Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.1.1 (asparaginase)
 2,695 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lymphoma was diagnosed in a 4-year-old spayed female Collie, and treatment with a combination chemotherapy protocol incorporating prednisone, L-asparaginase, vincristine, vinblastine, doxorubicin, and cyclophosphamide was initiated. The dog had signs of gastrointestinal tract toxicosis and myelosuppression after treatment with P-glycoprotein-substrate drugs (vincristine, vinblastine, and doxorubicin) even when dosages were reduced, but did not have signs of toxicosis after treatment with cyclophosphamide, a non-P-glycoprotein-substrate drug, even when administered at the full dosage. It was postulated that a deletion mutation in the canine MDR1 gene (deltaMDR1 295-298) could be responsible for the drug toxicoses in this dog. This mutation has been identified as the cause of a functional P-glycoprotein defect in Collies susceptible to the toxic effects of ivermectin, another P-glycoprotein-substrate drug. The MDR1 genotype of this dog consisted of 1 normal and 1 mutant MDR1 allele. Because P-glycoprotein contributes to renal, biliary, and intestinal excretion of P-glycoprotein-substrate drugs, it is possible that drug excretion was delayed in this patient, resulting in clinical signs of toxicosis.
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PMID:Increased toxicity of P-glycoprotein-substrate chemotherapeutic agents in a dog with the MDR1 deletion mutation associated with ivermectin sensitivity. 1462 96

Resistance to chemotherapy is an obstacle to the successful treatment of oncohematological malignances. Failure of therapeutic treatment may be due to the development of multidrug resistance (MDR), the mechanisms of which include upregulation of membrane-resident transporters that efflux chemotherapeutic drugs from tumor cells. Deregulation may occur at different levels: gene or protein expression or function depletion. Childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) cells and chronic lymphocytic leukemia (CLL) cells of adults were studied. ABCB1 (P-gp) and ABCG2 (BCRP) expression were determined by flow cytometry, rhodamine 123 (Rho123) and mitoxantrone were used for functional activity study of MDR proteins, sensitization of leukemic cells to drugs was quantified by methyl thiazolyl tetrazolium (MTT) assays. Appropriate gene expression was determined using semi-quantitative RT-PCR. No differences between expression of P-gp and BCRP and genes in primary and relapsed acute leukemia (AL) cells as well as in de novo and treated CLL samples were established. Higher expression of P-gp and BCRP proteins was detected in CLL lymphocytes compared to blast cells. Increased P-gp protein expression and function was detected in cells of CLL patients who had more aggressive therapy regimen. Doxorubicine, rubomycinum and L-asparaginase resistance correlates with P-gp overexpression and increased function in pediatric AL whereas vincristine resistance might be associated with P-gp protein expression in AL samples and impared P-gp function in CLL lymphocytes only. A tendency for the decreased doxorubicin cytotoxic activity was shown in BCRP-overexpressing cells both in children and adults leukemia. Multifactorial ANOVA showed that P-gp/MDR1 and BCRP as well as their function could not be used as unconditional and universal predictors of leukemia cell drug resistance in vitro. These results suggest that studied MDR transporter-proteins have a limited role per se in vitro and admittedly in vivo drug resistance estimated in leukemia patients or it is not yet fully understood unless would not be studied in aggregate. In any event, the expression and function studies of the proteins under investigation when singularly considered do not have a crucial significance for impact on drug resistance evaluation in all leukemia patients.
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PMID:ABCB1 and ABCG2 proteins, their functional activity and gene expression in concert with drug sensitivity of leukemia cells. 1963 83

Optimal salvage chemotherapy has not been established for lymphoid malignancy, which is refractory to the conventional cyclophosphamide, doxorubicin, vincristine, and prednisone regimen. To explore an effective regimen, we conducted a phase I pilot study of combination chemotherapy with methotrexate, ifosfamide, l-asparaginase and dexamethasone (MILD), which are unaffected by MDR1-encoded P-glycoprotein. A total of 18 patients with lethal lymphoid malignancy were enrolled over a 2-yr period. The median age was 63 yr. Eleven patients had T/NK-cell malignancies, six had B-cell malignancies, and one was diagnosed with a blastic plasmacytoid dendritic cell neoplasm. Patients aged >/=60 and <60 yr were planned to receive a set of starting doses of methotrexate and ifosfamide, which should induce myelosuppression. Eleven patients completed two courses of MILD therapy. Treatment-related death because of systemic mucormycosis was observed in one patient. Major treatment-related adverse events were grade 3 or more hematologic toxicities, which included lymphopenia corresponding to dose-limiting toxicity. The most common grade 3 non-hematologic toxicity was febrile neutropenia. Of the 14 evaluated patients, three achieved a complete response, and four showed a partial response. The overall response rate was 57%. It was very interesting that all of seven responders had T/NK-cell malignancies. MILD therapy was feasible and presented acceptable toxicity in patients with refractory or lethal lymphoid malignancies. The efficacy for T/NK-cell malignancies should be further evaluated.
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PMID:Activity and safety of combination chemotherapy with methotrexate, ifosfamide, l-asparaginase and dexamethasone (MILD) for refractory lymphoid malignancies: a pilot study. 2001 42

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

Epstein-Barr virus (EBV)-associated natural killer (NK)/T-cell lymphomas show a geographical predilection for Asian and South American populations and are rare in Western countries. They predominantly occur in extranodal sites, including the nasal or paranasal areas, and less frequently in the localized nodal lesion. Most of the tumor cells exhibit a cytotoxic phenotype, characterized primarily by the expression of granzyme B and perforin. EBV is usually detected in tumor cells by using EBV-encoded small RNA in situ hybridization (EBER), suggesting that EBV plays an important role in lymphomagenesis. In this chapter, we have described 2 diseases: 1) extranodal NK/T-cell lymphoma, nasal type (ENKL), representative of extranodal EBV-associated NK/T-cell lymphoma; and 2) nodal cytotoxic molecule-positive EBV-positive peripheral T-cell lymphoma, not specified type (CM + EBV + PTCL-N), representative of nodal lymphoma. Both ENKL and nodal CM + EBV + PTCL-N are intractable to standard chemotherapy. Although ENKL is sensitive to radiotherapy, it shows a poorer response to chemotherapeutic agents than other lymphomas because of P-glycoprotein expression. P-glycoprotein is a product of the multidrug resistance (MDR1) gene, which is a major cause of the refractoriness of malignant lymphomas to conventional chemotherapeutic regimens containing anthracycline. l-asparaginase-containing regimens such as SMILE (steroid, methotrexate, ifosfamide, l-asparaginase, and etoposide) are effective for ENKL. Evaluation of effective chemotherapy for nodal CM + EBV + PTCL-N is ongoing.
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PMID:Epstein-Barr virus-associated natural killer/T-cell lymphomas. 2376 37