|
 |
|||||||||||||||||||
|
|||||||||||||||||||
|
|||||||||||||||||||
 |
 |
|
|
HER-2-Targeted Antisense Oligonucleotide Results in Sensitization of Head and Neck Cancer Cells to Chemotherapeutic Agents
Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA
Address for correspondence: Esther H. Chang, Lombardi Cancer Center, Georgetown University Medical Center, Research Building, Room E420, 3970 Reservoir Road, NW, Washington, DC 20057-1469. Voice: 202-687-8418; fax: 202-687-8434. change{at}georgetown.edu Ann. N.Y. Acad. Sci. 1002: 78-89 (2003).
Existing HER-2 targeted therapies for human head and neck cancers, usually administered in combination with chemotherapeutic drugs or irradiation, include monoclonal antibodies to HER-2, receptor tyrosine kinase inhibitors and HER-2 specific immunotoxins. Instead of targeting the existing protein, interference with HER-2 mRNA translation by antisense oligonucleotides may be a more efficient method to downregulate levels of HER-2 protein for combination therapy. To test this hypothesis we have used a phosphorothioate pentadecamer, complementary to the HER-2 mRNA initiation codon region (AS HER-2 ODN), to increase sensitivity to four chemotherapeutic agents in human head and neck cancer cell lines, all of which express low levels of the HER-2 protein. To improve delivery into tumor cells, the AS HER-2 ODN was complexed with our previously established folate-liposome delivery system. Cell survival assays and Western blot analysis data demonstrated that folate-liposome mediated AS HER-2 oligonucleotide treatment inhibited cell growth and HER-2 expression, and induced apoptosis in SCC-25CP cells. Moreover, there was a synergistic effect on the percent of apoptotic cells. Additionally, the combination of folate-liposome-AS HER-2 ODN and CDDP had a synergistic effect on the induction of apoptosis. Using confocal microscopy, FITC labeled ODN (FITC-ODN) in complex with folate-liganded, rhodamine (Rh) labeled, cationic liposomes was observed to enter SCC-25CP head and neck tumor cells within 3 to 6 h. Intracellularly, the FITC-ODN separated from the Rh-folate-liposomes, and FITC-ODN accumulated in the nucleus while Rh-liposomes remained in punctate cytoplasmic structures. Thus, folate-liposome-mediated delivery of AS HER-2 ODN has potential as a new means of increasing the responsiveness of head and neck cancer to conventional chemotherapy.
Key Words: HER-2 • head and neck cancer cell lines • ligand liposome delivery • chemosensitization • antisense oligonucleotides • apoptosis This article has been cited by other articles:
| |||||||||||||||||||||||||||||
 |
 |
