Development of multidrug resistance in a primitive neuroectodermal tumor cell line.

Abstract

Drug resistance remains a formidable obstacle to the successful treatment of pediatric primitive neuroectodermal tumors. Resistance to chemotherapeutic agents may be related, in part, to expression of the multidrug resistance gene 1 (MDR1). The protein product of this gene, P-glycoprotein, confers resistance to multiple unrelated antineoplastic drugs. The cell line DAOY, derived from a primitive neuroectodermal tumor, was used as an in vitro model to examine the development of drug resistance. Cell lines resistant to actinomycin D were developed by the growth of DAOY in increasing concentrations of the drug. The IC50 (concentration of drug needed to induce a 50% reduction in cell growth) of the resultant lines to actinomycin D was more than 10 times that of the parental line. The resistant lines were cross-resistant to VP-16 (etoposide), despite lack of previous exposure to this drug. The resistance to actinomycin D was attenuated in the presence of verapamil, a known inhibitor of P-glycoprotein. The MDR1 gene was not expressed by the parental DAOY line at the messenger ribonucleic acid (RNA) and protein level. Expression of the MDR1 gene was documented in the resistant lines by RNA blot and immunoblot techniques. These results suggest that exposure to chemotherapeutic drugs can induce classical multidrug resistance in primitive neuroectodermal tumors.