Our long term objectives are to understand the mechanisms of action of topoisomerase-targeting antitumor drugs and to develop more effective antitumor drugs for cancer chemotherapy. In the past funding periods, we and others have established that both human DNA topoisomerase I and topoisomerase II are important antitumor drug targets. Their mechanisms of action have also been partially elucidated. More recently, some topoisomerase drugs have been shown to overcome MDR1-mediated resistance and to exhibit strong antitumor activity against many refractory human solid tumor xenografts in nude mice. To further understand the mechanisms of action of topoisomerase-targeting drugs and to develop more effective antitumor drugs for cancer chemotherapy, we plan to: (1) investigate the mechanism of action of DNA minor groove binding drugs which we have recently shown to be a new class of topoisomerase I-targeting drugs; (2) investigate the mechanism(s) of action naphthoquinones and quinolones which may represent a new class(es) of topoisomerase II-targeting drugs. The roles of both 170 kDa and 180 kDa isoforms of human DNA topoisomerase II in drug action will also be studied. (3) investigate the roles of topoisomerases in genome rearrangements using specific topoisomerase-targeting antitumor drugs. (4) investigate the mechanism of drug specificity of human MDR1 and to overcome MDR1-mediated resistance using topoisomerase-targeting antitumor drugs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA039662-11
Application #
2089899
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1985-04-01
Project End
1998-01-31
Budget Start
1994-04-01
Budget End
1995-01-31
Support Year
11
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Pharmacology
Type
Schools of Medicine
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Lin, Ren-Kuo; Ho, Chia-Wen; Liu, Leroy F et al. (2013) Topoisomerase II? deficiency enhances camptothecin-induced apoptosis. J Biol Chem 288:7182-92
Ban, Yi; Ho, Chia-Wen; Lin, Ren-Kuo et al. (2013) Activation of a novel ubiquitin-independent proteasome pathway when RNA polymerase II encounters a protein roadblock. Mol Cell Biol 33:4008-16
Chiang, Hsiao-Ling; Lin, Chi-Yu; Jan, Fan-Dan et al. (2012) A novel synthetic bipartite carrier protein for developing glycotope-based vaccines. Vaccine 30:7573-81
Su, Yee-Fun; Yang, Tsunghan; Huang, Hoting et al. (2012) Phosphorylation of Ubc9 by Cdk1 enhances SUMOylation activity. PLoS One 7:e34250
Wan, Shan; Pestka, Sidney; Jubin, Ronald G et al. (2012) Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells. PLoS One 7:e32542
Lin, Ren-Kuo; Zhou, Nai; Lyu, Yi Lisa et al. (2011) Dietary isothiocyanate-induced apoptosis via thiol modification of DNA topoisomerase II?. J Biol Chem 286:33591-600
Tsai, Yu-Chen; Pestka, Sidney; Wang, Lu-Hai et al. (2011) Interferon-? signaling contributes to Ras transformation. PLoS One 6:e24291
Feng, Wei; Satyanarayana, Mavurapu; Tsai, Yuan-Chin et al. (2009) 12-Substituted 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridines as novel topoisomerase I-targeting antitumor agents. Bioorg Med Chem 17:2877-85
Feng, Wei; Satyanarayana, Mavurapu; Tsai, Yuan-Chin et al. (2009) Novel topoisomerase I-targeting antitumor agents synthesized from the N,N,N-trimethylammonium derivative of ARC-111, 5H-2,3-dimethoxy-8,9-methylenedioxy-5-[(2-N,N,N-trimethylammonium)ethyl]dibenzo[c,h][1,6]naphthyridin-6-one iodide. Eur J Med Chem 44:3433-8
Sharma, Lisa; Tsai, Yuan-Chin; Liu, Angela A et al. (2009) Cytotoxicity and TOP1-targeting activity of 8- and 9-amino derivatives of 5-butyl- and 5-(2-N,N-dimethylamino)ethyl-5H-dibenzo[c,h][1,6]naphthyridin-6-ones. Eur J Med Chem 44:1471-6

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