Ribozymes as a Novel Approach for the Treatment of Human Pancreatic carcinoma

Current advances in the understanding of the genetic mechanisms of carcinogenesis and manipulation of gene expression have introduced gene therapy as a new strategy for cancer therapeutics. Recently, gene modulation using specific oligonucleotides have been developed and defined as an effective strategy for suppressing the function of genes (1 –4 ). The types of oligonucleotides used to modulate specific gene expression include triplex DNA, antisense DNA/RNA and ribozymes (catalytic RNAs; for a review see ref. 1 ). Antisense oligonucleotides are capable of altering the translation of mRNA and thus inhibit the transfer of information from the gene to the protein. Antisense-mediated gene modulation has been shown to be effective for gene therapy (5 –7 ). In contrast, ribozymes have been characterized as RNA molecules having site-specific catalytic activity (8 ,9 ). Trans-acting ribozyme molecules, such as “hammerhead” and “hairpin” ribozymes, possess a catalytic core and two flanking sequences which bind specifically to its target mRNA. Ribozymes are also occasionally defined as “partial” antisense molecules. However, compared to the classical an&sense-mediated gene modulation, ribozyme strategies have a few advantages due to their site-specific cleavage activity and catalytic potential (2 ,10 ). In recent years, researchers have described the efficacy of ribozymes against various oncogenes, such as ras , c-fos , and bcr-abl (11 ), the MDR-1 drug resistance gene (12 ,13 ), and the human immunodeficiency virus type 1 (10 ,14 ,15 ). Our Studies have previously demonstrated that anti-oncogene ribozymes effectively suppress the expression of targeted genes and result in the reversal of the malignant phenotype in human cancer cells (16 –24 ).