L-cysteine prodrug protects against cyclophosphamide urotoxicity without compromising therapeutic activity.
2(R,S)-D-ribo-(1',2',3',4'-Tetrahydroxybutyl)-thiazolidine-4(R)-ca rboxylic acid (RibCys) is a prodrug of L-cysteine that releases the sulfhydryl amino acid after nonenzymatic ring opening and hydrolysis. The L-cysteine then elevates glutathione (GSH) levels by stimulating its biosynthesis. RibCys was investigated for its ability to protect CDF1 mice from the potent urotoxicity of cyclophosphamide (CTX) without compromising the therapeutic utility of the drug. RibCys induced a significant reduction in weight loss of the animals and in bladder inflammation at 48 h after CTX administration; however, bladder tissue remained inflamed as compared with that in controls. Bladder histology also showed some pathological changes in the presence of RibCys. In contrast, all parameters of toxicity (body weight loss, bladder inflammation, and pathological abnormalities) had been virtually reversed by day 21 after administration. In tests against L1210 leukemia, RibCys did not interfere with CTX anticancer activity. From these preliminary studies, RibCys appears to be a likely candidate for protecting against long-term CTX toxicity, perhaps reversing the original damage caused by a very high dose, without compromising the therapeutic utility of the alkylating agent.
Roberts
J C
JC
Department of Medicinal Chemistry, University of Utah, Salt Lake City 84112.
Francetic
D J
DJ
Zera
R T
RT
D000818:Animals; D003520:Cyclophosphamide / Q000627:therapeutic use / Q000633:toxicity*; D003545:Cysteine / Q000494:pharmacology* / Q000627:therapeutic use / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D007939:Leukemia L1210 / Q000188:drug therapy; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000494:pharmacology* / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D053778:Thiazolidines; D013997:Time Factors; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D011355:Prodrugs; D013844:Thiazoles; D053778:Thiazolidines; C070066:2-(1',2',3',4'-tetrahydroxybutyl)thiazolidine-4-carboxylic acid; D003520:Cyclophosphamide; D005978:Glutathione; D003545:Cysteine