Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of P-glycoprotein (PGP), the product of the multi-drug resistance mdr1 gene was studied by immunocytochemistry on bone marrow slides using JSB1 monoclonal antibody and the alkaline phosphatase-antialkaline phosphatase (APAAP) and avidin-biotin-peroxidase (ABC) techniques in 82 cases of untreated myelodysplastic syndromes (MDS), of whom ten had evolved to AML (MDS-AML). The relationship between PGP expression, myeloperoxidase activity and immunophenotype of blast cells, karyotype and outcome was also analyzed. PGP expression was found in the blasts of 34 of the 82 patients (41%), the majority of blasts being stained in positive cases. PGP positivity was rare in 'low risk' MDS (RA and RARS: 2/12 cases) as opposed to 'high risk' MDS (RAEB, RAEB-T, CMML: 25/60 cases) and MDS-AML (7/10 cases) (p = 0.04). PGP expression was positively correlated to the presence of myeloperoxidase activity in less than 3% of blasts (p = 0.025), and CD34 antigen expression (p = 0.04), whereas CD33 antigen expression had borderline significance (p = 0.07), demonstrating that PGP expression predominated in blasts with an immature phenotype. An abnormal karyotype, and especially the presence of monosomy 7, was not correlated to a higher incidence of PGP expression, however. There was a trend for more frequent progression to AML and for shorter survival in PGP-positive cases, but differences with PGP-negative cases were not significant. Twenty patients received intensive anthracycline-Ara-C chemotherapy and ten (50%) achieved complete response, including 9/13 (69%) PGP-negative cases and 1/7 (14%) PGP-positive cases (p = 0.03). Twenty other patients were treated with low-dose Ara-C and ten (50%) responded (complete or partial response). PGP-positivity did not negatively affect response to low-dose Ara-C: 4/11 responses in PGP-negative, and 6/9 responses in PGP-positive patients (p = 0.18). Because the treatment choice in advanced MDS (especially between anthracycline-Ara-C or low-dose Ara-C, chemotherapy) is difficult, our preliminary therapeutic results suggest that the analysis of PGP expression could have practical importance in MDS. These findings however, will have to be confirmed on larger numbers of patients. Clinical trials using drugs potentially reverting mdr, activity could also be warranted in MDS.
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PMID:Expression of the multidrug resistance P-glycoprotein and its relationship to hematological characteristics and response to treatment in myelodysplastic syndromes. 751 32

P glycoprotein, the product of multidrug resistance (mdr1) gene, is frequently expressed in advanced myelodysplastic syndromes (MDS) with an excess of bone marrow blasts and could explain their frequent resistance to chemotherapy. P53 gene mutations are also found in 10 to 15% of advanced MDS. Because it has recently been suggested that normal p53 suppressed, but that mutated p53 activated, the mdr1 gene promoter, we tried to correlate p53 mutations and P glycoprotein expression in 34 patients with MDS and an excess of bone marrow blasts (> 5%). P glycoprotein expression was assessed by immunocytochemistry using JSB1 monoclonal antibody and was found positive in 13 out of the 34 patients. p53 mutations were detected both by immunocytochemistry using three different monoclonal antibodies and by single stranded conformation polymorphism (SSCP) analysis of exons 5 to 8 of the P53 gene. Both methods detected a point mutation in 5 out of the 34 patients. Only one out of the 5 patients with a p53 mutation expressed P glycoprotein, as compared to 12 out of the 29 patients without p53 mutations. This suggested the mutant and normal p53 are not major determinants of the regulation of mdr1 expression in vivo, at least in MDS.
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PMID:Relationship between p53 gene mutations and multidrug resistance (mdr1) gene expression in myelodysplastic syndromes. 790 57

Expression of P-glycoprotein (PGP), the product of the multidrug resistance gene (mdr1), is common in myelodysplastic syndromes (MDSs) and explains in part the low rate of complete remissions (CRs) obtained after aggressive chemotherapy. Reversion of the mdr phenotype to restore chemosensitivity has been the focus of many studies over the last ten years. Two phase III studies evaluated quinine for obtaining reversion of mdr gene expression in MDSs treated by aggressive chemotherapy. Results suggested better response rates and longer survival times in quinine-treated MDR-positive patients. However, the toxicity of quinine warrants further work aimed at developing other mdr phenotype reversion-inducing agents. Some such agents have proved superior over quinine in in vitro studies. Reversion of other mechanisms underlying chemoresistance in MDSs is a promising avenue of research.
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PMID:[Multi-drug resistance and myelodysplastic syndromes: a possible role for remission inducing agents?]. 956 29

Intensive chemotherapy produces a lower complete remission (CR) rate in the myelodysplastic syndromes (MDS) than in de novo acute myeloid leukaemia (AML), possibly due in part to a higher incidence of P glycoprotein (PGP) expression in MDS blast cells. We designed a randomized trial of intensive chemotherapy with or without quinine, an agent capable of reverting the multidrug resistance (mdr) phenotype, in patients aged < or = 65 years with high-risk MDS. Patients were randomized to receive mitoxantrone 12 mg/m2/d days 2-5 + AraC 1 g/m2/12 h days 1-5, with (Q+) or without (Q-) quinine (30 mg/kg/d). 131 patients were included. PGP expression analysis was successful in 91 patients. In the 42 PGP-positive cases, 13/25 (52%) patients in the Q+ group achieved CR, compared to 3/17 (18%) patients in the Q- group (P = 0.02) and median Kaplan-Meier survival was 13 months in the Q+ group, and 8 months in the Q- group (P = 0.01). No life-threatening toxicity was observed with quinine. In conclusion, the results of this randomized study show that quinine increases the CR rate and survival in PGP-positive MDS cases treated with intensive chemotherapy.
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PMID:Quinine improves the results of intensive chemotherapy in myelodysplastic syndromes expressing P glycoprotein: results of a randomized study. 973 53

Since leukemic cells primed by exposure to fludarabine exhibit enhanced accumulation of cytarabine triphosphate (the cytotoxic nucleotide of cytarabine), especially with continuous cytarabine (AraC) infusion, a phase II trial was designed to explore the feasibility and efficacy of a combination chemotherapy associating fludarabine, mitoxantrone (MXN), and high-dose cytarabine (continuous infusion) for high-risk P glycoprotein (PGP)-negative myelodysplastic syndromes (MDS) (FAM protocol). The outcomes of FAM-treated patients were compared with those of 32 PGP-negative MDS patients fulfilling identical inclusion and response criteria treated with MXN+AraC (1 g/m(2)/12 h d(1-5), MA protocol). A total of 29 patients (median age 55 years) were included in the FAM group. Six (21%) died from the procedure, and 16 (55%) achieved complete remission (CR). Of these, nine received consolidation chemotherapy, five were autografted and two were allografted in first CR. Abnormal karyotype was the only factor associated with poor survival. The overall median follow-up was 10.9 months. There was no significant difference between FAM and MA protocols with respect to CR rate, treatment-related mortality, duration of leukopenia, neutropenia, autologous stem cell transplantation feasibility, relapse-free survival, or overall survival. The duration of thrombocytopenia was significantly longer in the FAM protocol. In conclusion, the present results suggest that the combination therapy of fludarabine, MXN, and high-dose AraC does not improve CR rate, survival, or disease-free survival in high-risk MDS.
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PMID:A phase II study of intensive chemotherapy with fludarabine, cytarabine, and mitoxantrone in P glycoprotein-negative high-risk myelodysplastic syndromes. 1516 6