title: Preclinical studies with Ampligen (mismatched double-stranded RNA).
abstract: Historically, double-stranded (ds) RNAs have been largely over-looked as potentially valuable anticancer/antiviral drugs, primarily because of the many clinical toxicities and lack of efficacy associated with the first clinically tested dsRNA--polyinosinic-polycytidylic acid (rIn X rCn). However, studies summarized herein demonstrate that the therapeutic ratio of dsRNAs can be greatly enhanced by purposeful mispairing of bases. For example, a mispaired dsRNA, termed Ampligen (rIn X r(C12,U)n), shows strong antitumor activity in a variety of relevant test systems with little or none of the toxicities associated with rIn X rCn. Furthermore, Ampligen demonstrates a much wider therapeutic spectrum than that displayed to date by any single type of interferon (natural or recombinant DNA-derived). Importantly, Ampligen, the product of a straight-forward enzymatic synthesis, shows excellent lot-to-lot biological and biophysical specifications, which is often not the case with biologically derived new compounds. Furthermore, a significant fraction of human solid tumors, which are largely unresponsive to conventional chemotherapy or interferon (IFN), is sensitive to Ampligen in a fresh human tumor clonogenic assay. Indeed, whereas 50% of untreated and IFN-treated athymic mice engrafted with human renal cancer cells die within 20-22 weeks, mice treated with Ampligen survive a minimum of 32 weeks (p less than 0.0003). A summary of all animal models tested and human clinical trials to date demonstrates that Ampligen exerts a greater antitumor activity than IFN and has a superior therapeutic ratio compared to rIn X rCn.
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011070:Poly I-C; D011072:Poly U; D011131:Polyribonucleotides / Q000627:therapeutic use / Q000633:toxicity*; D014183:Transplantation, Heterologous; D014410:Tumor Stem Cell Assay / Q000379:methods
chemical_list: D007370:Interferon Type I; D011131:Polyribonucleotides; D011072:Poly U; C047490:poly(I).poly(c12,U); D011070:Poly I-C