The bleomycins are a family of glycopeptides derived antitumor antibiotics originally isolated from Streptomyces verticillus. Some of the bleomycins are used clinically for the treatment of squamous cell carcinomas and malignant lymphomas. While numerous studies of bleomycin have been carried out in the past few decades, few of these have addressed two remarkable properties of bleomycin, namely its tumor seeking properties and the way in which it targets its DNA substrates under physiological conditions. The present project is based on new strategies which provide (i) a facile method for monitoring the tumor seeking properties of bleomycin and (ii) an approach for identifying high affinity nucleic acid targets for bleomycin. Goals of the project include identification of the structural elements in bleomycin that are required for tumor targeting, as well as the cellular constituents that are recognized. Also proposed is the identification of DNA motifs that are bound and cleaved with exceptionally high efficiency by bleomycin.
The bleomycins are used clinically for the treatment of certain tumors that occur in soft tissues. The studies proposed here will facilitate an understanding of the way that this drug targets tumors, and binds to and degrades the nucleic acids in tumor tissue. As such, these studies will enable the preparation of bleomycins with improved properties.
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| Bhattacharya, Chandrabali; Yu, Zhiqiang; Rishel, Michael J et al. (2014) The carbamoylmannose moiety of bleomycin mediates selective tumor cell targeting. Biochemistry 53:3264-6 |
| Madathil, Manikandadas M; Bhattacharya, Chandrabali; Yu, Zhiqiang et al. (2014) Modified bleomycin disaccharides exhibiting improved tumor cell targeting. Biochemistry 53:6800-10 |
| Tang, Chenhong; Paul, Ananya; Alam, Mohammad P et al. (2014) A short DNA sequence confers strong bleomycin binding to hairpin DNAs. J Am Chem Soc 136:13715-26 |
| Roy, Basab; Hecht, Sidney M (2014) Hairpin DNA sequences bound strongly by bleomycin exhibit enhanced double-strand cleavage. J Am Chem Soc 136:4382-93 |
| Roy, Basab; Tang, Chenhong; Alam, Mohammad P et al. (2014) DNA methylation reduces binding and cleavage by bleomycin. Biochemistry 53:6103-12 |
| Schroeder, Benjamin R; Ghare, M Imran; Bhattacharya, Chandrabali et al. (2014) The disaccharide moiety of bleomycin facilitates uptake by cancer cells. J Am Chem Soc 136:13641-56 |
| Segerman, Zachary J; Roy, Basab; Hecht, Sidney M (2013) Characterization of bleomycin-mediated cleavage of a hairpin DNA library. Biochemistry 52:5315-27 |
| Yu, Zhiqiang; Schmaltz, Ryan M; Bozeman, Trevor C et al. (2013) Selective tumor cell targeting by the disaccharide moiety of bleomycin. J Am Chem Soc 135:2883-6 |
| Bozeman, Trevor C; Nanjunda, Rupesh; Tang, Chenhong et al. (2012) Dynamics of bleomycin interaction with a strongly bound hairpin DNA substrate, and implications for cleavage of the bound DNA. J Am Chem Soc 134:17842-5 |
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