RELATIONSHIPS BETWEEN DNA-DAMAGE AND GROWTH-INHIBITION INDUCED BY TOPOISOMERASE II-INTERFERING DRUGS IN DOXORUBICIN-SENSITIVE AND DOXORUBICIN-RESISTANT RAT GLIOBLASTOMA CELLS

We have evaluated the DNA breaks occurring after action of three topoi somerase II-interfering drugs (doxorubicin, etoposide and amsacrine) o n a line of rat glioblastoma cells in culture and its doxorubicin-resi stant 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 co mpared to their ability to damage DNA. We have shown that at low expos ure doses (lip to the IC50 of the drugs), the same low level of DNA da mage determined the same inhibition of cell growth in sensitive and re sistant cells, but that at higher exposure doses the resistant cells d eveloped special mechanisms allowing them to tolerate more DNA breaks than sensitive cells without lethal effects. The origin of this tolera nce of resistant cells to DNA breaks might be dire to special mechanis ms of protection of genomic sites hypersensitive to topoisomerase II-m ediated drug action, to alterations of topoisomerase II or to alterati ons of the molecular events leading to cell death after occurrence of DNA breaks.