Journal article
Mechanism of action of the dual topoisomerase-I and -II inhibitor TAS-103 and activity against (multi)drug resistant cells
Cancer chemotherapy and pharmacology, Vol.45(1), pp.78-84
01/03/2000
DOI: 10.1007/PL00006747
PMID: 10647506
Abstract
TAS-103 is a recently developed dual inhibitor of topoisomerase-I (topo- I) and topoisomerase-II (topo-II). TAS-103 has documented cytotoxicity in vitro and antitumor activity against a variety of mouse, rat, and human xenografts in vivo. Purpose: To determine TAS-103 activity against (multi)drug resistant cells in vitro and to delineate its mechanism of action. Methods: TAS-103 was evaluated for activity against three human multidrug-resistant cell lines representing resistance mediated by P- glycoprotein (Pgp)-, multidrug resistance protein (MRP), and lung resistance protein (LRP) as well as one camptothecin-resistant cell line associated with a mutated topo-I enzyme. Drug sensitivity following short (2 h), intermediate (6-8 h) and long term (24 h) exposures were compared. The mechanism of action was studied by evaluating inhibition of topoisomerase-I and -II specific DNA relaxation assays, drug-induced DNA/protein cross-link formation, and competitive DNA intercalation with ethidium bromide. Results: Increasing the exposure time only modestly potentiated TAS-103 cytotoxicity (3-5 fold) demonstrating a lack of strong exposure duration dependency. TAS-103 cytotoxicity was not affected by the presence of any of the drug resistance mechanisms studied. TAS-103 inhibits topo-I and -II activity in DNA relaxation assays, but in our assay system TAS-103 was found to have only a weak ability to induce DNA-protein crosslinks. DNA migration patterns in agarose gel electrophoresis indicate that TAS-103 can interact directly with DNA. Also its ability to displace ethidium bromide which has intercalated into the DNA provides an indication on the nature of drug-DNA interaction. Conclusions: TAS-103 cytotoxicity is not affected by the presence of Pgp, MRP, LRP or mutations in the CAM binding region of the topo-I enzyme and its growth-inhibitory effect appears to be weakly dependent on exposure duration. The presented evidence suggest that the inhibitory effects of TAS-103 on topo-I and -II may in part be related to its DNA binding rather than primarily through stabilization of topo-I or -II intermediates with DNA through specific binding to the enzymes.
Details
- Title: Subtitle
- Mechanism of action of the dual topoisomerase-I and -II inhibitor TAS-103 and activity against (multi)drug resistant cells
- Creators
- Hans Minderman - Roswell Park Cancer InstituteCarol Wrzosek - Roswell Park Cancer InstituteShousong Cao - Roswell Park Cancer InstituteTeruhiro Utsugi - Taiho PharmaceuticalTakashi Kobunai - Taiho PharmaceuticalYuji Yamada - Taiho PharmaceuticalYoucef M. Rustum - Roswell Park Cancer Institute
- Resource Type
- Journal article
- Publication Details
- Cancer chemotherapy and pharmacology, Vol.45(1), pp.78-84
- DOI
- 10.1007/PL00006747
- PMID
- 10647506
- ISSN
- 0344-5704
- eISSN
- 1432-0843
- Language
- English
- Date published
- 01/03/2000
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359773002771
Metrics
6 Record Views