Establishment and characterization of new cellular lymphoma model expressing transgenic human MDR1.
Multidrug resistance (MDR) due to the expression of the MDR1 gene and its P-glycoprotein (Pgp) product is a major factor in the prognosis and clinical outcome of patients with refractory lymphomas and other malignancies. The aim of our study was to establish a lymphoma, cellular system where a de novo acquisition of multidrug resistance is specifically related to overexpression of a transgenic, human MDR1. A multidrug sensitive lymphoma cell line (LM1) was established from a sporadic T-cell lymphoma of BALB/c mouse and was transduced by a retroviral vector containing the human MDR1 cDNA. The resultant cell variant (LM1/MDR) was characterized in comparison to the parental LM1 cells. The LM1/MDR cell variant is cross-resistant to DOX, COL, ACT D and VBL. This cell variant expresses the human MDR1 and exhibits de novo functional Pgp activity that can be blocked by the Pgp-modulators VRP and KT-5720. The acquired MDR of LM1/MDR is not accompanied with gene amplification, alternative splicing or up-regulation of the murine endogenous mdr1a, mdr1b, mrp1, mrp2 and mrp3 transporter-genes. Therefore, the acquired MDR is, specifically, human MDR1-dependent as it has been found in malignant cells of most lymphoma patients. Moreover, this system can be used as a model to study MDR and the efficacy of drugs and modulators on malignant cells where human Pgp is a major factor of multidrug resistance.
Findling-Kagan
Sarah
S
Laboratory of Molecular Immunobiology, Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel.
Sivan
Hamutal
H
Ostrovsky
Olga
O
Nagler
Arnon
A
Galski
Hanan
H
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017931:DNA Primers; D018432:Drug Resistance, Multiple; D006801:Humans; D007624:KB Cells; D008223:Lymphoma / Q000235:genetics*; D051379:Mice; D014162:Transfection
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D017931:DNA Primers