Cancer Chemotherapy and Pharmacology

, Volume 28, Issue 3, pp 166–170 | Cite as

L-Cysteine prodrug protects against cyclophosphamide urotoxicity without compromising therapeutic activity

  • Jeanette C. Roberts
  • David J. Francetic
  • Richard T. Zera
Original Articles L-Cysteine, Glutathione, Thiazolidine, Cyclophosphamide, Urotoxicity

Summary

2(R,S)-d-ribo-(1′,2′,3′,4′-Tetrahydroxybutyl)-thiazolidine-4(R)-carboxylic acid (RibCys) is a prodrug ofL-cysteine that releases the sulfhydryl amino acid after monenzymatic ring opening and hydrolysis. TheL-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 1210 leukemia, RibCys did not interfere with CTX anti-cancer 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.

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Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • Jeanette C. Roberts
    • 1
  • David J. Francetic
    • 1
  • Richard T. Zera
    • 2
  1. 1.Department of Medicinal ChemistryUniversity of UtahSalt Lake CityUSA
  2. 2.Department of Surgical PathologyHennepin County Medical CenterMinneapolisUSA

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