Multidrug resistance modulation in rhabdomyosarcoma and neuroblastoma cell lines.
Four rhabdomyosarcoma and three neuroblastoma cell lines were characterised for the presence of P-glycoprotein and MDR-1 expression using immunohistochemistry, northern analysis, RT-PCR and in situ mRNA hybridisation. None of the rhabdomyosarcoma lines were unequivocally positive in contrast to all three neuroblastoma lines. Chemosensitivity to cytotoxic agents was determined using the MTT assay and chemosensitisation by cyclosporin and verapamil was evaluated. In a single rhabdomyosarcoma line (HX 170) there was sensitisation to etoposide using verapamil but not to other drugs or using cyclosporin A. In contrast, in all three neuroblastoma lines both cyclosporin and verapamil sensitised to vincristine and doxorubicin. No evidence of sensitisation to etoposide was apparent. The sensitisation was most marked for vincristine, using either modulator and therefore the influence of modulator scheduling was evaluated with this drug in the neuroblastoma line SK N BE. Prolonged pre-exposure to modulator did not appear necessary and maximum sensitisation was apparent where either cyclosporin or verapamil was added 1-3 h prior to and post vincristine. Continuity of exposure was important and even a break of 30 min appeared to reduce sensitisation. These data confirm the potential for chemosensitisation in MDR-1 positive neuroblastoma cell lines and provide some basis for rational schedule design in clinical practice. Because of the probability that vincristine resistance is predominantly related to MDR-1 and less multifactorial than for other drugs such as doxorubicin or etoposide, this agent should be considered for inclusion in any clinical evaluation of MDR reversal strategies.
Cowie
F J
FJ
Children's Department, The Royal Marsden NHS Trust, Downs Road, Sutton, Surrey SM2 5PT, UK.
Pritchard-Jones
K
K
Renshaw
J
J
Pinkerton
C R
CR
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000970:Antineoplastic Agents / Q000633:toxicity*; D018288:Carcinoma, Small Cell; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity; D003520:Cyclophosphamide / Q000633:toxicity; D016572:Cyclosporine / Q000494:pharmacology*; D004317:Doxorubicin / Q000633:toxicity*; D018432:Drug Resistance, Multiple; D005047:Etoposide / Q000633:toxicity; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms; D008727:Methotrexate / Q000633:toxicity; D009447:Neuroblastoma; D012208:Rhabdomyosarcoma; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology*; D014750:Vincristine / Q000633:toxicity*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D016572:Cyclosporine; D003520:Cyclophosphamide; D014700:Verapamil; D002945:Cisplatin; D008727:Methotrexate