METHYL-BETA-CYCLODEXTRIN IN HL-60 PARENTAL AND MULTIDRUG-RESISTANT CANCER CELL-LINES - EFFECT ON THE CYTOTOXIC ACTIVITY AND INTRACELLULAR ACCUMULATION OF DOXORUBICIN

The purpose of this work was to determine the role of methyl-beta-cycl odextrin (MEBCD) in combination with doxorubicin (DOX) on the cellular proliferation of a sensitive parental and a multidrug-resistant human cancer cell line (HL-60 S and HL-60 R) and to study the effect of MEB CD on DOX intracellular accumulation. The cytotoxicity of DOX at five concentrations (50-50,000 nM) was evaluated with or without the coadmi nistration of four fixed noncytotoxic concentrations of MEBCD (100, 20 0, 500, and 1,000 mu M). Intracellular DOX concentrations were determi ned by a high-performance liquid chromatography (HPLC) method with flu orescence detection. MEBCD applied at 500 and 1000 mu M in combination with doxorubicin (DOX) significantly potentiated the activity of DOX used alone on both sensitive and multidrug-resistant cell lines; 50%, growth-inhibitory (IC50) ratios (ICS, MEBCD-DOX/IC50 DOX) were about 3 :4 and 1.6:4 for HL-60 S and HL-60 R, respectively. Moreover, intracel lular DOX accumulation, determined by HPLC during 6 h of drug exposure ? was about 2-4 times higher for cells treated with MEBCD in combinati on with DOX than in those treated with DOX alone. Similar results were obtained using other paired MCF 7 sensitive and resistant cell lines. Correlation between these results and an MEBCD-cell membrane interact ion was discussed. These initial data provide a basis for the potentia l therapeutic application of MEBCD in cancer therapy.