Preferential damage to defined regions of genomic DNA by AT-specific anticancer drugs

摘要: Summary A non-random distribution of DNA lesions in various domains the human genome may be important for selectivity antiproliferative action anticancer drugs. Recent investigations explored determinants region-specific damage to cellular cancer cells by comparing highly AT-specific drugs (bizelesin, adozelesin, U-78779, and tallimustine) a relatively non-specific drug, cisplatin. These studies consistently show that sequence specificity at nucleotide level long-range drug binding motifs analyzed “ silico ” predict well actual relative vulnerability specific regions Bizelesin is first small molecular weight demonstrated preferentially DNA. region because its motif non-randomly distributed, with clusters long (200–1000 bp) islands AT-rich substantial this an necessary factor accomplish damage. The less adozelesin targets similar as bizelesin but only marginal preference over other areas genome. Cisplatin not due low recognition omnipresence potential sites. High level, however, per se insufficient specificity. Tallimustine specific, despite very high Paradoxically, accordingly infrequent, tallimustine sites are distributed throughout nearly randomly, resembling much (and more numerous) consequences AT-islands targeted seem dramatically lethal than non reviewed findings provide proof principle targeting critical repetitive sequences (not necessarily coding regions), which allow clustering motif, can paradigm agents. notion regional should recognized essential extension rational design sequence-specific