Topoisomerase I (top1) inhibitors (camptothecins and other structurally diverse compounds) are effective and promising anticancer agents. Determinants of selectivity toward cancer cells and resistance are multifactorial. These factors can be separated in three groups. The first is related to alterations in drug distribution and metabolism. The second group includes both quantitative and qualitative (mutations) differences in top I. The third group includes resistance and sensitivity factors downstream from the cleavage complexes. They include DNA repair, cell cycle checkpoints and apoptosis, and are probably key to the relative selectivity of camptothecins toward cancer cells and to clinical resistance. Copyright 1999 Harcourt Publishers Ltd.
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