title: Multidrug resistance phenotype in patients with chronic lymphocytic leukemia as detected by immunofluorescence (FACS) and northern blot analysis.
abstract: The multidrug resistance (MDR) phenotype has been demonstrated to be related to the overexpression of P-glycoprotein, a 170 kDa transmembrane efflux pump. We studied P-glycoprotein expression in 40 patients with chronic B-cell leukemias by FACS analysis using MoAb c219, which recognizes both the MDR1 and the MDR3 gene product. We found significantly elevated P-glycoprotein expression in these patients as compared with normal controls. Patients who had received previous chemotherapy regimens containing MDR-related drugs showed significantly higher P-glycoprotein expression with MoAb c219 than those patients who had been untreated. Northern blot analysis of MDR1 and MDR3 gene expression in 32 of the patients gave a similar result: in the analysis of total RNA four of six patients (66%) pretreated with either vinca alkaloids or anthracyclines were MDR1 positive as opposed to 6 of 26 (23%) who had no treatment or treatment without these agents. In contrast, MDR3 expression was found more frequently (63%), but was randomly distributed in the differently treated groups. Increasing the sensitivity level by analysis of enriched mRNA (polyA+RNA) led to the detection of MDR1 and MDR3 expression all B-CLL patients. We conclude that a basic elevated P-glycoprotein expression is intrinsic in CLL cells, which is possibly upregulated under chemotherapy. This might be responsible for initial and acquired chemotherapy resistance in CLL patients. Follow-up of the B-CLL patients over 46 months showed that the median survival time for MDR1+ patients was 19 months as opposed to 46 months for MDR1- patients (p < 0.01). There was no statistical difference in survival between MDR3+ and MDR3- patients. In the MDR1+ group, eight of nine patients had developed resistance to the therapy with MDR-related drugs. The expression of MDR1 might, therefore, predict treatment failure with MDR-related drugs and be a negative prognostic factor.
authors.affiliation: Division of Hematology and Oncology, Beth Israel Hospital, Boston, MA 02215.
authors.forename: G
authors.initials: G
authors.lastname: Wulf
authors.forename: H
authors.initials: H
authors.lastname: Kluding
authors.forename: A D
authors.initials: AD
authors.lastname: Ho
authors.forename: M
authors.initials: M
authors.lastname: Doerner
authors.forename: H
authors.initials: H
authors.lastname: Doehner
authors.forename: C
authors.initials: C
authors.lastname: Manegold
authors.forename: W
authors.initials: W
authors.lastname: Hunstein
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins / Q000378:metabolism*; D002453:Cell Cycle; D004351:Drug Resistance; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm