Modification of alternative splicing pathways as a potential approach to chemotherapy

Many cancer-associated genes are alternatively spliced; their expression leads to the production of multiple splice variants. Although the functions of most of these variants are not well-defined, some have antagonistic activities related to regulated cell death mechanisms. In a number of cancers and cancer cell lines, the ratio of the splice variants is frequently shifted so that the anti-apoptotic splice variant predominates. This observation suggests that modification of splicing, which restores the proper ratio of alternatively spliced gene products, may reverse the malignant phenotype of the cells and offer a gene-specific form of anticancer chemotherapy. Our laboratory has extensively investigated the use of antisense oligonucleotides for shifting the splicing patterns of several genes. Potential application of this method for treatment of cancers, as well as of certain genetic disorders, is discussed.