Skip to main content

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

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.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    Anderson EE, Cobb OE, Glenn JF (1967) Cyclophosphamide hemorrhagic cystitis. J Urol 97: 857

    Google Scholar 

  2. 2.

    Arrick BA, Nathan CF (1984) Glutathione metabolism as a determinant of therapeutic efficacy: a review. Cancer Res 44: 4224

    Google Scholar 

  3. 3.

    Brock N, Pohl J, Stekar J (1981) Studies on the urotoxicity of oxazaphosphorine cytostatics and its prevention: I. Experimental studies on the urotoxicity of alkylating compounds. Eur J Cancer Clin Oncol 17: 595

    Google Scholar 

  4. 4.

    Brock N, Pohl J, Stekar J (1981) Studies on the urotoxicity of oxazaphosphorine cytostatics and its prevention: II. Comparative study on the uroprotective efficacy of thiols and other sulfur compounds. Eur J Cancer Clin Oncol 17: 1155

    Google Scholar 

  5. 5.

    Brock N, Pohl J, Stekar J, Scheef W (1982) Studies on the urotoxicity of oxazaphosphorine cytostatics and its prevention: III. Profile of action of sodium 2-mercaptoethane sulfonate (mesna). Eur J Cancer Clin Oncol 18: 1377

    Google Scholar 

  6. 6.

    Brock N, Hilgard P, Pohl J, Ormstadt K, Orrenius S (1984) Pharmacokintics and mechanism of action of detoxifying low-molecular-weight thiols. J Cancer Res Clin Oncol 108: 87

    Google Scholar 

  7. 7.

    Carter SK (1972) Single and combination nonhormonal chemotherapy in breast cancer. Cancer 30: 1543

    Google Scholar 

  8. 8.

    Cavalletti E, Tofanetti O, Zunino F (1986) Comparison of reduced glutathione with 2-mercaptoethane sulfonate to prevent cyclophosphamide-induced urotoxicity. Cancer Lett 32: 1

    Google Scholar 

  9. 9.

    Cooper JAD, Merrill WW (1989) Modulation of endoperoxide product levels and cyclophosphamide-induced injury by glutathione repletion. J Appl Physiol 67: 2316

    Google Scholar 

  10. 10.

    Glatt H, Oesch F (1985) Mutagenicity of cysteine and penicillamine and its enantiomeric selectivity. Biochem Pharmacol 34: 3725

    Google Scholar 

  11. 11.

    Glatt H, Protic-Samljic M, Oesch F (1983) Mutagenicity of glutathione and cysteine in the Ames test. Science 220: 961

    Google Scholar 

  12. 12.

    Gurtoo HL, Hipkins JH, Sharma SD (1981) Role of glutathione in the metabolism-dependent toxicity and chemotherapy of cyclophosphamide. Cancer Res 41: 3584

    Google Scholar 

  13. 13.

    Hacker MP, Ershler WB, Newman RA, Gamelli RL (1982) Effect of disulfiram (tetraethylthiuram disulfide) and diethyl dithiocarbamate on the bladder toxicity and antitumor activity of cyclophosphamide in mice. Cancer Res 42: 4490

    Google Scholar 

  14. 14.

    Heyn RM, Hollan R, Newton WA, Tefft M, Breslow N, Hartmann JR (1974) The role of combined chemotherapy in the treatment of rhabdomyosarcoma in children. Cancer 34: 2128

    Google Scholar 

  15. 15.

    Ishikawa M, Sasaki K-I, Takahanagi Y (1989) Injurious effect of buthionine sulfoximine, an inhibitor of glutathione biosynthesis, on the lethality and urotoxicity of cyclophosphamide in mice. Jpn J Pharmacol 51: 146

    Google Scholar 

  16. 16.

    Johnston RE, Hawkins HC, Weikel JH (1983) The toxicity ofN-acetylcysteine in laboratory animals. Semin Oncol 10: 17

    Google Scholar 

  17. 17.

    Karlson RL, Grofova I, Malthe-Sorenssen D, Fonnum F (1981) Morphological changes in rat brain induced byL-cysteine injection in newborn animals. Brain Res 208: 167

    Google Scholar 

  18. 18.

    Lang E, Goos M (1985) Hypersensitivity to mesna. Lancet II: 329

    Google Scholar 

  19. 19.

    Livingston RB, Carter SK (eds) (1970) Cyclophosphamide. In: Single agents in cancer chemotherapy. Plenum Press, New York, p 28

    Google Scholar 

  20. 20.

    Loehrer PJ, Williams SD, Einhorn LH (1983)N-Acetylcysteine and ifosfamide in the treatment of unresectable pancreatic adenocarcinoma and refractory texticular cancer. Semin Oncol 10: 72

    Google Scholar 

  21. 21.

    Meanwell CA, Blake AE, Kelly KA, Honigsberger L, Blackledge G (1986) Prediction of ifosfamide/mesna-associated encephalopathy. Eur J Cancer Clin Oncol 22: 815

    Google Scholar 

  22. 22.

    Miller LF, Rumack BH (1983) Clinical safety of high oral doses of acetylcysteine. Semin Oncol 10: 76

    Google Scholar 

  23. 23.

    Myers C, Bonow R, Palmeri S, Jenkins J, Corden B, Locker G, Doroshow J, Epstein S (1983) A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy byN-acetylcysteine. Semin Oncol 10: 53

    Google Scholar 

  24. 24.

    Ohno Y, Ormstad K (1985) Formation, toxicity and inactivation of acrolein during biotransformation of cyclophosphamide as studied in freshly isolated cells from rat liver and kidney. Arch Toxicol 57: 99

    Google Scholar 

  25. 25.

    Pohl J, Stekar J, Hilgard P (1989) Chloroacetaldehyde and its contribution to urotoxicity during treatment with cyclophosphamide or ifosfamide. Arzneimittelforschung 39: 704

    Google Scholar 

  26. 26.

    Roberts JC, Nagasawa HT, Zera RT, Fricke RF, Goon DJW (1987) Prodrugs ofL-cysteine as protective agents against acetaminophen-induced hepatotoxicity. 2-(Polyhydroxyalkyl)- and 2-(polyacetoxyalkyl)thiazolidine-4 (R)-carboxylic acids. J Med Chem 30: 1891

    Google Scholar 

  27. 27.

    Santos GW, Sensenbrenner LL, Anderson PN, Burke PJ, Klein DL, Slavin RE, Schacter B, Borgaonkar DS (1976) HL-A-identical marrow transplants in aplastic anemia, acute leukemia, and lymphosarcoma employing cyclophosphamide. Transplant Proc 8: 607

    Google Scholar 

  28. 28.

    Seitz DE, Katterjohn CJ, Rinzel SM, Pearce HL (1989) Thermodynamic analysis of the reaction of phosphoramide mustard with protector thiols. Cancer Res 49: 3525

    Google Scholar 

  29. 29.

    Sheffner AL (1963) The reduction in vitro in viscosity of mucoprotein solutions by a new mucolytic agent:N-acetyl-L-cysteine. Ann NY Acad Sci 106: 298

    Google Scholar 

  30. 30.

    Slavik M, Saiers JH (1983) Phase I clinical study of acetylcysteine's preventing ifosfamide-induced hematuria. Semin Oncol 10: 62

    Google Scholar 

  31. 31.

    Stekar J, Hilgard P, Holtei W, Riemer U (1990) Protection from ifosfamide-induced alopecia by topical thiols in young rats. Cancer Chemother Pharmacol 25: 306

    Google Scholar 

  32. 32.

    Teicher BA, Crawford JM, Holden SA, Lin Y, Cathcart KNS, Luchette CA, Flatow J (1988) Glutathione monoethyl ester can selectively protect liver from high-dose BCNU or cyclophosphamide. Cancer 62: 1275

    Google Scholar 

  33. 33.

    Tietz F (1969) Enzymatic method for quantitative determination of nanogram amounts of total and oxidized glutathione. Application to mammalian blood and other tissues. Anal Biochem 27: 502

    Google Scholar 

  34. 34.

    Tofanetti O, Cavalletti E, Besati A, Pratesi G, Pezzoni G, Zunino F (1985) Prevention of cyclophosphamide-induced urotoxicity by reduced glutathione and its effect on acute toxicity and antitumor activity of the alkylating agent. Cancer Chemother Pharmacol 14: 188

    Google Scholar 

  35. 35.

    Wagner T, Zink W, Schwieder G (1987) Influence of mesna and cysteine on the systematic toxicity and therapeutic efficacy of activated cyclophosphamide. J Cancer Res Clin Oncol 113: 160

    Google Scholar 

  36. 36.

    Zinke H, Woods JE (1977) Donor pretreatment in cadaver renal transplantation. Surg Gynecol Obstet 145: 183

    Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Jeanette C. Roberts.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Roberts, J.C., Francetic, D.J. & Zera, R.T. L-Cysteine prodrug protects against cyclophosphamide urotoxicity without compromising therapeutic activity. Cancer Chemother. Pharmacol. 28, 166–170 (1991). https://doi.org/10.1007/BF00685504

Download citation

Keywords

  • Leukemia
  • Glutathione
  • Cyclophosphamide
  • Carboxylic Acid
  • Sulfhydryl