ABSTRACT
Activation of oncogenes and deletion or mutation of tumor suppressor genes have been identified as key factors for malignant transformation of normal cells. This has suggested possibilities of exploitation of those oncogenes and altered tumor suppressor genes as targets for selective anticancer chemotherapy. It is thought that inhibition of expression or functions of oncogenes may trigger cancer cells to revert back to a normal phenotype or undergo apoptosis and may make normal cells less susceptible to transformation. Antisense oligonucleotide (AS ODN) technology is one method for intervening in the expression of transforming genes at the level of mRNA, or at the level of DNA by triplex formation. Unlike typical pharmaceuticals which regulate functions of important proteins (e.g., receptors, ion channels, enzymes and components of cytoskeleton) or many standard oncolytics that directly modify DNA, AS ODNs directly bind RNA or DNA without modification and control expression of the targeted gene and subsequent expression of its protein product. The therapeutic utilities of AS ODN are not limited to selective anticancer therapy, but potentially range from genetic diseases to infectious diseases, including cardiovascular disease and AIDS (Bennett and Schwartz, 1995; Carter and Lemoine, 1993; Hélène, 1991; Neckers et 40 al., 1992). Since late 1991, significant and growing numbers of Investigational New Drug Applications (INDs) have been received for clinical studies of AS ODNs. The majority of these investigations are at phase I-II level, but at least one has progressed to phase III. Primarily AS ODNs with phosphorothioate modified backbones have been used in these INDs. Though still limited, significant amounts of both clinical and preclinical information are available to us from sources such as the scientific literature and the proprietary data from the INDs. In an effort to expedite the entry of new and potentially effective AS ODN products into clinical testing and to facilitate the marketing approval of AS ODNs that are found to be safe and effective in clinical trials, this chapter discusses the design and timing of preclinical studies considered important for the development of anticancer AS ODN drugs based on our current experience. The issues discussed are similar to those previously outlined in our earlier publications that provide general guidance for preclinical development of AS ODNs (Black et al., 1993,1994). This discussion focuses on those issues in the context of oncolytic drug development.
