The overall object of this application is to explore the possibility that human DNA ligase I could be a potential target in anticancer therapy by investigating the relationship between DNA ligase I expression and the neoplastic process. Human DNA ligase I is an essential enzyme required during DNA replication, transcription, repair, and recombination by joining single- and double-stranded DNA with the formation of phosphodiester bonds. There is compelling evidence that human DNA ligase I is much more active in rapidly proliferating cells such as tumor cells. This suggests that DNA ligase I could be a very interesting and unique target for anticancer agents and that there is a very strong possibility for achieving the selectivity against rapidly proliferating tumor cells by using DNA ligase I-interactive agents. The applicant proposes to test the hypothesis that human DNA ligase I expression is tightly related to the neoplastic process, and targeting human DNA ligase I offers a potential for enhanced therapeutic benefit. The following specific aims are proposed: 1) Assess human DNA ligase I levels in human tumors versus normal tissue. 2) Investigate the regulatory mechanisms of human DNA ligase I gene expression. 3) Test whether DNA ligase I inhibition produces antitumor activity using antisense strategy in preclinical in vitro and in vivo evaluation systems. 4) Develop a sensitive and reproducible assay for DNA ligase I.
