Drugs that show protective effects from ricin toxicity in in vitro protein synthesis assays.
We used an in-vitro, inhibition of protein synthesis assay (PSI) to test a wide variety of drugs for possible therapeutic use against ricin, a toxic glycoprotein that causes death in animals by inhibiting protein synthesis. Selection of test drugs was based on possible interference with ricin activity at different stages of the toxic process. Most of the drugs tested had no effect on ricin-induced PSI, were toxic when tested alone, or enhanced the toxicity of ricin. The only ones showing protection were galactose, lactose, and several derivatives of these sugars, Brefeldin A (BFA), 3'-azido-3'-deoxythymidine (AZT), and a purine derivative (BM33203). THe sugar derivatives provided 50% protection against a PSI ED99 of ricin (0.1 micrograms/ml). Concentrations of BFA greater than 0.5 micro M caused about 50% PSI by itself, but blocked any further inhibitory effects of ricin. AZT, at optimum concentrations, reached a maximum protection level of about 40% in the presence of an ED99 dose of ricin, while the nucleoside derivative, BM33203 and AZT appeared to have an additive effect, showing up to 80% protection from an ED99 dose of ricin. Drugs showing protection in the PSI cell assay showed no protection from ricin in a cell-free translation assay used to determine if they would block ricin at the protein synthesis site.
Thompson
W L
WL
Toxicology Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702-5011, USA.
Scovill
J P
JP
Pace
J G
JG
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D020126:Brefeldin A; D002240:Carbohydrate Sequence; D002522:Chlorocebus aethiops; D003517:Cyclopentanes / Q000494:pharmacology; D004357:Drug Synergism; D005690:Galactose / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007785:Lactose / Q000494:pharmacology; D008969:Molecular Sequence Data; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D012156:Reticulocytes / Q000166:cytology / Q000187:drug effects; D012276:Ricin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014709:Vero Cells / Q000166:cytology / Q000187:drug effects*; D015215:Zidovudine / Q000494:pharmacology
D000963:Antimetabolites; C098167:BM 33203; D003517:Cyclopentanes; D007093:Imidazoles; D011500:Protein Synthesis Inhibitors; D020126:Brefeldin A; D015215:Zidovudine; D012276:Ricin; D007785:Lactose; D005690:Galactose