Following rituximab, the two patients in partial response and two in complete response unconfirmed converted to complete response. With a median follow-up of 239 days from transplant (range, 61 to 727 days), all patients remain alive and well with no documented relapses. Samples for molecular monitoring have been drawn from the stem-cell graft, and serially from the peripheral blood and bone marrow of patients at baseline, preapheresis, pretransplant, and post-transplant at 3-month intervals. This data shows that ASCT followed by rituximab immunotherapy is feasible and safe in patients with MCL. Although patient numbers are low and follow-up time is short, preliminary results are encouraging. Rituximab may convert partial responders to complete responders. The durability of responses will be determined with longer follow-up.
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PMID:Immunotherapy with rituximab following high-dose therapy and autologous stem-cell transplantation for mantle cell lymphoma. 1184 90

Synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine dinucleotides (CpG ODN) are potent immunostimulatory agents that can activate various immune cell subsets. We have found that CpG ODN show a variety of effects that could be useful in enhancing the efficacy of antibody therapy of lymphoma. In a mouse model, CpG ODN alone had no effect on survival of animals inoculated with lymphoma. In contrast, CpG ODN plus monoclonal antibody (MAb) was more effective at inhibiting tumor growth than MAb alone or MAb plus control ODN. Cytosine-guanine ODN plus MAb cured mice with a large tumor burden that could not be cured with MAb therapy alone. We also evaluated the effects of CpG ODN on the phenotype of human malignant B cells. Cytosine-guanine ODN upregulated the expression of a number of antigens, including CD20. The upregulation of CD20 was most extensive in cells that had low baseline expression of this antigen. We conclude that CpG ODN enhances the efficacy of MAb in a murine lymphoma model, most likely by activating effector cells, and upregulates expression of CD20 on primary human malignant B cells. Given the effects of CpG ODN on both target antigen expression and effector-cell function, further evaluation of the combination of CpG ODN plus rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) and CpG ODN plus other MAbs is warranted.
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PMID:Synergism between cytosine-guanine oligodeoxynucleotides and monoclonal antibody in the treatment of lymphoma. 1184 95

Lymphomas are among the tumors most responsive to chemotherapeutic agents and radiation therapy. Despite chemotherapeutic and radiological advances, tumor cell resistance still remains a problem, and the toxicity of chemotherapy and radiation therapy limits their potential. Less toxic therapies for lymphoma have been continued to search for effectiveness. Since the discovery of the hybridoma technology by Kohler and Milstein in 1975, utilizing antibodies as targeted therapy for lymphoma has been investigated for many years. After 20 years of clinical trials, monoclonal antibody therapy of lymphoma enters the new millennium ready for 'prime time'. Investigators' early enthusiasm was dampened by problems with tumor targeting, HAMA, and allergic reactions, but important advances in molecular biology and chelation chemistry have led to new and improved reagents. Rituximab(IDEC-C2B8) has already been approved by the FDA in USA and the Ministry of Welfare and Labour in Japan for relapsed CD20-positive lymphomas and indolent B-cell lymphoma including mantle cell lymphoma, respectively. Ibritumomab tiuxetan and iodine-131 anti-B1 antibody have an excellent anti-lymphoma profile, and both appear to have higher response rates than rituximab. Results from the rituximab vs. ibritumomab tiuxetan phase III trial clearly favor the latter especially in %CR. Radiolabeled Lym-1, T101, LL2, and anti-Tac data will be forthcoming. Continued refinements of immunotoxins will establish their possible therapeutic role, and a variety of antibody conjugates including drugs, prodrugs, nonprotein toxins, and other agents, will continue to be studied in the clinic. Bispecific antibodies for lymphoma are also in early clinical testing. Over the next 10 years, many of the major advances in lymphoma therapy will be antibody-based.
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PMID:[Development of monoclonal antibody therapy for malignant lymphoma]. 1190 66

In multiple myeloma (MM), circulating malignant B cells are proposed as the proliferative compartment of the disease. In view of the close relationship between multiple myeloma and primary plasma cell leukemia (PCL), an anti-CD20 antibody treatment might also be considered as consolidation for patients with PCL. A 55-year-old patient diagnosed with PCL achieved complete remission after autologous transplantation. A total of four weekly courses of rituximab (375 mg/m(2)) were administered. Prior to antibody therapy, CD20+ cells comprised 22.6% of the mononuclear cells in peripheral blood (PB) assessed by flow cytometry and were enriched by magnetic activated cell sorting (MACS). In the enriched CD20+ fraction, 0.093% clonotypic cells were detected using a quantitative polymerase chain reaction (PCR) assay based on limiting dilutions. The proportion of clonotypic cells was 0.034% in PB and 0.032% in bone marrow (BM). Rituximab depleted CD20+ cells completely in PB and BM. Tumor load in PB and BM at day 40 and in PB at day 70 did not change in comparison to prior to therapy (0.037% in PB, 0.026% in BM). At day 90, the tumor load increased to 0.066% in PB. At day 120, the patient relapsed with 0.65% CD38++/CD138+/CD20- plasma cells and furthermore no CD20+ B cells in PB. The expansion of plasma cells was accompanied by an increase in the tumor load in both compartments (PB: 0.65%, BM: 1.8%). The accumulation of plasma cells during disease progression without the reappearance of CD20+ cells did not sustain the role of circulating clonotypic B cells as proliferative compartment in our patient. However, it cannot be excluded that rituximab was not able to eradicate malignant B cells, which subsequently contributed to relapse.
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PMID:Anti-CD20 antibody as consolidation therapy in a patient with primary plasma cell leukemia after high-dose therapy and autologous stem cell transplantation. 1190 96

There is currently no standard first-line treatment for indolent non-Hodgkin's lymphoma (NHL) because there is no curative treatment. In asymptomatic patients, treatment with chemotherapy does not improve survival compared with a "watch and wait" approach. Improved treatment strategies, with curative intent, are thus required for indolent NHL. Rituximab is effective and well tolerated in the treatment of indolent NHL and can be considered for asymptomatic patients, where the side effects of chemotherapy may outweigh the benefits. In addition, rituximab does not compromise the use of subsequent chemotherapy in patients who relapse. A study of rituximab monotherapy in patients with low-tumor-burden follicular lymphoma has shown high rates of both clinical remission and molecular remission (clearance of bcl-2-positive cells from blood and/or bone marrow). After 2 years, half the patients relapsed, indicating that improved strategies are still required. Efforts to improve the efficacy of rituximab have included repeated administrations of the antibody and combined administration with chemotherapy or interferon-alpha2a. The optimal role of rituximab in first-line therapy for indolent NHL will be determined through randomized clinical trials.
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PMID:Increasing treatment options in indolent non-Hodgkin's lymphoma. 1204 May 27

Various clinical observations suggest that non-Hodgkin's lymphomas (NHLs), particularly those of low histologic grade, can be controlled by immunologic mechanisms. Although many effective therapies exist for the initial treatment of low grade lymphomas, none are curative and most have significant toxic side effects. Several promising lymphoma tumor antigen vaccines are being studied at medical centers throughout North America. I favor the scientific evaluation of a therapeutic strategy for follicular NHL that places immune-based therapies forward in the treatment algorithm to the initial therapeutic decision point. Active immunotherapies (therapeutic tumor vaccines) are instituted in tandem with initial cytoreductive chemotherapy, and followed by passive monoclonal antibody therapies. The tumor-specific idiotype vaccines are favored because of their demonstrated potential for clinical activity in numerous human studies and their lack of significant toxic side effects. Rituximab and other monoclonal antibodies directed at normal B-cell antigens are known to abrogate the host's ability to mount primary humoral immune responses, including antitumor antibodies evoked by tumor vaccines. Therefore, one should consider deferring the use of these agents until after an attempt at generating a host humoral antitumor response using investigational tumor vaccines. Chemotherapy regimens containing highly immunosuppressive agents (ie, fludarabine) or organ dose-limiting toxicities (ie, doxorubicin) may be best reserved for later in the disease course for those failing the more conservative approaches and for cases with adverse prognostic features. This strategy may give patients the greatest chance at prolonged remission or cure while minimizing acute and chronic toxicities, although its impact on overall survival has not been proven. Low grade NHLs remain the proving ground for this treatment philosophy. Hopefully, in the future, similar strategies may be applicable to NHLs of other grades and histologies.
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PMID:Vaccine therapies for non-Hodgkin's lymphoma. 1207 67

Humanizing xenogenic monoclonal antibodies (MAbs) by genetic engineering has greatly improved their therapeutic utility and efficacy. The chimeric CD20 MAb C2B8 (Rituximab) is a prominent representative of this new generation of therapeutic MAbs and has been proposed as a treatment of choice for recurrent follicular non-Hodgkin's lymphomas. Treatment of CD20+ B cells with MAb C2B8 triggers several cell-damaging actions including complement-mediated lysis (CDL), antibody-dependent cellular cytotoxicity (ADCC), and MAb-induced induction of apoptosis. We provide an overview of the most prominent mechanisms underlying the efficacy of antibody treatment. We introduce our concept of cross-priming of cytotoxic T-cell responses promoted by apoptosis incucing antibodies. Treatment of tumor cells with antibodies that are capable of inducing a proapoptotic signal via their cell surface target structure may not only contribute to their direct killing but also may induce cellular responses against the tumor, which may have a long-lasting protective effect. We report, using the example of C2B8 anti-CD20 treatment of lymphoma cells, that MAb C2B8-induced apoptosis of lymphoma cells not only kills these cells but also promotes uptake and cross-presentation of lymphoma cell-derived peptides by antigen-presenting dendritic cells (DC), induces maturation of DC, and allows the generation of specific CTL.
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PMID:Cross-priming of cytotoxic T cells promoted by apoptosis-inducing tumor cell reactive antibodies? 1207 53

In previous experiments, 125I-labeled 1F5 (anti-CD20)was found to kill B-lymphoma cells efficiently and specifically.Unexpectedly, the number of antibody (Ab) molecules taken up per cell was much larger than the number of antigen sites on the cell surface. The present studies were designed to explain this apparent discrepancy. Incubation with fluorophore-conjugated 1F5, using the Raji cell line, demonstrated that the Ab accumulated in large amounts in a juxtanuclear spot. Double labeling showed that the same spot was labeled by transferrin, but the transferrin labeling was much faster (45 min versus 18 h). Experiments with brefeldin A demonstrated that the spot stained was distinct from the Golgi cisternae; thus, it appears to be the endocytic recycling compartment. A fluorescent Fab fragment of 1F5 produced much weaker, barely detectable staining of the juxtanuclear spot. Experiments with three other B-lymphoma cell lines demonstrated marked heterogeneity among them. With Ramos cells, 1F5 and transferrin localized to multiple smaller intracellular spots, rather than a single large spot. There were also major differences between different Abs to CD20, as tested on Raji cells. Rituximab showed some staining of the juxtanuclear spot, but not as homogeneously as the staining with 1F5. B1 and L27 were not tested as thoroughly but did not appear to stain the juxtanuclear spot. Such internalization may have a major impact on the therapy of this tumor type with conjugates of anti-CD20 Abs. However, internalization did not correlate with sensitivity to specific killing by 125I-labeled 1F5.
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PMID:Intracellular accumulation of the anti-CD20 antibody 1F5 in B-lymphoma cells. 1217 4


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