Relationships between DNA damage and growth inhibition induced by topoisomerase II-interfering drugs in doxorubicin-sensitive and -resistant rat glioblastoma cells.

We have evaluated the DNA breaks occurring after action of three topoisomerase II-interfering drugs (doxorubicin, etoposide and amsacrine) on a line of rat glioblastoma cells in culture and its doxorubicin-resistant variant. DNA breaks were quantified by alkaline unwinding in the presence of a dye exhibiting a quenching of fluorescence with single stranded DNA. The antiproliferative activity of the three drugs was compared to their ability to damage DNA. We have shown that at low exposure doses (up to the IC50 of the drugs), the same low level of DNA damage determined the same inhibition of cell growth in sensitive and resistant cells, but that at higher exposure doses the resistant cells developed special mechanisms allowing them to tolerate more DNA breaks than sensitive cells without lethal effects. The origin of this tolerance of resistant cells to DNA breaks might be due to special mechanisms of protection of genomic sites hypersensitive to topoisomerase II-mediated drug action, to alterations of topoisomerase II or to alterations of the molecular events leading to cell death after occurrence of DNA breaks.