ASSESSMENT OF DRUG-INDUCED DYSREGULATIONS AMONG 7 RESISTANCE-ASSOCIATED GENES IN HUMAN TUMOR-CELL LINES

Drug-resistance in cell lines and in malignant human tumours is associ ated with dysregulation of several genes, including mdr1, MRP1, GST-pi , bcl-2, DNA topoisomerase II alpha and beta, and thymidine kinase I. mRNA expression was evaluated by quantitative RT-PCR coupled with HPLC in three human tumour cell lines and drug-resistant (DR)-sublines. DR sublines from RPMI-8226 and KB cells specifically overexpressed the m dr1 gene without major changes observed in other putative DR-associate d genes. In contrast, the DR-H69 cells exhibited a 34-fold overexpress ion of the MRP gene accompanied by significant down-regulation of both DNA topoisomerase II alpha and bcl-2 mRNA gene expression, by factors of 43 and 13, respectively. These results demonstrate the concomitant down-regulation of topoisomerase II alpha and bcl-2 genes in response to DR. Furthermore, differential patterns of gene dysregulations appe ar to vary depending upon both the drug used to select resistance and cellular origin.