Structural requirements of endotoxic glycolipid for antitumor and toxic activity.
Endotoxic glycolipids extracted from the polysaccharide heptose-less Re mutant of Salmonella typhimurium were hydrolyzed with alkaline and acid reagents. Treatment with hydroxylamine caused the liberation of all O-ester linked fatty acids and resulted in abrogation of the toxicity (lethality to chick embryos) and ability to regress tumors (line-10 tumors in strain 2 guinea pigs). Treatment with dilute sodium hydroxide caused partial removal of O-ester linked fatty acids without loss of these activities. Toxicity and tumor-regressive potency were retained after removal of 2-keto-3-deoxyoctonate (KDO) by exposing the glycolipids to sodium acetate solution at pH 4.5. The majority of the glycolipids of the endotoxic extracts were rendered non-toxic but retained antitumor activity when hydrolyzed with boiling 0.1 N hydrochloric acid, which split KDO and glycosidic phosphate from the glycolipid molecules. Non-toxic glycolipid fractions possessing antitumor activity were separated from the acid hydrolysate by means of preparative thin layer chromatography. It was concluded that glycosidic bound phosphate and at least a portion of the fatty acids of the lipid A moiety are essential for toxicity, but that this phosphate is not an essential structural feature for tumor-regression activity.
D000818:Animals; D000970:Antineoplastic Agents / Q000032:analysis*; D002642:Chick Embryo; D002855:Chromatography, Thin Layer; D004731:Endotoxins / Q000032:analysis* / Q000627:therapeutic use; D006017:Glycolipids / Q000032:analysis*; D006168:Guinea Pigs; D007928:Lethal Dose 50; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy; D012486:Salmonella typhimurium / Q000032:analysis*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004731:Endotoxins; D006017:Glycolipids