Ribozymes

Enzymes are organic catalysts that speed up biological reactions. Although the majority of known enzymes are proteins, some RNA molecules, ribozymes, also display catalytic activity. Ribozymes are involved in a variety of cellular processes, but their most interesting property from the standpoint of cancer therapy is their ability to cleave messenger RNA (mRNA) molecules. When an mRNA is cleaved, it can no longer be translated to produce protein. By targeting the mRNAs encoding proteins with pathological roles in cancer, ribozymes can slow or inhibit cancerous growth.

Ribozymes possess two key regions that participate in the cleavage of mRNA. One region binds to the target RNA sequence and the other is responsible for cleavage of the target site. The binding of the ribozyme to the target involves pairing of the two RNA molecules and is very specific. This allows for the design of ribozymes directed against particular mRNA molecules. If the nucleotide sequence of an mRNA is known, a ribozyme can be designed to specifically cleave that mRNA. The results of the human genome project promise to be critical in identifying specific genes/proteins important in cancer, giving ribozyme designers many targets. By targeting particular mRNAs, ribozymes can combat specific stages of cancerous growth, including cell proliferation, drug resistance, and metastasis.

The animation below shows the binding of a ribozyme to mRNA and its cleavage of the mRNA into two pieces.

Some of the genes that have been targeted include:

• ras -an oncogene that drives cancer cell proliferation^{(1) (2)} More on ras
• c-fos - encodes a protein that promotes transcription of other genes ⁽³⁾
• MDR1 - encodes a transmembrane protein involved in resistance to chemotherapy drugs.^{(4) (5)} More on MDR
• MMP-9 - an enzyme involved in tumor metastasis ⁽⁶⁾
• VEGFR-1 - a receptor for the vascular endothelial derived growth factor.  A ribozyme treatment, Angiozyme® (RPI.4610), was the first ribozyme drug developed.⁽⁷⁾  It was tested in kidney cancer but is no longer in clinical testing.

No ribozyme drugs have been approved by the FDA.

Check for clinical trials of ribozyme-based treatments (NCI).

1. Ohta Y, et al. "H-ras ribozyme-mediated alteration of the human melanoma phenotype." Ann NY Acad Sci (1994). 716: 242-53. [PUBMED]
2. Wang CH, Tsai LJ, Tsao YP, Hsieh JT, Chien WW, Liao CL, Wang HW, Liu HS, Chen SL. "Recombinant adenovirus encoding H-ras ribozyme induces apoptosis in laryngeal cancer cells through caspase- and mitochondria-dependent pathways." Biochem Biophys Res Commun. 2002 Nov 15;298(5):805-14. [PUBMED]
3. Scanlon KJ, et al. "Ribozyme-mediated cleavage of c-fos mRNA reduces gene expression of DNA synthesis enzymes and metallothionein." PNAS (1991). 88 (23): 10591-5. [PUBMED]
4. Scanlon KJ, et al. "Ribozyme-mediated reversal of the multidrug-resistant phenotype." PNAS (1994). 91(23): 11123-7. [PUBMED]
5. Nagata J, Kijima H, Hatanaka H, Asai S, Miyachi H, Abe Y, Yamazaki H, Nakamura M, Watanabe N, Mine T, Kondo T, Scanlon KJ, Ueyama Y. "Reversal of drug resistance using hammerhead ribozymes against multidrug resistance-associated protein and multidrug resistance 1 gene." Int J Oncol. 2002 Nov;21(5):1021-6. [PUBMED]
6. Hua J and Muschel RJ. "Inhibition of matrix metalloproteinase 9 expression by a ribozyme blocks metastasis in a rat sarcoma model system." Cancer Res (1996). 56: 5279-82. [PUBMED]
7. Weng DE, Usman N. Angiozyme: a novel angiogenesis inhibitor. Curr Oncol Rep. 2001 Mar;3(2):141-6. [PUBMED]
8. Weng DE, Usman N. "Angiozyme: a novel angiogenesis inhibitor." Curr Oncol Rep. 2001 Mar;3(2):141-6. [PUBMED]
9. Sirna Therapeutics. "Specialty Programs: Angiozyme." Online. Available. http://www.sirna.com/rnai/specialty.html. Oct. 21, 2004 [http://www.sirna.com/rnai/specialty.html]