Seminars in oncology
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Seminars in oncology · Dec 2000
ReviewChemotherapy sensitization by rituximab: experimental and clinical evidence.
For most lymphomas, chemotherapy is palliative because of an inability to overcome drug resistance within the lymphoma cells and attempts at overcoming specific drug resistance mechanisms, such as multidrug resistance, have had limited success. However, accumulating evidence suggests that the ability to activate apoptotic pathways may be an important determinant of chemotherapy sensitivity and presents a potentially important new therapeutic strategy. Studies have shown that distinct cellular thresholds exist for apoptosis, and it is likely that multiple developmental and environmental factors converge in a dynamic process to regulate this set point. ⋯ Monoclonal antibodies against the CD20 receptor have been shown to directly induce apoptosis and may serve to modulate the threshold for chemotherapy-induced apoptosis. Recent clinical studies of the monoclonal antibody, rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA), and combination chemotherapy have produced unexpectedly high rates of response and progression-free survival, suggesting rituximab improves the efficacy of chemotherapy. Taken together, the results from in vitro and clinical studies suggest that rituximab may modulate the sensitivity of B-cell lymphomas to chemotherapy.
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Seminars in oncology · Dec 2000
Randomized Controlled Trial Clinical TrialHigh-dose rituximab therapy in chronic lymphocytic leukemia.
Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA) is a chimeric monoclonal antibody that targets mature B cells in most lymphoid B-cell malignancies. Rituximab is approved by the US Food and Drug Administration for therapy for recurrent B-cell lymphoma. In initial clinical trials the activity in small lymphocytic lymphoma, the counterpart of chronic lymphocytic leukemia (CLL), was less than 20%. ⋯ No unusual toxicity was noted at higher doses. Further exploration of the dosing schedule of rituximab in CLL and development of combination therapies is necessary. This agent shows promise for interaction in combined chemoimmunotherapy strategies for front-line and relapsed patients with CLL.
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Seminars in oncology · Dec 2000
ReviewNew insights into anti-HER-2 receptor monoclonal antibody research.
Abnormalities in the expression, structure, or activity of proto-oncogene products contribute to the development and maintenance of the malignant phenotype. For example, c-erbB-2 encodes the HER-2 receptor (also known as c-erbB-2 or c-neu) that is overexpressed, amplified, or both in a number of human malignancies including breast, ovarian, colon, lung, prostate, and cervical cancers. In addition to deregulation of cell-surface HER receptors, cancer cells often show excessive activation and/or nonattenuation of growth factor--inducible signaling components, as well as their downstream transcription factors. ⋯ Using in vitro models, recent studies have shown that HER-2 overexpression may not be a prerequisite for invasion of breast cancer cells, as HER-2 activation by heregulin, which binds to HER-3 or HER-4 and transphosphorylates HER in noninvasive breast cancer cells, could lead to increased motility, enhanced gelatinolytic activity, and invasion. Furthermore, these ligand-driven phenotypic changes were completely suppressed by trastuzumab, which also blocked interactions between HER-2 and HER-3 receptors in heregulin-treated breast cancer cells, and inhibited the phosphatidylinositol-3' kinase-dependent pathway, but not the mitogen-activated protein kinase pathway. These phenotypic effects of anti-HER-2 monoclonal antibody are of special interest, because they point to potential therapeutic effects of trastuzumab in inhibiting the invasion and metastasis of breast cancer with low receptor expression.
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Seminars in oncology · Dec 2000
Multicenter Study Clinical TrialRituximab as first-line systemic therapy for patients with low-grade lymphoma.
Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA), the first monoclonal antibody available for the systemic treatment of cancer, yields a 48% response rate in patients with refractory low-grade non-Hodgkin's lymphoma. This preliminary report describes the use of rituximab, instead of standard chemotherapy, in 39 previously untreated patients with stages II-IV low-grade non-Hodgkin's lymphoma All patients received rituximab 375 mg/m2 by intravenous infusion for 4 consecutive weeks and were evaluated for response at week 6. Patients with stable disease or an objective response received repeat 4-week courses at 6-month intervals, for a maximum of four treatment cycles. ⋯ Treatment was well tolerated. The high level of activity suggests that initial treatment with rituximab is a reasonable option in this group of patients, and that repeat maintenance courses at 6-month intervals are feasible and well tolerated. Further follow-up evaluation is necessary to determine the merits of this approach compared with traditional chemotherapeutic treatment.
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Seminars in oncology · Dec 2000
ReviewOverview of idiopathic thrombocytopenic purpura: new approach to refractory patients.
Idiopathic thrombocytopenic purpura is a disorder in which autoantibodies are made to platelets, resulting in accelerated platelet destruction. The diagnosis may be made in outpatients who are previously well or in patients with multiple medical conditions and medications. There are no unequivocal ways to distinguish immune thrombocytopenias from other thrombocytopenias, even with state-of-the-art tests including anti-platelet antibodies, thrombopoietin, glycocalicin, and platelet reticulocyte counts. ⋯ Treatment of idiopathic thrombocytopenic purpura should be individualized. Substantial platelet increases are seen in more than 50% of patients who receive intravenous IgG, intravenous anti-D, steroids, or splenectomy. Two additional agents showing promising clinical trial experience are anti-CD40 ligand and rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA).