Potential clinical application of antioncogene ribozymes for human XXXX .

@entity5 @entity984 @entity1149 @entity2 @entity70935 @entity876 @entity995
@entity1149 frequently contains oncogenetic defects (mutations in ras, @entity995 , and @entity876 genes) that contribute to disease pathophysiology. Recent studies and clinical trials have focused on gene therapy approaches that either replace the function of defective @entity5 -suppressor genes such as @entity876 or inactivate mutant oncogenes such as ras. Ribozymes are RNA molecules with highly specific intrinsic enzymatic activity against target RNA sequences, which can discriminate mutant sequences that differ by a single base from their wild-type counterparts. Following binding to the RNA substrate by base-pair complementation, the ribozyme cleaves the target RNA irreversibly, then releases itself for new rounds of subsequent cleavage, resulting in significantly improved target:effector stoichiometry as compared with antisense oligonucleotides of the same specificity. Transcript-specific ribozymes have been used extensively for experimental oncogene inactivation. Ribozymes are effective for targeting mutant ras, @entity876 , or the multidrug-resistant gene product for @entity2 cells in vitro. However, their in vivo effect is not well defined against this malignancy. We recently characterized the antitumor properties of an anti- @entity984 ribozyme specific for the @entity984 codon 12 mutation ( @entity70935 ). When delivered as a transgene by an adenoviral vector (ADV), the @entity984 ribozyme (KRbz) suppressed growth of @entity2 xenografts expressing the relevant mutation, whereas the corresponding antisense sequence lacking catalytic activity did not. Multiple intratumoral (3-5) injections of KRbz-ADV were effective in producing complete @entity5 regressions of preexisting @entity5 xenografts. Clinical trials are under consideration to examine the applicability of this anti- @entity984 ribozyme for treatment of @entity1149 expressing the relevant mutation.
