Antisense oligonucleotides are potentially powerful tools for cancer therapy. The manipulation of gene expression using antisense technology is now well established in cell biological experimentation. However, the therapeutic utilization of antisense oligonucleotides in cancer has been impeded by (1) lack of understanding of the pharmacodynamic behavior of these compounds in vivo and (2) by the inefficient delivery of these compounds to their sites of action in the cytoplasm and nucleus of tumor cells. The overall goals of this application are (1) systematically identify and evaluate improved approaches for the efficient delivery of antisense oligonucleotides to the cytoplasm and nucleus of cells in culture (2) to establish a rational basis for antisense therapy of tumors by evaluating the kinetics accumulation and subsequent distribution of oligonucleotides in host and tumor tissues (3) to utilize this information to design approaches to efficiently deliver therapeutic antisense oligonucleotides to tumor cells in vivo. Initially the applicant will use simple reporter gene system in CHO cells to rapidly identify promising approaches for oligonucleotide therapy. The applicant will then test these approaches in more stringent cancer related cell culture models including multidrug resistant 3T3 cells and ras-transformed human colon carcinoma cells. Approaches that lead to efficient oligonucleotide delivery in vitro will be further evaluated in terms of pharmacokinetics, tumor tissue uptake and subcellular distribution in human colon carcinoma xenografts in nude mice. Finally delivery approaches that are promising in both in vitro and in vivo contexts will be evaluated for their ability to enhance the pharmacological and therapeutic efficacy of ant-Ki-ras oligonucleotides in the colon xenograft model. This integrated and systematic approach to transport and delivery problems and antisense oligonucleotides will hasten their development as useful chemotherapeutic agents.
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