MDR1 gene overexpression and altered degree of methylation at the promoterregion in bladder cancer during chemotherapeutic treatment

Overexpression of the multidrug resistance I (MDR1) gene is closely associa ted with the clinical outcome of hematopoietic malignancies, but the altera tion of its expression during chemotherapeutic treatment and the precise me chanism underlying MDR1 gene overexpression in solid tumors remains unclear . We determined the expression and degree of methylation at the promoter of the MDR1 gene in bladder cancer, The mRNA levels of the MDR1 gene were fou nd to be markedly enhanced, 3.5- to 5.7-fold higher in bladder cancers afte r chemotherapeutic treatment than those in untreated primary tumors. The MD R1 gene was overexpressed in recurrent tumors in 89% of patients who showed rerecurrence, whereas overexpression was observed in 25% of the patients w ithout re-recurrence. A statistically significant inverse correlation exist ed between MDR1 expression and the methylation of 5'CpG sites at the promot er in patients with bladder cancer after chemotherapeutic treatment, with t he degree of methylation at several CpG sites, rather than other specific s ites, involved in this regulation. Consistent with the increase in MDR1 exp ression, the frequency of patients with a hypermethylated promoter decrease d to 50 and 17% after intravesical and systemic chemotherapy, respectively. Thus, overexpression of the MDR1 gene might be a prognostic marker for int ravesical recurrence, whereas methylation of the promoter region negatively regulates MDR1 expression and the appearance of multidrug resistance media ted by beta -glycoprotein in bladder cancers.