Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extranodal natural killer (NK)/T-cell lymphoma, nasal type, and aggressive NK-cell leukemia are rare, and their standard therapy has not been established. They are Epstein-Barr virus-associated lymphoid malignancies, and tumor cells express P-glycoprotein leading to multidrug resistance of the disease. Patients with stage IV, relapsed or refractory diseases have a dismal prognosis, with survival measured in months only. To develop an efficacious chemotherapeutic regimen, we conducted a dose-escalation feasibility study of a new chemotherapeutic regimen, SMILE, comprising the steroid dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide. The components of SMILE are multidrug resistance-unrelated agents and etoposide. Etoposide shows both in vitro and in vivo efficacy for Epstein-Barr virus-associated lymphoproliferative disorders. Eligible patients had newly diagnosed stage IV, relapsed or refractory diseases after first-line chemotherapy, were 15-69 years of age, and had satisfactory performance scores (0-2). Four dose levels of methotrexate and etoposide were originally planned to be evaluated. At level 1, six patients with extranodal NK/T-cell lymphoma, nasal type, were enrolled. Their disease status was newly diagnosed stage IV (n = 3), first relapse (n = 2), and primary refractory (n = 1). All of the first three patients developed dose-limiting toxicities, and one of them died of sepsis with grade 4 neutropenia. A protocol revision stipulating early granulocyte colony-stimulating factor administration was made. Two out of three additional patients developed dose-limiting toxicities that were all manageable and transient. For the six enrolled patients, the overall response rate was 67% and the complete response rate was 50%. Although its safety and efficacy require further evaluation, we recommend a SMILE chemotherapy dose level of 1 for further clinical studies.
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PMID:Phase I study of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy for advanced-stage, relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma and leukemia. 1829 94

The natural killer (NK)-cell neoplasms are rare, representing less than 1% of non-Hodgkin lymphoma, except in Asia and Latin America, where they represent 3% to 6%. NK-cell neoplasms include immature acute leukemias; a blastic NK-cell lymphoma, which is obsolete because of its plasmacytoid dendritic-cell origin; and mature NK neoplasms, comprising extranodal NK/T-cell lymphoma (ENKL), nasal-type; aggressive NK-cell leukemia; and chronic NK-cell lymphoproliferative disorders, which are often reactive. Epstein-Barr virus is usually detected in tumor cells of ENKL and aggressive NK-cell leukemia. The latter two mature NK neoplasms are relatively chemoresistant because of the frequent expression of P-glycoprotein. Early radiation is advocated for localized nasal ENKL. Stem cell transplantation is recommended for advanced disease, owing to a poor prognosis. Novel agents, including chemotherapy, inhibitors of molecular pathways, and monoclonal antibodies, are under investigation.
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PMID:Natural killer-cell neoplasms. 2042 14

Extranodal NK/T cell lymphoma, nasal type (ENKL) with advanced stage and aggressive NK-cell leukemia (ANKL) are highly aggressive neoplasms with a dismal clinical outcome. It is well known that P-glycoprotein, which is a product of MDR1 gene and related to multi-drug resistance, is expressed on tumor cells of ENKL or ANKL. This is a major reason for the refractoriness to conventional chemotherapeutic regimens for malignant lymphoma containing anthracycline. However, recent studies have identified that several drugs including L: -asparaginase, methotrexate and alkylators show excellent effect for these tumors. The SMILE (steroid, methotrexate, ifosfamide, L: -asparaginase and etoposide) regimen is one of the promising regimens for advanced or relapsed/refractory ENKL, but its myelotoxicity is strong. ANKL needs another treatment strategy because of a systemic disease progression and extensive organ insufficiency. Optimal treatment scheme using such effective agents for these unfavorable NK-cell tumors should further be explored.
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PMID:Treatment of advanced extranodal NK/T cell lymphoma, nasal-type and aggressive NK-cell leukemia. 2111 47

The current World Health Organization (WHO) classification includes two types of natural killer (NK)-cell lymphomas: extranodal NK/T-cell lymphoma, nasal type (ENKL), and aggressive NK-cell leukemia (ANKL). These diseases are mostly endemic to East Asia and Latin America. The Epstein-Barr virus (EBV) is usually detected in tumor cells, suggesting that EBV plays an important role in lymphomagenesis. At the site of origin, ENKL can be divided into two major subtypes: nasal and extranasal diseases. The advanced disease presentation, highly aggressive clinical course, and poor prognosis of the latter are analogous to ANKL. It is well known that P-glycoprotein, which is a product of the multi-drug resistance (MDR1) gene, is expressed on neoplastic cells of ENKL or ANKL. This is a major cause of the refractoriness of malignant lymphoma to conventional chemotherapeutic regimens containing anthracycline. Recent studies, however, have identified that L-asparaginase-containing regimens, such as SMILE (steroid, methotrexate, ifosfamide, L-asparaginase and etoposide), are effective for ENKL. Considering the myelotoxicity of SMILE, its use in the treatment of ANKL needs some modifications, but this treatment scheme is promising in improving the prognosis of NK-cell lymphomas.
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PMID:NK/T-cell lymphomas: pathobiology, prognosis and treatment paradigm. 2263 6

Introduction: Natural killer (NK)/T-cell lymphomas are aggressive malignancies that present predominantly in nasal and adjacent sites (nasal subtype), occasionally in skin, gastrointestinal tract and other tissues (non-nasal), and rarely as disseminated disease with a leukemic phase (aggressive NK-cell leukemia, or leukemia/lymphoma, subtype).Areas covered: The diagnosis and treatment of NK/T-cell lymphoma are discussed, based on a PubMed literature search. The diagnostic criteria for NK/T-cell lymphoma are highlighted, followed by an update of the diagnostic and prognostic importance (on presentation, at interim and end-of-treatment) of plasma EBV DNA as a surrogate biomarker of lymphoma load. Prognostic models based on clinicopathologic features and EBV DNA load are discussed. For stage I/II NK/T-cell lymphomas, combined chemotherapy, and radiotherapy gives the best results, with their concomitant or sequential administration equally efficacious. For stage III/IV NK/T-cell lymphoma, chemotherapy is the mainstay of treatment. Conventional anthracycline-based regimens for B-cell lymphomas are ineffective. Recommended regimens combine L-asparaginase with other drugs not affected by P-glycoprotein. For relapsed/refractory patients, immune checkpoint blockade with antibodies against programmed cell death protein 1 has shown much promise.Expert opinion: Current strategies result in durable remissions in a significant proportion of NK/T-cell lymphomas. Immune checkpoint inhibition and other novel approaches are promising for relapsed/refractory cases.
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PMID:Recent advances in the diagnosis and treatment of natural killer/T-cell lymphomas. 3148 2