Toxicology of antisense therapeutics.
Targeting unique mRNA molecules using antisense approaches, based on sequence specificity of double-stranded nucleic acid interactions should, in theory, allow for design of drugs with high specificity for intended targets. Antisense-induced degradation or inhibition of translation of a target mRNA is potentially capable of inhibiting the expression of any target protein. In fact, a large number of proteins of widely varied character have been successfully downregulated using an assortment of antisense-based approaches. The most prevalent approach has been to use antisense oligonucleotides (ASOs), which have progressed through the preclinical development stages including pharmacokinetics and toxicological studies. A small number of ASOs are currently in human clinical trials. These trials have highlighted several toxicities that are attributable to the chemical structure of the ASOs, and not to the particular ASO or target mRNA sequence. These include mild thrombocytopenia and hyperglycemia, activation of the complement and coagulation cascades, and hypotension. Dose-limiting toxicities have been related to hepatocellular degeneration leading to decreased levels of albumin and cholesterol. Despite these toxicities, which are generally mild and readily treatable with available standard medications, the clinical trials have clearly shown that ASOs can be safely administered to patients. Alternative chemistries of ASOs are also being pursued by many investigators to improve specificity and antisense efficacy and to reduce toxicity. In the design of ASOs for anticancer therapeutics in particular, the goal is often to enhance the cytotoxicity of traditional drugs toward cancer cells or to reduce the toxicity to normal cells to improve the therapeutic index of existing clinically relevant cancer chemotherapy drugs. We predict that use of antisense ASOs in combination with small molecule therapeutics against the target protein encoded by the antisense-targeted mRNA, or an alternate target in the same or a connected biological pathway, will likely be the most beneficial application of this emerging class of therapeutic agent.
Jason
Tracey L H
TL
Cancer Research Laboratories, London Regional Cancer Centre, London, Ontario, Canada N6A 4L6.
Koropatnick
James
J
Berg
Randal W
RW
D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods; D019254:Genes, bcl-2 / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008668:Metallothionein / Q000502:physiology / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy*; D016376:Oligonucleotides, Antisense / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D012173:Retinitis / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013873:Thionucleotides / Q000009:adverse effects; D014018:Tissue Distribution
D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D008668:Metallothionein; C091346:fomivirsen