The overall objective of this application is to explore the possibility that AT-specific DNA-reactive drugs could preferentially target nuclear matrix-bound oncogene domains. AT-rich domains that are associated with the nuclear matrix play a crucial role in the organization and regulation of DNA replication. Organization of such domains on the nuclear matrix is different both in tumor vs. normal cells and active vs inactive genes. The applicant has shown that several anti tumor, AT-specific, DNA-reactive drugs can bind matrix-associated replication regions, including domains of activated c-myc. Tumor-specific organization of c-myc replication on the nuclear matrix could be a basis for selective drug action in tumor cells. He proposes to test the hypothesis that targeting replication-related regions of activated c-myc offers a potential for enhanced therapeutic benefits. Using the quantitative PCR-stop assay, he will determine the ability of the anti tumor drug bizelesin and other AT-specific, DNA-reactive drugs to preferentially affect the replication domains, matrix associated region (MAR) and origin of replication (ORI) of the c-myc gene. Also, he will verify whether the differences in the c-myc association with the nuclear matrix between tumor and normal cells affect drug ability to damage c-myc sequences. Finally, he will test the idea that abrogation of DNA replication by drug-induced lesions in c-myc MAR and ORI sites can lead to cell death. Understanding drug effects on c-myc oncogene replication domains will provide leads for the design of new therapeutic strategies. The following specific aims are proposed: 1. Determine bizelesin's ability to modify the replication domains of the c-myc oncogene. 2. Determine how association with the nuclear matrix affects the susceptibility of c-myc replication domains to bizelesin. 3. Compare bizelesin's effects on the replication of c-myc MAR sequences in tumor cells vs normal cells.
| Woynarowski, Jan M (2004) AT islands - their nature and potential for anticancer strategies. Curr Cancer Drug Targets 4:219-34 |
