Potential Use of Multiple Antisense Oligonucleotide Analogs for Cancer Prevention and Therapy

Abstract

Antisense oligonucleotide (ASO) analogs have been used to counteract the effects of mutated genes and have been developed as therapeutic agents. Several such formulations have been subjected to clinical trials against cancer and have been passed by the FDA for clinical use. However, cancer is a complex genetic disease in which multiple mutations are known to occur for tumors to develop. Three basic stages have been delineated: 1. Loss of cell growth control by both oncogenes and tumor suppressor genes; 2. Angiogenesis, the production of capillary growth factors to allow blood supply; 3. Metastasis allows cancer cells to invade normal tissue. In principle, using three ASOs to down-regulate the products of the mutated genes controlling these specific processes should be possible and this could be an effective preventive method against cancer. In an alternative approach, genetic analysis of cancer cells using microarrays have shown that cassettes of genes are up- and down-regulated compared to normal tissue. Using this information ASOs could be used to down-regulate mutated genes that are up-regulated. In general ASO analog sequences could be used to target the unique pre-mRNA splice sites of selected genes in order to suppress carcinogenesis in vitro in selected cancer cell lines and subsequently in vivo in chosen mouse models. Computer programs will be used to calculate doses of a cocktail of ASOs to be administered to individual mice and ultimately patients as their tumor genetic profile changes over time.