ABSTRACT

"A drug may be broadly defined as any chemical agent which affects living protoplasm..." (Goodman and Oilman, 1941). This long held opinion is now truly expanded by the use of synthetic DNA and biological vectors. The pharmacological understanding of oligonucleotides with molecular masses between 5,000 and 10,000 grams/mole is limited to the past 10 to 20 years. This limited history is the basis for controversy regarding the most appropriate therapeutic uses, the selection of appropriate expressed target genes, the mechanism of action, toxicity, and efficient methods of detection. The justification for progression to clinical trials with the antisense p53 phosphorothioate oligonucleotide included reproducible efficacy demonstrated with patient samples, favorable pharmacokinetics, and minimal toxicity in mice, rats, and monkeys. These favorable pharmacological properties were simultaneous with the ability to prepare multiple gram quantities of pure and highly characterized phosphorothioate oligodeoxynucleotides.