DNA topoisomerase II rescue by catalytic inhibitors
Identifieur interne : 002948 ( Main/Exploration ); précédent : 002947; suivant : 002949DNA topoisomerase II rescue by catalytic inhibitors
Auteurs : Peter Buhl Jenen [Danemark] ; Maxwell Sehested [Danemark]Source :
- Biochemical Pharmacology [ 0006-2952 ] ; 1997.
English descriptors
- KwdEn :
- Teeft :
- Aclarubicin, Antagonistic effect, Antitumor, Cancer chemother pharmacol, Catalytic, Catalytic cycle, Catalytic inhibitor, Catalytic inhibitors, Chloroquine, Cytosine arabinoside, Cytotoxicity, Essential enzyme, Etoposide, High dose etoposide, Inhibitor, Jensen, Normal tissue, Nuclear enzyme, Other topo, Plasma membrane, Proc natl acad, Sehested, Topo, Topoisomerase.
Abstract
Abstract: The nuclear enzyme DNA topoisomerase II (topo II) is the target of important antitumor agents such as etoposide. Recent work has classified topo II targeting drugs into either topo II poisons that act by stabilizing enzyme-DNA cleavable complexes leading to DNA breaks, or topo II catalytic inhibitors that act at stages in the catalytic cycle of the enzyme where both DNA strands are intact and, therefore, do not cause DNA breaks. Accordingly, catalytic inhibitors are known to abrogate DNA damage and cytotoxicity caused by topo II poisons. In this commentary, we have focused on the possibilities of enabling high-dose therapy with the topo II poison etoposide by protection of normal tissue with catalytic inhibitors, analogous to folinic acid rescue in high-dose methotrexate treatment. Thus, we have demonstrated recently that ( + )-1,2-bis(3,5-dioxopiperazinyl-1-yl) propane (ICRF-187) enabled a 3- to 4-fold dose escalation of etoposide in mice. Two high-dose etoposide models are described, namely use of the weak base chloroquine in tumors with acidic extracellular pH and targeting of CNS tumors with protection of normal tissue by the bisdioxopiperazine ICRF-187. In conclusion, high supralethal doses of topo II poisons in combination with catalytic inhibitor protection form a new strategy to improve the antitumor selectivity of etoposide and other topo II poisons. Such an approach may be used to overcome problems with drug resistance and drug penetration.
Url:
DOI: 10.1016/S0006-2952(97)00116-0
Affiliations:
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Le document en format XML
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<front><div type="abstract" xml:lang="en">Abstract: The nuclear enzyme DNA topoisomerase II (topo II) is the target of important antitumor agents such as etoposide. Recent work has classified topo II targeting drugs into either topo II poisons that act by stabilizing enzyme-DNA cleavable complexes leading to DNA breaks, or topo II catalytic inhibitors that act at stages in the catalytic cycle of the enzyme where both DNA strands are intact and, therefore, do not cause DNA breaks. Accordingly, catalytic inhibitors are known to abrogate DNA damage and cytotoxicity caused by topo II poisons. In this commentary, we have focused on the possibilities of enabling high-dose therapy with the topo II poison etoposide by protection of normal tissue with catalytic inhibitors, analogous to folinic acid rescue in high-dose methotrexate treatment. Thus, we have demonstrated recently that ( + )-1,2-bis(3,5-dioxopiperazinyl-1-yl) propane (ICRF-187) enabled a 3- to 4-fold dose escalation of etoposide in mice. Two high-dose etoposide models are described, namely use of the weak base chloroquine in tumors with acidic extracellular pH and targeting of CNS tumors with protection of normal tissue by the bisdioxopiperazine ICRF-187. In conclusion, high supralethal doses of topo II poisons in combination with catalytic inhibitor protection form a new strategy to improve the antitumor selectivity of etoposide and other topo II poisons. Such an approach may be used to overcome problems with drug resistance and drug penetration.</div>
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