Topoisomerase I (top I)inhibitors (camptothecins and other structurally div
erse compounds) are effective and promising anticancer agents. Determinants
of selectivity toward cancer cells and resistance are multifactorial. Thes
e factors can be separated in three groups. The first is related to alterat
ions in drug distribution and metabolism. The second group includes both qu
antitative and qualitative (mutations) differences in top I. The third grou
p includes resistance and sensitivity factors downstream from the cleavage
complexes. They include DNA repair, cell cycle checkpoints and apoptosis, a
nd are probably key to the relative selectivity of camptothecins toward can
cer cells and to clinical resistance.