Lack of elevated drug efflux in adriamycin-resistant immunoblastic B lymphoma cells with mdr1 overexpression.
A multidrug-resistant (MDR) subline of the immunoblastic B lymphoma cell line was established by sequentially selecting in increasing concentrations of adriamycin. The adriamycin-resistant cell line (HOB1/ADR) demonstrated resistance to a wide spectrum of chemotherapeutic agents including MDR drugs (Vinca alkaloids and anthracycline), antimicrotubule drug (colchicine), and DNA-damaging agents (cisplatin and mitomycin C). The expression of human mdr1 gene, as analyzed by RT-PCR and Western blotting, revealed a 13-15-fold increase in resistant cells. Unexpectedly, HOB1/ADR cells demonstrated a lack of reduced accumulation and of enhanced efflux of adriamycin. More than 60% adriamycin was effluxed at the same rate in both cell lines within 10 min. In contrast, the initial rate of vincristine accumulation was reduced by 3 fold in this resistant cell line. The maximal level of vincristine accumulation was 50% lower in the resistant cells than the parental cells. The maximal efflux rate was enhanced by 5 fold in the resistant cells. Inhibition of vincristine resistance by verapamil associated with restoration of drug accumulation, suggesting that acquired resistance in these cells is due to P-glycoprotein. These studies demonstrated that immunoblastic B lymphoma cells selected for adriamycin resistance preferentially developed P-glycoprotein-mediated vincristine efflux which plays an important role in vincristine resistance. In contrast, the resistant cells did not elevate adriamycin efflux, suggesting an additional mechanism responsible for adriamycin resistance.
Chao
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CC
Department of Biochemistry, Chang Gung Medical College, Taoyuan, Taiwan, Republic of China.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D018628:Gene Dosage; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D016393:Lymphoma, B-Cell / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D010641:Phenotype; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000493:pharmacokinetics / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D012333:RNA, Messenger; D014750:Vincristine; D004317:Doxorubicin; D014700:Verapamil