Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of patients with non-Hodgkin's lymphoma (NHL) is frequently hampered by development of chemoresistance. Rituximab is a chimeric mouse antihuman CD20 antibody that offers an alternative; however, its mechanism of action is not clearly understood. Treatment of lymphoma cell lines with Rituximab sensitizes the cells to the cytotoxic and apoptotic effects of therapeutic drugs, e.g., cisplatin, fludarabine, vinblastine, and Adriamycin. This study investigated the mechanism(s) involved in the reversal of drug resistance by Rituximab therapy. NHL cells synthesize and secrete antiapoptotic cytokines implicated in drug resistance, including interleukin (IL)-6, IL-10, and tumor necrosis factor alpha. We hypothesized, therefore, that sensitization by Rituximab may be due in part to modification of cytokine production. In this study, examination of cytokine secretion by NHL 2F7 tumor cells revealed down-regulation of IL-10 by Rituximab treatment. Moreover, cytotoxicity assays using exogenous IL-10 and IL-10-neutralizing antibodies demonstrated that IL-10 serves as an antiapoptotic/protective factor in these tumor cells against cytotoxic drugs. Furthermore, expression in 2F7 cells of the protective factor, Bcl-2, was shown to be dependent on IL-10 levels and down-regulated by Rituximab. Other gene products such as Bax, Bcl-x, Bad, p53, c-myc, and latent membrane protein-1 (LMP) were not affected by Rituximab treatment. Drug sensitization, as well as down-regulation of both IL-10 and Bcl-2, was corroborated in experiments using the NHL cell line 10C9. The Ramos and Daudi NHL cell lines were not sensitizable, nor did their Bcl-2 or IL-10 levels change. These studies demonstrate that one mechanism by which Rituximab sensitizes NHL to chemotherapeutic drugs is mediated through down-regulation of antiapoptotic IL-10 autocrine/paracrine loops and Bcl-2. The clinical relevance of these findings is discussed.
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PMID:Inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin's lymphoma to apoptosis. 1129 68

We report five cases of Burkitt lymphoma arising in organ transplant recipients. There were four men and one woman with a mean age of 35 years. All were solid organ recipients with three renal, one liver, and one double lung transplantation. The time interval between organ transplantation and lymphoma averaged 4.5 years. Patients typically presented with high-stage disease with generalized lymphadenopathy and bone marrow involvement. Histology showed classic Burkitt lymphoma or atypical variant/Burkitt-like morphology. C-MYC rearrangement, including three cases with immunoglobulin heavy chain and two cases with lambda light chain, and Epstein-Barr virus were detected in all the cases. Additional chromosomal abnormalities were present in two of three cases and p53 mutation was found in one of three cases. Aberrant genotype and phenotype were frequently encountered, including minor monoclonal or oligoclonal T-cell populations and undetectable surface immunoglobulin light chain expression. Four patients received antilymphoma regimens, with combination chemotherapy (three patients) and/or Rituximab (three patients), in addition to reduction of immunosuppression. All four patients achieved complete remission. We conclude that posttransplant Burkitt lymphoma represents a characteristic clinicopathologic entity and occurs later after transplantation. Genotypic and phenotypic aberrations are often present. Rituximab may be an effective alternative to conventional combination chemotherapy in the treatment of a posttransplant Burkitt lymphoma.
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PMID:Burkitt lymphoma arising in organ transplant recipients: a clinicopathologic study of five cases. 1276 87

MDM2 oncogene is overexpressed in many human cancers including breast, colon, and prostate cancer, and MDM2 levels are associated with poor prognosis in patients with cancer. Here, we summarize the investigation of the functions of MDM2 oncogene in human cancer growth and the value of MDM2 as a drug target for prostate cancer therapy by using antisense to inhibit MDM2 expression. Antisense anti-human-MDM2 oligonucleotides and mismatch controls were tested in in vitro and in vivo human cancer models for antitumor activity. Targeted gene products and related proteins were analyzed and the antitumor activity was determined when the oligonucleotides were used alone or in combination with cancer chemotherapeutics and radiation therapy. The antisense oligonucleotide specifically inhibited MDM2 expression in a dose- and time-dependent manner, resulting in significant antitumor activity in vitro and in vivo. The antisense oligonucleotides also potentiated the effects of p53 activation and p21 induction by chemotherapeutic agents 10-hydroxycamptothecin, adriamycin, 5-fluorouracil, and paclitaxel. In a dose-dependent manner, the antisense oligonucleotide showed antitumor activity in nude mice bearing human cancer xenografts and increased therapeutic effectiveness of the chemotherapeutic agents irinotecan, paclitaxel, and Rituxan and radiation therapy. These results indicate that MDM2 has a role in various tumor growth through both p53-dependent and p53-independent mechanisms, indicating that MDM2 inhibitors have a broad spectrum of antitumor activities in human cancers regardless of p53 status. These results provide a basis for clinical evaluation of antisense anti-MDM2 oligonucleotides as chemosensitizer and radiosensitizer.
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PMID:Chemosensitization and radiosensitization of human cancer by antisense anti-MDM2 oligonucleotides: in vitro and in vivo activities and mechanisms. 1475 37

Therapeutic options for chronic lymphocytic leukemia (CLL) have been limited, with low complete response rates (CR) and no treatments demonstrating a survival advantage. The recent introduction of the monoclonal antibodies rituximab and alemtuzumab into clinical trials for patients with CLL has generated promising results. Rituximab targets the CD20 antigen and demonstrates varied single-agent activity that is highly dependent upon the dosing schedule and treatment status of the patient. More importantly, when rituximab is combined with fludarabine or fludarabine and cyclophosphamide, a high frequency of CR and prolonged progression-free survival are observed without an appreciable increase in significant toxicity. Alemtuzumab targets the more ubiquitously expressed CD52 antigen and is therefore associated with a higher frequency of toxicity, particularly immunosuppression, but has appreciable activity in fludarabine refractory CLL. Additionally, alemtuzumab is effective against CLL clones that have p53 mutations or deletions. Future efforts in developing combination strategies with rituximab, alemtuzumab, and potentially other new antibodies offer great promise for the future treatment of CLL.
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PMID:Antibody therapy for chronic lymphocytic leukemia: a promising new modality. 1532 5

Rituximab is widely used for the treatment of B-cell non-Hodgkin's lymphoma (NHL), and encouraging results have been obtained. However, some CD20-positive NHL show minimal response to rituximab, indicating that the treatment effect depends on the presence or absence of an unidentified factor. We analyzed the relationship between the effect of rituximab plus chemotherapy and expression of Ki-67, p53 and bcl-2 and several clinical variables in cases of B-NHL, particularly follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Forty-four patients were included in the present study, and the overall treatment response rate was 68%. Twelve of 30 patients (40%) achieved a complete response, five (16%) reached an unconfirmed complete response and 13 (43%) achieved a partial response. A high serum lactate dehydrogenase level and International Prognostic Index of high or high intermediate risk were associated with a decreased response in the case of FL. Immunohistochemical assays were performed in 18 FL patients (55%) and 15 DLBCL patients (45%). Significant correlation was found between an inferior response to treatment and high Ki-67 expression in the cases of FL (P = 0.006). p53 and bcl-2 expression did not correlate significantly with the response rate. The cell cycle appears to be an important factor in the efficacy of rituximab treatment. Ki-67 expression might be a predictor of efficacy of rituximab plus chemotherapy.
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PMID:Efficacy of rituximab plus chemotherapy in follicular lymphoma depends on Ki-67 expression. 1536 34

Overexpression of c-Myc and inactivation of p53 are hallmarks of human Burkitt's lymphomas. We had previously showed that transduction of murine p53-null bone marrow cells with a Myc-encoding retrovirus is sufficient for B lymphomagenesis. To address the role of Myc in tumor sustenance, we generated lymphomas induced by the Myc-estrogen receptor fusion protein (MycER). Engrafted hosts were continuously treated with the ER ligand 4-hydroxytamoxifen (4-OHT) to allow tumor formation. Subsequent inactivation of MycER via 4-OHT deprivation resulted in tumor stasis but only partial regression. At the cellular level, dormant neoplastic lymphocytes withdrew from mitosis and underwent further B-cell differentiation. Concomitantly, they up-regulated genes involved in lymphocyte proliferation and survival, most notably interleukin 10 receptor alpha (IL10Ralpha) and CD20, the target for antibody therapy with Rituxan. We found that overexpression of IL10Ralpha affords significant proliferative advantages and in 4-OHT-deprived animals correlates with eventual tumor relapse. Both dormant and relapsing tumors maintain IL10Ralpha expression suggesting that they might be sensitive to emerging drugs targeting the IL-10 pathway. Up-regulation of CD20 following Myc inactivation was also observed in immortalized human lymphocytes. Importantly, in this system, Myc(OFF)CD20(HIGH) cells were more prone to Rituxan-induced apoptosis than Myc(ON)CD20(MED). Thus, targeting Myc, while moderately effective on its own, shapes the phenotype of dormant neoplastic cells and sensitizes them to adjuvant molecular therapies.
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PMID:Inactivation of Myc in murine two-hit B lymphomas causes dormancy with elevated levels of interleukin 10 receptor and CD20: implications for adjuvant therapies. 1595 95

Splenic marginal zone lymphoma with or without villous lymphocytes (SLVL/SMZL) is a low grade B-cell lymphoma that affects patients in the sixth decade and has a median survival greater than 10 years. A substantial proportion of patients die from causes unrelated to the disease. Close to a third of the patients do not require intervention and a policy of watch and see is reasonable and recommended. There are several therapeutic options that have proved effective in these patients. Due to the natural history of the lymphoma, the main goal of all these treatments is to achieve control of the disease rather than its eradication. Retrospective designs of all documented studies, the lack of uniform response criteria and the heterogeneity in the patient's features makes interpretation of the data difficult. Splenectomy remains one of the first line options in patients fit for surgery. Amongst chemotherapy, purine analogues, in particular fludarabine in combination or not with Rituximab and Rituximab alone have a greater efficacy than alkylating agents in terms of achieving better quality of response and longer progression free survival; therefore these agents are recommended particularly in patients who are not candidates for surgery or relapse after splenectomy. In the small proportion of patients with concomitant hepatitis C virus (HCV) infection, Interferon-alpha, ribavirin or a combination of both has demonstrated a significant activity with responses correlating with clearance of HCV RNA in the blood; therefore, these agents should be considered in the therapeutic scenario as a first line in these small cohort of patients. Patients that transform to high-grade lymphoma and the minority that have TP53 abnormalities should be treated with other schedules. Prospective randomized trials would be desirable to ascertain the independent prognostic factors and the biological features that predict disease progression and drug resistance to device the optimal management and treatment for SLVL/SMZL.
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PMID:Splenic marginal zone lymphoma with and without villous lymphocytes. 1768 Feb 18

In vitro CD40-stimulated chronic lymphocytic leukemia (CLL) cells are resistant to cytotoxic drugs. In sharp contrast, we here show that CD40 stimulation sensitizes CLL cells to rituximab-mediated cell death. This increased sensitivity is specific for anti-CD20 treatment. Rituximab-mediated death in CD40-stimulated CLL cells shows rapid kinetics (within hours), and is caspase and p53 independent, but depends on extracellular Ca(2+) and reactive oxygen species (ROS) production. By increasing basal ROS production, CD40 stimulation sensitizes CLL cells to rituximab-mediated death. Our findings provide a rationale for combination treatment of CLL with cytotoxic drugs and anti-CD20 monoclonal antibodies.
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PMID:CD40 stimulation sensitizes CLL cells to rituximab-induced cell death. 2140 46

Richter's transformation, or Richter's syndrome, is an uncommon clinicopathological condition observed in about 5% to 10% of patients with chronic lymphocytic leukemia (CLL). "Richter's transformation" refers to the development of aggressive lymphoma during the course of CLL. Diffuse large B-cell lymphoma occurs in the majority of cases of Richter's transformation. Clinically, patients with Richter's transformation present with an aggressive disease course with rapidly enlarging lymph nodes, hepatosplenomegaly, and elevated serum lactate dehydrogenase levels. Specific risk factors for the development of Richter's transformation in a patient with CLL have yet to be identified; however, TP53 disruption, c-MYCabnormalities, unmutated immunoglobulin heavy chain (IGHV) < 2%, non-del13q cytogenetics, CD38 gene polymorphisms, stereotypy, and VH4-39 gene usage may predispose to Richter's transformation. The prognosis is generally poor, with a median survival of about 10 months. Development of rituximab (Rituxan)-containing intensive chemotherapy regimens and chemo-immunotherapy regimens (eg, R-HyperCVAD [rituximab plus hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone] or OFAR [oxaliplatin (Eloxatin), fludarabine, and ara-C]) have improved response rates but have not clearly affected long-term outcomes. Allogeneic stem-cell transplantation may offer a chance for prolonged survival.
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PMID:Richter's transformation in chronic lymphocytic leukemia. 2341 93

Rituximab is the first line drug to treat non Hodgkin's lymphoma (B-NHL) alone or in combination with chemotherapy. However, 30-40% of B-NHL patients are unresponsive to rituximab or resistant after therapy. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is a novel member of PEBP family and functions as an anti-apoptotic molecule. In this study, we found hPEBP4 to be expressed in up to 90% of B-cell lymphoma patients, but in only 16.7% of normal lymph nodes. Interestingly, hPEBP4 overexpression inhibited rituximab-mediated complement dependent cytotoxicity (R-CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) in B-NHL cells while downregulation of hPEBP4 augmented the therapeutic efficacy of rituximab both in vitro and in vivo. Furthermore, hPEBP4 silencing sensitized the primary B-acute lymphocytic leukemia (B-ALL) cells to R-CDC. During rituximab-mediated complement dependent cytotoxicity, hPEBP4 was recruited to the cell membrane in a PE-binding domain dependent manner and inhibited R-CDC induced calcium flux and reactive oxygen species (ROS) generation. These events contributed to the decrease of cell death induced by R-CDC in B-cell lymphomas. Meanwhile, hPEBP4 knockdown potentiated the chemosensitization of the rituximab in B-cell lymphoma cells by regulating the expression of Bcl-xl, Cycline E, p21(waf/cip1) and p53 and the activation of caspase-3 and caspase-9. Considering that hPEBP4 conferred cellular resistance to rituximab treatment and was preferentially expressed in lymphoma tissue, it could be a potential valuable target for adjuvant therapy for B-cell lymphoma.
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PMID:Silencing of human phosphatidylethanolamine-binding protein 4 enhances rituximab-induced death and chemosensitization in B-cell lymphoma. 2345 Oct 95


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