POISONS OF TYPE-I AND TYPE-II DNA TOPOISO MERASES

Over the past decade, DNA topoisomerase I and II appeared to be the ta rgets of some antitumor agents: CPT-II and topotecan derived from Camp tothecin which interact with topoisomerase I; Actinomycin D, Adriamyci n and daunorubicin, Elliptinium Acetate, Mitoxantrone, Etoposide and T eniposide, Amsacrine which interact with topoisomerase II. The multipl e fonctions of these enzymes are important as they play a role during replication, transcription, recombination, repair and chromatine organ isation. Particularly, they relax torsional constraints which appear w hen intertwined DNA strands are separated while replication fork or RN A polymerases are moving. To some extent, topoisomerase I and II are s tructurally and functionally different. Moreover, topoisomerase I is n ot indispensable for a living cell whereas topoisomerase II is. Drug-t opoisomerase interaction which probably leads to antitumoral effect of the compounds studied in this review is not a trivial inhibition of t he enzyme but rather a poisoning due to stabilization of cleavable com plexes between the, enzyme and DNA. These stabilized complexes are lik ely to induce apoptosis-like programmed cell death, which is character ised by DNA fragmentation. However, it appears that it is the collisio n of the replication fork with the drug-stabilized cleavable complex t hat is responsible for the cytotoxicity of the drug: poisoning of topo isomerases by antitumor agents lends to a new concept of ''dynamic tox icity''. Although they interact with a common target, topoisomerase II poisons have differential effects on macromolecules syntheses, cell c ycle and chromosome fragmentation; a few compounds may produce free ra dicals. Because of these differential effects in addition to quantitat ive and qualitative variations of stabilized cleavable complexes, in p articular DNA sequences on which topoisomerase II is stabilized, these antitumor agents do not resemble each other; Cellular resistance to t opoisomerases poisons results of two principal types of alteration: ta rget and/or drug transport modification. Decreased ability to form the cleavable complex in resistant cells may be the consequence of both d ecreased amount of topoisomerase or altered enzyme. On the other hand, overexpression of membrane P-glycoprotein, which pumps drugs out of t he cell by an energy dependent process provokes a decreased accumulati on of these drugs. Cross resistances to other drugs are mainly under c ontrol of these two different mechanisms of resistance. A complete kno wledge of their individual effects and mechanisms of resistance would allow a better clinical use of topoisomerases poisons, especially when administred in combination chemotherapy.