Cowie, Fiona Jane; (1995) Multidrug resistance in paediatric solid tumours: identification and potential reversal. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Multidrug resistance (MDR) is increasingly recognised as an important factor in both refractory and relapsed paediatric solid tumours, although at present most work has been carried out in the leukaemias or adult solid tumours. The aims of this study were to establish the pleiotropic multidrug resistance status of selected paediatric tumour cell lines, its modulation by non cytotoxic drugs, and to report a clinical study using cyclosporin A to modulate resistance. The MTT assay was used to assess the chemosensitivity of a panel of ten cell lines (four rhabdomyosarcoma, three neuroblastoma, one T cell leukaemia, and two small cell lung - as controls). Reversal of resistance using verapamil and cyclosporin was investigated and in particular the potential importance of duration and schedule of exposure of cells to modulator was assessed. Molecular methods were used to document expression of the mdr 1 gene product (immunocytochemistry) and mRNA (RT PCR, northern blot and in situ hybridisation). A clinical study of patients with relapsed paediatric malignancy is reported using cyclosporin A as a modulating agent combined with etoposide. The effect of cyclosporin on etoposide kinetics was determined. Those cell lines which displayed a resistant phenotype consistent with MDR also expressed the mdr 1 mRNA. Reversal of drug resistance in these lines was demonstrated with both verapamil and cyclosporin. The timing of administration of modulator does not appear to be of critical importance, though in some cases the duration of exposure has a significant effect upon cytotoxicity. Although these methods to assess MDR were successfully applied to fresh cell lines, it was not possible to determine the MDR status using fixed tissue from treated and untreated rhabdomyosarcoma specimens. In children with refractory or relapsed sarcomas use of cyclosporin A as a continuous infusion to modulate etoposide resistance was both tolerable and in some cases resulted in a useful response, in part this response could be due to the altered kinetics of etoposide.

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