THERAPEUTIC DIFFERENTIATION IN A HUMAN RHABDOMYOSARCOMA CELL-LINE SELECTED FOR RESISTANCE TO ACTINOMYCIN-D

Classical cytotoxic treatment of rhabdomyosarcoma (RMS) is accompanied often by significant morbidity and poor response. The use of cytotoxi c agents may induce a multidrug resistance phenotype, which plays an i mportant role in the sensitivity of tumoral cells to drugs. Using acti nomycin D, a drug of choice in the treatment of RMS, we induced resist ance in the TE.32.7 human RMS cell line, The TE.32.7-DAC-resistant cel l line exhibited cross-resistance to vincristine and doxorubicin and s howed mdrI/P-glycoprotein over-expression, suggesting that this mechan ism was involved in the reduction in intracellular drug concentration and may be responsible for the failure of treatment of RMS with classi cal cycles of cytotoxics. Furthermore, this resistant cell line showed increased expression of the muscle differentiation markers desmin and alpha-actinin and ultrastructural changes which clearly indicated myo genic differentiation, Our findings suggest that, although this tumor is probably arrested along the normal myogenic pathway to maturation, induction of cell differentiation with anti-neoplastic drugs may be an alternative therapeutic approach, However, the failure of TE.32.7-DAC cells to completely re-enter the program of myogenic differentiation supports the hypothesis that multidrug resistance is a major obstacle in differentiation therapy for RMS. (C) 1998 Wiley-Liss, Inc.