Drugs

, Volume 57, Issue 3, pp 293–308 | Cite as

Chemoprotectants

A Review of their Clinical Pharmacology and Therapeutic Efficacy
Review Article

Abstract

Dose-limiting toxicity secondary to antineoplastic chemotherapy is due to the inability of cytotoxic drugs to differentiate between normal and malignant cells. The consequences of this may include impairment of patient quality of life, because of toxicity, and reduced tumour control because of the inability to deliver adequate dose-intensive therapy against the cancer. Specific examples of toxicity against normal tissues include cisplatin-related neurotoxicity and nephrotoxicity, myelotoxicity secondary to treatment with alkylating agents and carboplatin, oxazaphosphorine-induced haemorrhagic cystitis, and cumulative dose-related cardiac toxicity secondary to anthracycline treatment.

Chemoprotectants have been developed as a means of ameliorating the toxicity associated with cytotoxic agents by providing site-specific protection for normal tissues, without compromising antitumour efficacy. Clinical trials with toxicity protectors must include sufficient dose-limiting events for study, and assessment of both toxicity (allowing for measurement of efficacy of protection) and antitumour effect. Several chemoprotective compounds have now been extensively investigated, including dexrazoxane, amifostine, glutathione, mesna and ORG 2766.

Dexrazoxane appears to complex with metal co-factors including iron, to reduce the incidence of anthracycline-induced cardiotoxicity, allowing the delivery of higher cumulative doses of anthracyclines without the expected consequence of cardiomyopathy. Numerous studies have demonstrated that sulfur-containing nucleophiles, including amifostine, glutathione, and mesna can specifically bind cisplatin- or alkylating agent—generated free radicals or alkylating agent metabolites to reduce the incidence of cisplatin-associated neurotoxicity and nephrotoxicity, or alkylating agent-associated myelosuppression and urothelial toxicity. These studies, in the majority of instances, have not revealed any evidence of reduction in antitumour efficacy.

Further randomised trials are required to identify the optimal role of chemo-protectants when used alone or in combination with other toxicity modifiers including haemopoietic growth factors.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Teicher BA. Antitumour alkylating ageents. In: De Vita VT, Hellman S, Rosenberg S, editors. Cancer: principles and practices of oncology. Philadelphia (PA): Lippincott-Raven, 1997: 405–18Google Scholar
  2. 2.
    Nagai N, Hotta K, Yamamura H, et al. Effects of sodium thiosulfate on the pharmacokinetics of unchanged cisplatin and on the distribution of platinum species in the rat kidney: protective effects against cisplatin nephrotoxicity. Cancer Chemother Pharmacol 1995; 36(5): 404–10PubMedCrossRefGoogle Scholar
  3. 3.
    Capizzi RL. The preclinical basis for broad-spectrum selective cytoprotection of normal tissues from cytotoxic therapies by amifostine (ethyol). Eur J Cancer 1996; 32A (Suppl. 4): S5–16PubMedCrossRefGoogle Scholar
  4. 4.
    Yang JL, Fernandes DJ, Speicher L, et al. Biochemical determinants of the cytoprotective effect of amifostine [abstract]. Proc Am Assoc Cancer Res 1995; 36: 290Google Scholar
  5. 5.
    List A, Brasfield F, Heaton R, et al. Stimulation of haematopoiesis by amifostine in patients with myelodysplastic syndrome. Blood 1997; 90: 3364–9PubMedGoogle Scholar
  6. 6.
    Nagy B, Grdina DJ. Protective effects of 2-[(aminopropyl)-amino] ethanethiol against bleomycin and nitrogen mustard-induced mutagenicity in V79 cells. Int J Radiat Oncol Biol Phys 1986; 12: 1475–8PubMedCrossRefGoogle Scholar
  7. 7.
    Glick JH, Glover DJ, Weiler C, et al. Phase I controlled trials of WR-2721 and cyclophosphamide. Int J Radiat Oncol Biol Phys 1984; 10: 1777–80PubMedCrossRefGoogle Scholar
  8. 8.
    Glover D, Glick JH, Weiler C, et al. Phase I trials of WR-2721 and cisplatin. Int J Radiat Oncol Biol Phys 1984; 10: 1781–4PubMedCrossRefGoogle Scholar
  9. 9.
    Van der Vijgh WJF, Korst AEC. Amifostine (ethyol): pharmacokinetic and pharmacodynamic effects in vivo. Eur J Cancer 1996; 32A (Suppl. 4): s26–30PubMedCrossRefGoogle Scholar
  10. 10.
    Adamson PC, Balis FM, Belasco JE, et al. A phase I trial of amifostine (WR-2721) and melphalan in children with refractory cancer. Cancer Res 1995; 55: 4069–72PubMedGoogle Scholar
  11. 11.
    Schiller JH, Storer B, Berlin J, et al. Amifostine, cisplatin and vinblastine in metastatic non-small-cell lung cancer: a report of high response rates and prolonged survival. J Clin Oncol 1996; 14: 1913–21PubMedGoogle Scholar
  12. 12.
    Glover D, Glick JH, Weiler C, et al. WR-2721 and high dose cisplatin: an active combination in the treatment of metastatic melanoma. J Clin Oncol 1987; 5(4): 574–8PubMedGoogle Scholar
  13. 13.
    Kemp G, Rose P, Lurain J, et al. Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of randomized control trial in patients with advanced ovarian cancer. J Clin Oncol 1996; 14: 2101–12PubMedGoogle Scholar
  14. 14.
    Bukowski RM. Amifostine (ethyol): dosing, administration and patient management guidelines. Eur J Cancer 1996; 32A (Suppl. 4): S46–9PubMedCrossRefGoogle Scholar
  15. 15.
    Wadler S, Haynes H, Beitler JJ, et al. Management of hypocalcemic effects of WR2721 administered on a daily times five schedule with cisplatin and radiation therapy. J Clin Oncol 1993; 11(8): 1517–22PubMedGoogle Scholar
  16. 16.
    Glover D, Glick JH, Weiler C, et al. WR-2721 protects against the haematological toxicity of cyclophosphamide: a controlled phase II trial. J Clin Oncol 1986; 4: 584–8PubMedGoogle Scholar
  17. 17.
    Shpall E, Stemmer S, Hami L, et al. Amifostine (WR-2721) shortens the engraftment period of 4-hydroperoxycyclophosphamide — purged bone marrow in breast cancer patients receiving high dose chemotherapy with autologous bone marrow support. Blood 1994; 83: 3132–7PubMedGoogle Scholar
  18. 18.
    Poplin EA, Lorusso P, Lokich JJ, et al. Randomised clinical trial of mitomycin-C with or without pretreatment with WR-2721 in patients with advanced colorectal cancer. Cancer Chemother Pharmacol 1994; 33: 415–9PubMedCrossRefGoogle Scholar
  19. 19.
    Betticher DC, Anderson H, Ranson M, et al. Carboplatin combined with amifostine, a bone marrow protectant in the treatment of non-small cell lung cancer: a randomised phase II study. Br J Cancer 1995; 72: 1551–5PubMedCrossRefGoogle Scholar
  20. 20.
    Budd GT, Ganapathi R, Adelstein DJ, et al. Randomized trial of carboplatin plus amifostine versus carboplatin alone in patients with advanced solid tumours. Cancer 1997; 80: 1134–40PubMedCrossRefGoogle Scholar
  21. 21.
    Trissel LA, Martinez JF. Compatibility of amifostine with selected drugs during simulated Y-site administration. Am J Health Syst Pharm 1995; 52(10): 2208–12PubMedGoogle Scholar
  22. 22.
    Pernkopf I, Tesch G, Dempe K, et al. Binding of epirubicin to human plasma proteins and red blood cells — in vitro interaction with the cytoprotectant amifostine. Pharmazie 1996; 51(11): 897–901PubMedGoogle Scholar
  23. 23.
    Elakawi Z, Zdanowics J, Creaven PJ, et al. Induction to gamma glutamyl transpeptidase mRNA by platinum complexes in a human ovarian carcinoma cell line. Oncol Res 1996; 8(10-11): 415–23Google Scholar
  24. 24.
    Zunino F, Pratesi G, Micheloni A, et al. Protective effect of reduced glutathione against cisplatin induced renal and systemic toxicity and its influence on the therapeutic activity of the antitumour drug. Chem Biol Interact 1989; 70: 89–101PubMedCrossRefGoogle Scholar
  25. 25.
    Tedeschi M, De Cesare A, Oriana S, et al. The role of glutathione in combination with cisplatin in the treatment of ovarian cancer. Cancer Treat Rev 1991; 18: 253–9PubMedCrossRefGoogle Scholar
  26. 26.
    Perego P, Paolicchi A, Tongiani R, et al. The cell specific anti-proliferative effect of reduced glutathione is mediated by gamma-glutamyl transpeptidase-dependent extracellular pro-oxidant reactions. Int J Cancer 1997; 71: 246–50PubMedCrossRefGoogle Scholar
  27. 27.
    Hamers FPT, Braklee JH, Cavaletti E, et al. Reduced glutathione protects against cisplatin-induced neurotoxicity in rats. Cancer Res 1993; 53: 544–9PubMedGoogle Scholar
  28. 28.
    Cavaletti G, Minoia C, Schieppati M, et al. Protective effects of glutathione on cisplatin neurotoxicity in rats. Int J Radiat Oncol Biol Phys 1994; 29(4): 771–6PubMedCrossRefGoogle Scholar
  29. 29.
    Leone R, Fracasso ME, Soresi E, et al. Influence of glutathione administration on the disposition of free and total platinum in patients after administration of cisplatin. Cancer Chemother Pharmacol 1992; 29: 385–90PubMedCrossRefGoogle Scholar
  30. 30.
    Di Re F, Bohm S, Oriana S, et al. High-dose cisplatin and cyclophosphamide with glutathione in the treatment of advanced ovarian cancer. Ann Oncol 1993; 4: 55–61PubMedGoogle Scholar
  31. 31.
    Fontanelli R, Spatti G, Raspagliesi F, et al. A preoperative single course of high dose cisplatin and bleomycin with glutathione protection in bulky stage IB/II carcinoma of the cervix. Ann Oncol 1992; 3: 117–21PubMedGoogle Scholar
  32. 32.
    Parnis FX, Coleman RE, Harper PG, et al. Arandomised double blind placebo controlled clinical trial assessing the tolerability and efficacy of glutathione as an adjuvant to escalating doses of cisplatin in the treatment of advanced ovarian cancer. Eur J Cancer 1995; 31A: 1721PubMedCrossRefGoogle Scholar
  33. 33.
    Bogliun G, Marzorati L, Marzola M, et al. Neurotoxicity of cisplatin +/− reduced glutathione in the first line treatment of advanced ovarian cancer. Int J Gynaecol Cancer 1996; 6: 415–9CrossRefGoogle Scholar
  34. 34.
    Colombo N, Bini S, Micelli D, et al. Weekly cisplatin +/− glutathione in relapsed ovarian carcinoma. Int J Gynaecol Cancer 1995; 5: 81–6CrossRefGoogle Scholar
  35. 35.
    Cascinu S, Cordella L, Del Ferro E, et al. Neuroprotective effect of reduced glutathione on cisplatin-bound chemotherapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 1995; 13(1): 26–32PubMedGoogle Scholar
  36. 36.
    De Konig P, Brakkee JH, Gispen WH. Methods for producing a reproducible crush injury in the sciatic and tibial nerve of the rat and rapid and precise testing of return of sensory function: beneficial effects of melanocortins. J Neurol Sci 1986; 74: 237–46CrossRefGoogle Scholar
  37. 37.
    Van der Hoop RG, Hamers FPT, Neijt JP, et al. Protection against cisplatin induced neurotoxicity by ORG 2766: histological and electrophysiological evidence. J Neurol Sci 1994; 126: 109–15CrossRefGoogle Scholar
  38. 38.
    Hamers FPT, Pette C, Neijt JP, et al. The ACTH(4–9) analog, ORG 2766, prevents taxol-induced neuropathy in rats. Eur J Pharmacol 1993; 233: 177–8PubMedCrossRefGoogle Scholar
  39. 39.
    Gerritsen van der Hoop R, Vecht CJ, van der Burg MEL, et al. Prevention of cisplatin neurotoxicity with an ACTH(4–9) analogue in patients with ovarian cancer. N Engl J Med 1990; 322: 89–94CrossRefGoogle Scholar
  40. 40.
    van Gerven JMA, Hovestadt A, Moll JWB, et al. The effects of ACTH (4–9) analogue on development of cisplatin neuropathy in testicular cancer: a randomized trial. J Neurol 1994; 241: 432–5PubMedCrossRefGoogle Scholar
  41. 41.
    Hovestadt A, van ber Burg ME, Verbiest HB, et al. The course of neuropathy after cessation of cisplatin treatment combined with ORG-2766 or placebo. J Neurol 1992; 239: 143–6PubMedCrossRefGoogle Scholar
  42. 42.
    Roberts JA, Jenison EL, Kim K, et al. A randomized multicenter, double-blind, placebo-controlled, dose-finding study of ORG-2766 in the prevention or delay of cisplatin-induced neuropathies in women with ovarian cancer. Gynecol Oncol 1997; 67: 172–7PubMedCrossRefGoogle Scholar
  43. 43.
    Young RC, Ozols RF, Myers CE. The anthracycline antineoplastic drugs. N Engl J Med 1981; 305: 139–53PubMedCrossRefGoogle Scholar
  44. 44.
    Pigram WJ, Fuller W, Amilton LDH. Stereochemistry of intercalations: interaction of daunomycin with DNA. Nature 1972; 235: 17–9CrossRefGoogle Scholar
  45. 45.
    Twewy KM, Rowe TC, Yang L, et al. Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science 1984; 226: 466–8CrossRefGoogle Scholar
  46. 46.
    Lenaz L, Page JA. Cardiotoxicity of adriamycin and related anthracyclines. Cancer Treat Rev 1976; 3: 111–20PubMedCrossRefGoogle Scholar
  47. 47.
    Von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979; 91: 710–7Google Scholar
  48. 48.
    Lipshultz SE, Colan SD, Gelber RD, et al. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 1991; 324: 808–15PubMedCrossRefGoogle Scholar
  49. 49.
    Steinherz LJ, Steinherz PG, Tan CT, et al. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 1991; 266: 1672–7PubMedCrossRefGoogle Scholar
  50. 50.
    Davies KJ, Doroshow JH. Redox cycling of anthracyclines by cardiac mitochondria: anthracycline radical formation by NADPH dehydrogenase. J Biol Chem 1986; 261: 3060–7PubMedGoogle Scholar
  51. 51.
    Bachur NR, Gordon SL, Gee MV. A general mechanism for microsomal activation of quinone anticancer agents to free radicals. Cancer Res 1978; 38: 1745–50PubMedGoogle Scholar
  52. 52.
    Goodman J, Hochstein P. Generation of free radicals and lipid peroxidation by redox cycling of Adriamycin and daunomycin. Biochem Biophys Res Commun 1977; 7: 797–803CrossRefGoogle Scholar
  53. 53.
    Doroshow JH, Locker GY, Baldinger J, et al. The effect of doxorubicin on hepatic and cardiac glutathione. Res Commun Chem Pathol Pharmacol 1979; 36: 285–95Google Scholar
  54. 54.
    Myers CE, Bonow R, Palmeri S, et al. A randomised controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine. Semin Oncol 1983; 10 Suppl. 1: 53–5PubMedGoogle Scholar
  55. 55.
    Legha S, Wang YM, Mackay B, et al. Clinical and pharmacological investigation of the effects of alpha-tocopherol on adriamycin cardiotoxicity. Ann N Y Acad Sci 1982; 393: 411–8PubMedCrossRefGoogle Scholar
  56. 56.
    Zweier JL, Gianni L, Muindi J, et al. Differences in O2 reduction by the iron complexes of adriamycin and daunomycin; the importance of the sidechain hydroxyl group. Biochem Biophys Acta 1986; 884: 326–36PubMedCrossRefGoogle Scholar
  57. 57.
    Sugioka KA, Nakano M. Mechanisms of phospholipid peroxidation induced by ferric iron-ADP adriamycin co-ordination complex. Biochem Biophys Acta 1982; 713: 333–43PubMedCrossRefGoogle Scholar
  58. 58.
    Herman EH, Mhatre R, Chadwick D. Modification of some of the toxic effects of daunomycin (NSC-82151) by pre-treatment with anti-neoplastic agents ICRF-159 (NSC-129943). Toxicol Appl Pharmacol 1974; 27: 517–26PubMedCrossRefGoogle Scholar
  59. 59.
    Herman EH, Witiak DT, Hellman K, et al. Biological properties of ICRF-159 and related bisdioxopiperazinecompounds. Adv Pharmacol Chemother 1985; 19: 249–301CrossRefGoogle Scholar
  60. 60.
    Wang G, Finch MD, Trevan D, et al. Reduction of daunomycin toxicity by razoxane. Br J Cancer 1981; 43: 871–7PubMedCrossRefGoogle Scholar
  61. 61.
    Yeung TK, Jaenke RS, Wilding D, et al. The protective activity of ICRF-187 against doxorubicin-induced cardiotoxicity in the rat. Cancer Chemother Pharmacol 1992; 30: 58–64PubMedCrossRefGoogle Scholar
  62. 62.
    Herman EH, Ferrans VJ. Pretreatment with ICRF-187 provides long-lasting protection against chronic daunorubicin cardiotoxicity in rabbits. Cancer Chemother Pharmacol 1986; 16: 102–6PubMedCrossRefGoogle Scholar
  63. 63.
    Liesman J, Belt R, Haas C, et al. Phase I evaluation of ICRF-187 in the treatment of patients with advanced malignancy. Cancer 1981; 47: 1959–62CrossRefGoogle Scholar
  64. 64.
    Von Hoff DD, Howser D, Lewis BJ, et al. Phase I study of ICRF-187 using a daily for 3 days schedule. Cancer Treat Rep 1981; 65: 249–52Google Scholar
  65. 65.
    Speyer JL, Green MD, Kramer E, et al. Protective effects of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. N Engl J Med 1988; 319: 745–52PubMedCrossRefGoogle Scholar
  66. 66.
    Speyer JL, Green MD, Zeleniuch-Jacquotte A, et al. ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol 1992; 10: 117–27PubMedGoogle Scholar
  67. 67.
    ten Bokkel-Huinink WW, Schreuder JE, Dubbleman R, et al. ICRF-187 protects against doxorubicin induced cardiomyopathy [abstract]. Ann Oncol 1992; 3 Suppl 1: A221Google Scholar
  68. 68.
    Weisberg SR, Rosenfeld CS, York RM, et al. Dexrazoxane (ADR 529, ICRF-187, Zinecard) protects against doxorubicin-induced chronic cardiotoxicity. Proc Am Soc Clin Oncol 1992; 11: 190Google Scholar
  69. 69.
    Swain SM, Whaley FS, Gerber MC, et al. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 1997; 15: 1318–32PubMedGoogle Scholar
  70. 70.
    Venturini M, Michelotti A, Del Mastro L, et al. Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer. J Clin Oncol 1996; 14: 3112–20PubMedGoogle Scholar
  71. 71.
    Feldman JE, Jones SE, Weisberg SR, et al. Advanced small cell lung cancer treated with CAV chemotherapy and cardioprotective agent dexrazoxane (ADR-529, ICRF-187, Zinecard). Proc Am Soc Clin Oncol 1992; 11: 993Google Scholar
  72. 72.
    Wexler LH, Andrich MP, Venzon D, et al. Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin. J Clin Oncol 1996; 14: 362–72PubMedGoogle Scholar
  73. 73.
    Swain SM, Whaley FS, Gerber MC, et al. Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. J Clin Oncol 1997; 15: 1333–40PubMedGoogle Scholar
  74. 74.
    Hochster H, Liabes L, Wadler S, et al. Pharmacokinetics of the cardioprotector ADR-529 (ICRF-187) in escalating doses combined with fixed dose doxorubicin. J Natl Cancer Inst 1992; 84: 1725–30PubMedCrossRefGoogle Scholar
  75. 75.
    Basser RL, Sobol MM, Duggan G, et al. Comparative study of the pharmacokinetics and toxicity of high-dose epirubicin with or without dexrazoxane in patients with advanced malignancy. J Clin Oncol 1994; 12: 1659–66PubMedGoogle Scholar
  76. 76.
    Bryant BM, Jarman M, Ford HT. Prevention of ifosphosphamide-induced urothelial toxicity with 2-mercaptoethane sulphonate sodium (mesnum) in patients with advanced carcinoma. Lancet 1980; II: 657–9CrossRefGoogle Scholar
  77. 77.
    Cox PJ. Cyclophosphamide cystitis: identification of acrolein as the causative agent. Biochem Pharmacol 1979; 28: 2045–9PubMedCrossRefGoogle Scholar
  78. 78.
    Fleming RA, Cruz JM, Webb CD, et al. Urinary elimination of cyclophosphamide alkylating metabolites and free thiols following two administration schedules of high-dose cyclophosphamide and mesna. Bone Marrow Transplant 1996; 17: 497–501PubMedGoogle Scholar
  79. 79.
    Brock N, Pohl J, Stekar J, et al. Studies on the urotoxicity of oxazaphosphorine cystostatics and its prevention —III: profile of action of sodium 2-mercaptoethane sulfonate (Mesna). Eur J Cancer Clin Oncol 1982; 18: 1377–87PubMedCrossRefGoogle Scholar
  80. 80.
    Scheef W, Klein HO, Brock N, et al. Controlled clinical studies with an antidote against the urotoxicity of oxazaphosphorines: preliminary results. Cancer Treat Rep 1979; 63: 501–5PubMedGoogle Scholar
  81. 81.
    Fukuoka M, Negoro S, Masuda N, et al. Placebo-controlled double-blind comparative study on the preventive efficacy of mesna against ifosfamide-induced urinary disorders. J Cancer Res Clin Oncol 1991; 117: 473–8PubMedCrossRefGoogle Scholar
  82. 82.
    Vose JM, Reed EC, Pippert GC, et al. Mesna compared with continuous bladder irrigation as uroprotection during high dose chemotherapy and transplantation: a randomized trial. J Clin Oncol 1993; 11: 1306–10PubMedGoogle Scholar
  83. 83.
    Munshi NC, Loehrer Sr PJ, Williams SD, et al. Comparison of N-acetylcysteine and mesna as uroprotectors with ifosfamide combination chemotherapy in refractory germ cell tumours. Invest New Drugs 1992; 10: 159–63PubMedCrossRefGoogle Scholar
  84. 84.
    Legha S, Papadopoulos N, Plager C, et al. A comparative evaluation of the uroprotective effect of mercaptoethane sulfonate (mesna) and N-acetylcysteine (NAC) in sarcoma patients treated with ifosfamide. Proc Am Soc Clin Oncol 1990; 9: 1205Google Scholar
  85. 85.
    Pohl VJ, Brock N, Schneider B, et al. Zur Pharmakokinetik von uromitexan. Methods Find Exp Clin Pharmacol 1981; 3 Suppl. 1: 95–101Google Scholar
  86. 86.
    Burkert H. Clinical overview of mesna. Cancer Treat Rev 1983; 10: 175–81PubMedCrossRefGoogle Scholar
  87. 87.
    Burkert H, Lucker PW, Wetzelsberger N, et al. Bioavailability of orally administered mesna. Arzneimittel Forschung 1984; 34: 1597–600PubMedGoogle Scholar
  88. 88.
    Katz A, Epelman S, Anelli A, et al. A prospective randomized evaluation of three schedules of mesna administration in patients receiving an ifosfamide-containing chemotherapy regimen: sustained efficacy and simplified administration. J Cancer Res Clin Oncol 1995; 121: 128–31PubMedCrossRefGoogle Scholar
  89. 89.
    Dorr RT. Chemoprotectants for cancer chemotherapy. Semin Oncol 1991; 18 Suppl. 2: 48–58PubMedGoogle Scholar
  90. 90.
    Goren MR Oral administration of mesna with ifosfamide. Semin Oncol 1996; 23 Suppl. 6: 91–6PubMedGoogle Scholar
  91. 91.
    Cerny T, Graf A, Rohner P, et al. Subcutaneous continuous infusion of ifosfamide and cyclophosphamide in ambulatory cancer patients: bioavailability and feasibility. J Cancer Res Clin Oncol 1991; 117 Suppl. 4: 129–34CrossRefGoogle Scholar
  92. 92.
    Markman M, Kennedy A, Webster K, et al. Continuous subcutaneous administration of mesna to prevent ifosfamide-induced haemorrhagic cystitis. Semin Oncol 1996; 23 Suppl. 6: 97–8PubMedGoogle Scholar
  93. 93.
    Benyoussef IC, Bottlaender A, Pfister HR, et al. Allergic contact dermatitis from mesna. Contact Dermatitis 1996; 34: 228–9PubMedCrossRefGoogle Scholar
  94. 94.
    Reinhold-Keller E, Mohr J, Christophers E, et al. Mesna side-effects which imitate vasculitis. Clin Invest 1992; 70: 698–704CrossRefGoogle Scholar

Copyright information

© Adis International Limited 1999

Authors and Affiliations

  1. 1.Department of Medical OncologyPrince of Wales HospitalRandwickAustralia

Personalised recommendations