A key problem in the effective treatment of patients with
cancer (both
leukemia and solid
tumors) is to distinguish between
tumor and normal cells. This problem is the main reason why current treatments for
cancer are often ineffective. There have been remarkable advances in our understanding of the molecular biology of
cancer that provides new selective
tumor destruction mechanisms. The molecular characterization of the
tumor-specific
chromosomal abnormalities has revealed that fusion
proteins are the consequence in the majority of
cancers. These fusion
proteins result from chimeric genes created by the translocations, which form chimeric
mRNA species that contain exons from the genes involved in the translocation. Obviously, these chimeric molecules are attractive therapeutic targets since they are unique to the disease (they only exist in the
tumor cells but not in the normal cells of the patient), allowing the design of specific anti-
tumor drugs. Inhibition of chimeric gene expression by anti-
tumor agents specifically kills leukemic cells without affecting normal cells. As therapeutic agents targeting chimeric genes, zinc-finger
proteins, antisense RNAs or hammerhead-based
ribozymes have been used. All of these agents have some limitations, indicating that new therapeutic tools are required as gene inactivating agents that should be able to inhibit any chimeric fusion gene product. Recently, we have used the
catalytic RNA subunit of
RNase P from Escherichia coli, which can be specifically directed to cut any
mRNA sequence, to specifically destroy
tumor-specific fusion genes created as a result of
chromosomal translocations. In this chapter, we will review the advances made to selectively destroy
tumor cells through specific inhibition of products resulting from
chromosomal translocations.