BIRICODAR (VX-710; Incel): an effective chemosensitizer in neuroblastoma.
Clinical studies have suggested that both MDR1 and MRP may play a significant role in the chemosensitivity and outcome of neuroblastoma. To clarify the nature of multidrug resistance (MDR) in this tumour a series of six neuroblastoma cell lines have been characterized with regard to P-glycoprotein, MRP and LRP expression using immunocytochemistry and expression of MDR1, MRP, LRP and topoisomerase II genes using reverse transcription polymerase chain reaction (RT-PCR). By RT-PCR, all lines expressed MRP, five expressed LRP and four expressed MDR1, but protein levels of each of these were variable. Chemosensitization to a range of MDR-associated drugs (vincristine, doxorubicin, etoposide, taxotere, topotecan) and non-MDR-associated drugs (cisplatin, melphalan) by three modulating agents, cyclosporin A, PSC 833 and the novel Biricodar (VX-710; Incel), was evaluated using a colourimetric cytotoxicity assay (MTS). Alteration of daunorubicin efflux by these agents was evaluated using FACS analysis. Clonogenic assay was used to study the influence of these chemosensitizers on vincristine cytotoxicity. Marked sensitization to vincristine was observed in MDR1-positive lines, and a similar but less consistent effect was seen with taxotere, doxorubicin and etoposide. With MRP-positive, MDR-negative lines, only VX-710 caused consistent sensitization. These data confirm MDR1 and MRP expression as contributory factors in chemoresistance in neuroblastoma and indicate that VX-710 may be a useful modulator of both mechanisms and worthy of clinical evaluation in this tumour.
Yanagisawa
T
T
Section of Paediatrics, The Institute of Cancer Research/Royal Marsden NHS Trust, Sutton, Surrey, UK.
Newman
A
A
Coley
H
H
Renshaw
J
J
Pinkerton
C R
CR
Pritchard-Jones
K
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000187:drug effects; D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis / Q000187:drug effects; D004268:DNA-Binding Proteins; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000187:drug effects; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000096:biosynthesis* / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D014750:Vincristine / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D010880:Piperidines; D011725:Pyridines; D012269:Ribosomal Proteins; C106077:biricodar; D014750:Vincristine; D004250:DNA Topoisomerases, Type II