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

The role of high-dose etoposide in the initial treatment of newly diagnosed adult ALL was assessed in a combined clinical and laboratory study. Therapy on protocol JH8802 consisted of two induction modules, module 1 containing prednisone, vincristine, high-dose etoposide and L-asparaginase (L-asp), followed by module 2 containing cytarabine (Ara-C) and daunorubicin (DNR). Patients achieving a complete remission (CR) underwent bone marrow transplantation (BMT) or intensive maintenance therapy. Results were compared to the preceding protocol (JH8302), which was similar except for omission of etoposide and L-asp. The CR rate following module 1 was 45% on protocol JH8802 and 9% on protocol JH8302 (p < 0.0002). Nonetheless, the two protocols had similar CR rates following module 2 (69% on protocol JH8302; 77% on JH8802) and indistinguishable survivals. Laboratory investigations performed on blasts harvested prior to chemotherapy revealed two factors that could potentially contribute to decreased etoposide sensitivity in ALL blasts. A flow microfluorimetry-based assay of nuclear DNR accumulation detected small P-glycoprotein (Pgp)-mediated decreases in drug accumulation in a quarter of the samples. Western blotting demonstrated that topoisomerase II was present in all samples but was diminished in amount compared to the Molt3 human ALL cell line. Immunoperoxidase staining with affinity-purified antibodies revealed that topo II alpha, the target for etoposide, was detectable in only a minority of the blasts (median 7.5%, range < 1-35%) at diagnosis. These observations raise the possibility that alterations in drug accumulation and diminished target enzyme levels might both limit the long-term efficacy of a single course of high dose etoposide administered early in the treatment of adult ALL.
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PMID:Addition of etoposide to initial therapy of adult acute lymphoblastic leukemia: a combined clinical and laboratory study. 902 88

P-glycoprotein (P-gp), lung resistance-related protein (LRP) and multidrug resistance-associated protein (MRP) expression, and blast cell intracellular daunorubicin accumulation (IDA) were evaluated in 95 previously untreated cases of adult acute lymphoblastic leukaemia (ALL) using flow cytometry. Forty-five out of 95 (47%) patients were P-gp positive (+), 12/66 (18%) were LRP+ and 11/66 (17%) were MRP+. Eighteen out of 66 (28%) patients showed a simultaneous multidrug resistance (MDR)-related protein expression higher than controls for more than one protein, while 24/66 (36%) cases did not overexpress any protein. Twenty-one out of 24 (87%) cases overexpressing at least one MDR-related protein had a defect in accumulating daunorubicin into their blast cells, while only 4/24 (16%) cases who did not overexpress any protein had similar features. The complete remission rates were similar in MDR-positive and -negative (-) patients but relapses within 6 months were more frequent in P-gp+ cases, and therefore the disease-free survival duration was shorter in P-gp+ than in P-gp- patients (P = 0.01). The number of MRP+ and/or LRP+ cases was too small to be able to draw any conclusion on their role in affecting or predicting therapy outcome. In conclusion, P-gp overexpression associated with a defect in daunorubicin accumulation is a frequent feature in adult ALL at onset and seems to be related to poorer therapy outcome and, consequently, a shorter disease-free survival. LRP and MRP overexpression seems to be a rare event and no conclusion can be drawn on its prognostic role.
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PMID:P-glycoprotein, lung resistance-related protein and multidrug resistance-associated protein in de novo adult acute lymphoblastic leukaemia. 1184 7

Age has important prognostic impact in acute lymphoblastic leukemia (ALL). Adults with ALL have a worse prognosis compared to children. This may be due to different, unfavorable biology, poor treatment tolerance, drug resistance, higher expression of drug resistance related proteins. The lymphoblasts from adult ALL show an increased in vitro resistance to cytotoxic drugs, including prednisolone, dexamethasone, cytosine arabinoside, daunorubicin, L-asparaginase and methotrexate. Glucocorticoid resistance may be a fundamental difference between children, adolescents and adults with ALL, which may underlie different biological aspects and also explain the difference in prognosis. It seems that in vitro resistance to prednisolone with respect to the age might be a continuous variable in ALL patients, except infants. The greater the age, the higher the in vitro resistance to prednisolone. This may be due to induction of various defense mechanisms, such as an activation of P-glycoprotein, which develops throughout the life and protect the human against xenobiotics. Among a number of various drug resistance mechanisms, only several weak differences between adults and children with ALL have been reported including higher P-glycoprotein expression, lower methotrexate polyglutamate accumulation and possibly more often p53 gene mutations in adults. Intrinsic resistance, induction of drug resistance proteins expression during chemotherapy and co-existence of various mechanisms are common phenomena in adult ALL. It seems that age itself, more than drug resistance profile, reflects factors which have direct effect on chemotherapy response in adult ALL.
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PMID:In vitro drug resistance profiles of adult acute lymphoblastic leukemia: possible explanation for difference in outcome to similar therapeutic regimens. 1199 61

Concurrent resistance mechanisms, such as P-glycoprotein (PGP) and bcl-2, may contribute to a worse outcome in adult acute lymphoblastic leukaemia (ALL). Between 1990 and 2000, we analysed PGP and bcl-2 by flow cytometry, using two anti-PGP (C219 and JSB-1) monoclonal antibodies (mAbs) and an anti-bcl-2 mAb in 115 de novo adult ALL patients. Both a longer overall survival (OS) and longer disease-free survival (DFS) were observed in PGP-negative patients (23%vs 0% at 3 years, P = 0.011 and 29%vs 0% at 2 years, P = 0.006 for C219 respectively; 42%vs 0% at 1.5 years, P = 0.004 and 53%vs 0% at 8.5 months, P = 0.00006 for JSB-1 respectively). Bcl-2 positivity was associated with a significantly higher complete remission rate (90%vs 66%, P = 0.01). Moreover, in 69 patients not presenting with either t(9;22) or B-mature immunophenotype, PGP negativity (JSB-1) maintained its significant favourable prognostic impact with regard to OS (41%vs 0% at 1.5 years, P = 0.009) and DFS (83%vs 0% at 6 months, P = 0.0005). Importantly, within a subset of 62 patients with normal (n = 31) or unknown (n = 31) karyotype, PGP (JSB-1)-negative patients showed both a significantly longer OS and DFS (63%vs 0% at 1.4 years, P = 0.018 and 84%vs 0% at 6 months, P = 0.001 respectively). In multivariate analysis, JSB-1 (P = 0.008) and cytogenetics (P = 0.02) were found to be independent prognostic factors with regard to DFS. Therefore, in adult ALL, PGP and bcl-2 represent sensitive indicators of clinical outcome, and potential targets of novel molecules aimed at overcoming chemoresistance and recurrent relapses.
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PMID:P-glycoprotein and BCL-2 levels predict outcome in adult acute lymphoblastic leukaemia. 1278 Jul 87

Acute lymphoblastic leukemia (ALL) is now curable in 60-80% of children. In adults, in spite of adopting treatment protocols based on therapy for childhood ALL, the disease is still curable in 30-40% of patients only. These worse results of therapy may be due to the induction of various cell defence mechanisms, such as activation of P-glycoprotein, which protects man against xenobiotics. Among a number of various multi-drug resistance mechanisms, differences between adults and children with ALL have been found only for higher P-glycoprotein expression and possibly more often p53 gene mutations in adults. Induction of expression of drug resistance proteins during chemotherapy and co-existence of various mechanisms are common phenomena in adult ALL. Differences in resistance to different drugs might contribute to the impact of age on the outcome of ALL. The underlying mechanisms for these differences are still largely unknown; however, knowledge about drug resistance mechanisms can lead to new therapeutic options.
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PMID:Differences in significance of drug resistance mechanisms between adult and childhood acute lymphoblastic leukemia. 1280 6

P-glycoprotein (P-gp), a membrane transporter encoded by MDR1 gene, influences pharmacokinetics of anti-cancer drugs and contributes to multi-drug resistance phenotype in adult acute lymphoblastic leukemia (ALL). In this study, we explored prognostic and functional role of single nucleotide polymorphism C3435T in MDR1 gene in 44 adult Caucasian patients with ALL. We found that the outcome of chemotherapy as well as MDR1 gene expression, P-gp expression and P-gp activity in isolated ALL blast cells were comparable among the patients carrying different MDR1 genotypes. Our results suggest that C3435T polymorphism in MDR1 gene is not a major prognosticator in adult ALL.
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PMID:Multi-drug transporter MDR1 gene polymorphism and prognosis in adult acute lymphoblastic leukemia. 1638 13