Chemosensitization and drug accumulation effects of VX-710, verapamil, cyclosporin A, MS-209 and GF120918 in multidrug resistant HL60/ADR cells expressing the multidrug resistance-associated protein MRP

Germann, Ursula A.; Ford, Pamella J.; Shlyakhter, Dina; Mason, Valerie S.; Harding, Matthew W.

doi:10.1097/00001813-199702000-00005

Cited by 128 publications

(94 citation statements)

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“…This suggests that the rhabdomyosarcoma lines may also have low levels of MRP which is affected by VX710 but to a lesser effect by PSC833 (Germann et al, 1997b). This is supported by the observation that all the cell lines express mrp1 mRNA ( Table 2).…”

Section: Discussionmentioning

confidence: 63%

Characterization and modulation of drug resistance of human paediatric rhabdomyosarcoma cell lines

2000

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The role of multidrug resistance (MDR) and p53 functional status in the treatment of paediatric rhabdomyosarcoma is unclear. We have characterized a panel of seven human rhabdomyosarcoma cell lines for MDR and p53 phenotype. None of the cell lines had P-glycoprotein (P-gp) or multidrug resistance-related protein (MRP) detectable by Western blotting, whereas immunohistochemistry suggested that very low levels of MDR proteins may be present in some of the lines. RT-PCR studies indicated that mdr-1 , mrp-1 and lrp mRNA was present in 5/7, 7/7 and 5/7 lines respectively. The function of p53 is compromised in six of the lines, either through mutation of the p53 gene or by overexpression of mdm-2 . The sensitivity of many of the cell lines to vincristine could be modulated above 2-fold and as high as 16-fold using two modulating agents, PSC833 and VX710 (with VX710 being a significantly more potent modulator of the rhabdomyosarcoma lines). PSC833 also increased vincristine accumulation in all of the lines from 1.2- to 2.2-fold. These results suggest that some of these cell lines have low levels of multidrug resistance. The level of MDR proteins is very low and therefore difficult to detect, but may be sufficient to confer low-level, but clinically relevant, resistance to some cytotoxic agents, especially vincristine. These cell lines will therefore provide a suitable model to test new strategies in treatment and for further understanding relationships between protein expression and drug resistance. © 2000 Cancer Research Campaign

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Section: Discussionmentioning

confidence: 63%

Characterization and modulation of drug resistance of human paediatric rhabdomyosarcoma cell lines

2000

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“…Further evidence of direct high affinity interaction between VX-710 and P-gp is found in the concentration-dependent stimulation of P-gp ATPase activity. The concentrations of VX-710 required to reverse MDR in vitro in a range of cell lines assessed using rhodamine, sestamibi and labelled doxorubicin are similar to cyclosporin A (Germann et al, 1997a(Germann et al, , 1997b. It is unclear to what extent the compound acts as a competitive ligand for binding sites of cytotoxics.…”

Section: Discussionmentioning

confidence: 99%

BIRICODAR (VX-710; Incel™): an effective chemosensitizer in neuroblastoma

et al. 1999

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Summary 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.

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“…Rhodamine is a better substrate for Pgp than MRP1, but the rhodamine efflux assay with a long (2 h) efflux is a sensitive method to detect both Pgp-and MRP1-mediated efflux. 19,24,25 Comparison of H33342 and rhodamine efflux may provide another functional assay for discriminating Pgp from MRP1.…”

Section: Discussionmentioning

confidence: 99%