Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:A9QXG9 (bcl-2)
 7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The concept of targeted therapy for patients with advanced cancer has intrigued researchers for many years. The lymphoid malignancies are particularly good candidates for this therapeutic approach, due to the identification of multiple lymphocyte-specific antigens. The recent introduction of rituximab marks the beginning of a new era in the treatment of lymphoid malignancies. Rituximab is one of the most active single agents for patients with refractory indolent lymphoma, producing response rates of approximately 50%, with low toxicity and a brief duration of treatment. Additional uses of rituximab are being evaluated in ongoing clinical trials, and are briefly reviewed. As a first-line agent, responses of approximately 70% are produced in patients with indolent lymphoma, with minimal toxicity. A substantial percentage of patients can be successfully retreated with rituximab, with second remission durations longer than the first remission (14-16 months versus 12 months). Multiple combination regimens using rituximab plus chemotherapy are also being evaluated. Although the role of these combined approaches is incompletely defined, high complete response rates can be obtained, with a higher rate of molecular complete remission (i.e., eradication of detectable bcl-2 rearrangements) than has been observed in patients receiving chemotherapy alone. Rituximab is also being evaluated in other CD20(+) lymphoid malignancies including large-cell lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. Within the next 12 months, several additional monoclonal antibodies will be available for the treatment of lymphoid malignancies. These include the radioimmunoconjugates tositumomab (Bexxar) and ibritumomab (Zevalin), as well as Campath-1H (anti-CD52) monoclonal antibody. Early clinical data with each of these agents are also briefly reviewed.
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PMID:Monoclonal antibody therapy in lymphoid malignancies. 1104 Feb 73

Bcl-2 functions as a key survival factor for lymphocytes and is highly expressed in a majority of non-Hodgkin's lymphomas. The ability of oblimersen sodium (Genasense, previously known as G3139) to target bcl-2 messenger RNA and decrease Bcl-2 protein levels has the potential to enhance the activity of cytotoxic chemotherapy. Pretreatment with oblimersen followed by cyclophosphamide (Cytoxan, Neosar) markedly improved survival relative to single-agent cyclophosphamide in a murine xenograft model. Oblimersen has also enhanced the cytotoxicity of a variety of other agents against non-Hodgkin's lymphoma, including etoposide, rituximab (Rituxan), and alemtuzumab (Campath). An initial phase I study of oblimersen in non-Hodgkin's lymphoma demonstrated modest single-agent activity. Recent reports suggest that oblimersen may add to the activity of R-CHOP (rituximab-cyclophosphamide/doxorubicin/vincristine/prednisone) in previously untreated mantle cell lymphoma and to rituximab alone in a variety of subtypes of relapsed non-Hodgkin's lymphoma. Additional studies in both treatment-naive and relapsed patients will define the role of oblimersen in the treatment of non-Hodgkin's lymphoma.
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PMID:Targeting the proapoptotic factor Bcl-2 in non-Hodgkin's lymphoma. 1565 Nov 74

Bcl-2 protein is upregulated in a wide variety of lymphoid malignancies, including chronic lymphocytic leukemia (CLL). The protein is thought to be responsible for maintaining the viability of malignant lymphoid cells and may contribute to chemotherapy and radiotherapy resistance. Previous studies have shown that reduction of bcl-2 expression by antisense therapy sensitizes cells to chemotherapy-induced apoptosis. In vitro, the Bcl-2 antisense drug oblimersen sodium (Genasense, previously known as G3139) enhances the apoptotic response in CLL cells to fludarabine (Fludara), corticosteroids, alemtuzumab (Campath), and rituximab (Rituxan). A phase I trial in patients with refractory/relapsed CLL showed that patients with CLL were more sensitive to oblimersen than patients with solid tumors. The maximum tolerated oblimersen dose was 3 mg/kg/d, and the most common dose-limiting reaction was hypotension, frequently in association with high spiking fever. In this study, oblimersen displayed limited single-agent activity, including tumor lysis syndrome, transient decreases in circulating CLL cells, and reduction of splenomegaly and size of lymph nodes. Major responses were observed in 9% of patients. Subsequently, a phase III trial evaluating fludarabine and cyclophosphamide with or without oblimersen (3 mg/kg/d for 7 days) was initiated in patients with relapsed or refractory CLL. This trial recently completed accrual of 241 patients.
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PMID:Potential therapeutic applications of oblimersen in CLL. 1565 Nov 75

For many years, alkylating agents, especially chlorambucil, have been considered the drugs of choice for first-line treatment of progressive and symptomatic chronic lymphocytic leukemia (CLL). More recently, treatment approaches have included purine nucleoside analogs (PNAs), fludarabine or cladribine (2-CdA), and monoclonal antibodies (MoAbs). PNAs are highly active in patients with CLL, previously treated and untreated. Significantly higher overall response and complete response in patients treated initially with fludarabine or 2-CdA than in those treated with chlorambucil- or cyclophosphamide-based combination regimens have been recently confirmed in prospective, randomized trials. However, the median survival times do not differ among the patients treated with PNA and alkylating agents. The MoAbs directed against CD52 antigen (alemtuzumab) and CD20 antigen (rituximab) also demonstrate significant activity in CLL and should be used in patients with disease that is refractory to PNAs. Combination therapies with PNAs and cyclophosphamide, and especially with rituximab, are more active than monotherapy with PNAs in regard to response rate and possible survival. Because most patients are older and there is no survival time advantage for alkylating agents or PNA therapies, we recommend chlorambucil as the first-line treatment, with PNAs for consideration as the second-line therapy. PNAs alone or in combination with cyclophosphamide and rituximab as first-line treatment are an option in younger patients, who may be candidates for consolidation therapy with alemtuzumab and/or stem cell transplantation. Alemtuzumab may be an effective treatment for patients refractory to PNAs. Several biological parameters have been gaining increasing importance to evaluate the prognosis of patients with CLL and define optimal therapeutic strategy. Moreover, novel therapies are being evaluated, especially in patients refractory to PNAs, including those targeting the antiapoptotic bcl-2 family of proteins and receptors, vaccines, and allogenic stem cell transplantation, especially after nonmyeloablative chemotherapy.
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PMID:New agents in chronic lymphocytic leukemia. 1661 76

Chronic lymphocytic leukemia (CLL) is a clonal disease characterized by proliferation and accumulation of small CD5-positive B cells. More than 50% of patients are asymptomatic at diagnosis and usually require no treatment. However, treatment is needed in the advanced and progressive disease. Chlorambucil with or without steroids has been the drug of choice for many years in previously untreated patients with CLL. The purine nucleoside analogs (PNAs), fludarabine (FA), cladribine (2-CdA-chlorodeoxyadenosine) and pentostatin (DCF, 2'-deoxycoformycin) also have been introduced for treatment of CLL. Significantly higher overall response (OR) and complete response (CR) and longer progression free survival (PFS) in patients with CLL treated with FA or 2-CdA have been confirmed in randomized, multicenter trials and more recently in meta-analysis. However, the median survival time did not differ between patients treated with PNA and alkylating agents. Combination therapies with PNAs and cyclophosphamide and especially with cyclophosphamide and rituximab are more active than monotherapy in terms of OR, CR and PFS. Several reports have shown significant activity of alemtuzumab in previously untreated and pretreated patients even when refractory to FA. Alemtuzumab also can be used in CLL as a preparative regimen before stem cell transplantation (SCT) and to eliminate minimal residual disease (MRD). Recently, several new agents have shown promise in treating CLL, including new monoclonal antibodies, agents targeting bcl-2 family of proteins, antisense oligonucleotides and other agents. Moreover, autologous and allogenic hematopoietic cell transplantations are increasingly considered for treatment of patients with CLL. In this review current therapeutic strategies in CLL are presented.
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PMID:Recent progress in the management of chronic lymphocytic leukemia. 1790 94