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

Abstract

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

Effects of standard chemotherapy on tumor growth and regulation of multidrug resistance genes and proteins in childhood rhabdomyosarcoma

“…MDM2 is often over-expressed in soft tissue sarcomas. In RMS, an over-expression of MDM2 was found in vitro [3] and in tumor samples [30]. MDM2 protein binds and suppresses tumor supressor gene p53 [31].…”

“…The two main histopathological subtypes of this malignancy in children are embryonal and alvelolar RMS [2]. Patient's prognosis depends on the localization of the primary lesion [3,4], histological subtype [3,5], stage of disease [3,6], and the age at diagnosis [3,7].…”

A review of selected anti-tumour therapeutic agents and reasons for multidrug resistance occurrence

“…It has anti-tumour activity against relapsed ovarian cancer (Morris 2003) and endometrial cancer (Holloway 2003). Many research centres concentrate on ciclosporin and verapamil -Pgp and MRP modulators (Cocker et al 2000;Fu et al 2002) -but the results of the research are quite controversial (Davidson et al 2002;Garraway & Chabner 2002).…”

Establishment of a rhabdomyosarcoma xenograft model in human-adapted mice

“…Patient's prognosis depends on the primary tumor localization, histological subtype, stage of disease, and the age at diagnosis (2)(3)(4). Despite treatment efforts in localized disease, in which survival rates have improved from 25 to 70% in the last decades (5), patients with metastatic disease still have a poor outcome (6).…”