Antisense-Based Cancer Drugs

Proteins are the molecular machines of life. They are responsible for most of the cells functions, including maintenance of structure, signaling processes and metabolism. The blueprints for all proteins are carried in DNA (deoxyribonucleic acid). In order for the DNA to become a protein an intermediate step is required, whereby the DNA is transcribed into the message RNA (ribonucleic acid) or mRNA.

Antisense drugs are small, chemically modified strands of DNA. These oligonucleotides are engineered in a sequence that is exactly opposite to the coding (sense) sequence of mRNA for the purpose of binding to that mRNA. Upon binding to the mRNA a duplex is formed. This duplex recruits an enzyme that degrades the mRNA portion of the duplex, thereby inhibiting the production of the intended protein. When these compounds bind tightly to the disease-causing sequence, the genetic process is inhibited, thus disabling the pathogenic process. This is called antisense technology because the strands of genetic material that get translated into a protein are called "sense" strands, and so "antisense" drugs are meant to stop that translation process.

ISIS112989 (OGX-011) is an inhibitor of the secretory protein clusterin (sCLU), which is in the CLU family of proteins. sCLU acts as a cell-survival protein and is over-expressed in response to tumor killing strategies, such as chemotherapy, hormone ablation and radiation therapy. sCLU has been associated with preventing cell death in tumors, a function that may be related to its ability to clear cell debris after damage from tumor killing strategies. Inhibiting sCLU is intended to enhance the effects of traditional therapies in cancer treatment.

LY2181308 targets survivin, a molecule that allows the survival of cells that would normally undergo programmed cell death or apoptosis. When cancer cells grow, they appear to need the help of survivin. The molecule is abundant in many types of cancers, including colon, brain, lung, skin and others, but nearly nonexistent in normal cells.

LY2275796 targets eukaryotic initiation factor-4E (eIF-4E), a protein that is upregulated or overexpressed in a variety of cancers, including breast, head and neck, prostate, lung, bladder, colon, thyroid and non-Hodgkin's lymphomas. The molecule facilitates the synthesis of tumor angiogenic factors (factors that facilitate the growth of new blood vessels to support the development and progression of tumors), growth factors and survival factors by selectively enhancing their translation.

Genasense inhibits production of Bcl-2, a protein that is highly expressed in malignant cell from patients with cancers. Bcl-2 regulates a critical pathway in the body known as programmed cell death (or apoptosis). Cancer cells frequently develop multiple defects in this pathway that can delay or completely prevent cell death, even after treatment with high doses of chemotherapy. High levels of Bcl-2 are believed to be a fundamental cause of the inherent resistance of cancer cells to being killed by contemporary forms of anticancer therapy. Bcl-2 expression has been linked to lower response, faster time to cancer progression, and markedly decreased survival. By reducing the amount of Bcl-2 in cancer cells, Genesense may enhance the effectiveness of current anticancer treatments.

MG98 is an antisense compound and an inhibitor of DNA methyltransferase. Methyltransferase is associated with silencing tumor suppressor genes via hypermethylation. MG98 is used to enhance tumor suppressor genes by inhibiting DNA methyltransferase.