Drug Safety

, Volume 11, Issue 3, pp 153–162 | Cite as

A Review of the Use of Chemoprotectants in Cancer Chemotherapy

  • Craig Lewis
Review Articles Drug Experience


Dose-limiting toxicity secondary to antineoplastic chemotherapy is principally due to the inability of the drugs to differentiate between normal and malignant cells. This results in normal tissue damage, as well as the desired antitumour effect. Toxicity may be acute, as in cisplatin-induced nephrotoxicity or alkylating agent myelotoxicity and haemorrhagic cystitis, or cumulative, as in anthracyclinerelated cardiac toxicity or cisplatin neurotoxicity. The consequences of this often include serious adverse effects and the inability to deliver adequate dose-intensive therapy against the cancer.

Chemoprotective agents have been developed to provide site-specific protection against normal tissue toxicity, without compromising antitumour activity. Several chemoprotective compounds have recently been developed, including dexrazoxane (ICRF-187), amifostine (ethiofos; WR-2721), mesna and ORG-2766. Initial results confirm their promise as selective protective agents, although further randomised trials are required to identify their optimal role when used alone or in combination with other toxicity modifiers, including haematopoietic growth factors, with the ultimate aim being adequate dose escalation of chemotherapy to overcome tumour resistance.


Ifosfamide Amifostine Mesna Dexrazoxane Haemorrhagic Cystitis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Handa K, Sato S. Generation of free radicals of quinone group containing anti-cancer chemicals in NADPH-microsome system as evidenced by initiation of sulfite oxidation. Jpn J Cancer Res 1975; 66: 43–75Google Scholar
  2. 2.
    Pigram WJ, Fuller W, Amilton LDH. Stereochemistry of intercalation: interaction of daunomycin with DNA. Nature 1972; 235: 17–9CrossRefGoogle Scholar
  3. 3.
    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
  4. 4.
    Davies KJ, Doroshow JH. Redox cycling of anthracyclines by cardiac mitochondria I: antracycline radical formation by NADPH dehydrogenase. J Biol Chem 1986; 261: 3060–7PubMedGoogle Scholar
  5. 5.
    Bachur NR, Gordon SL, Gee MV. A general mechanism for microsomal activation of quinone anti-cancer agents to free radicals. Cancer Res 1978; 38: 1745–50PubMedGoogle Scholar
  6. 6.
    Thayer WS. Adriamycin stimulated superoxide formulation in submitochondrial particles. Chem Biol Interact 1977; 19: 265–78PubMedCrossRefGoogle Scholar
  7. 7.
    Combs AB, Acosta D. Toxic mechanisms of the heart: a review. Toxicol Pathol 1990; 18: 593–6Google Scholar
  8. 8.
    Doroshow JH, Locker GY, Baldinger J, et al. The effect of doxorubicin on hepatic and cardiac glutathione. Res Commun Chem Pathol Pharmacol 1979; 26: 285–95PubMedGoogle Scholar
  9. 9.
    Legha S, Wang YM, Mackay B, et al. Clinical and pharmacological investigation of the effects of alpha-tocopherol on adriamycin cardiotoxicity. Ann NY Acad Sci 1982; 393: 411–8PubMedCrossRefGoogle Scholar
  10. 10.
    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
  11. 11.
    Myers CE, Gianna L, Zweier J, et al. The role of iron in adriamycin biochemistry. Fed Proc 1986; 45: 2792–7PubMedGoogle Scholar
  12. 12.
    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
  13. 13.
    Herman EH, Mhatre R, Chadwick D. Modification of some of the toxic effects of daunomycin (NSC-82151) by pretreatment with anti-neoplastic agent ICRF-159 (NSC-129943). Toxicol Appl Pharmacol 1974; 27: 517–26PubMedCrossRefGoogle Scholar
  14. 14.
    Herman EH, Witiak DT, Hellman K, et al. Biological properties of ICRF-159 and related bisdioxopiperazine compounds. Adv Pharmacol Chemother 1985; 19: 249–301CrossRefGoogle Scholar
  15. 15.
    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
  16. 16.
    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
  17. 17.
    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
  18. 18.
    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
  19. 19.
    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
  20. 20.
    Liesmann J, Belt R, Haas C, et al. Phase I evaluation of ICRF-187 (NSC-169780) in patients with advanced malignancy. Cancer 1981; 47: 1959–62PubMedCrossRefGoogle Scholar
  21. 21.
    Coleman N, Bump E, Kramer R. Chemical modifiers of cancer treatment. J Clin Oncol 1988; 6: 709–33PubMedGoogle Scholar
  22. 22.
    Spencer CM, Goa KL. Amifostine: a review of its pharmacodynamic and phamocokinetic properties, and therapeutic potential as a radioprotective and cytotoxic chemoprotector. Drugs. In pressGoogle Scholar
  23. 23.
    Schuchter LM, Luginbuhl WE, Meropol NJ. The current status of toxicity protectants in cancer therapy. Semin Oncol 1992; 19: 742–51PubMedGoogle Scholar
  24. 24.
    Calabro-Jones P, Aguilera JA, Ward JF, et al. Uptake of WR-2721 derivatives by cells in culture: identification of the transported form of the drug. Cancer Res 1988; 48: 3634–40PubMedGoogle Scholar
  25. 25.
    Smoluk GD, Fahey RC, Calabro-Jones PM, et al. Radioprotection of cells in culture by WR-2721 and derivatives: form of the drug responsible for protection. Cancer Res 1988; 48: 3614–7Google Scholar
  26. 26.
    Yuhas JM. Active versus passive absorption kinetics as the basis for selective protection of normal tissues by S-2-(3-aminoprophylamino)-ethylphosphorothioic acid. Cancer Res 1980; 40: 1519–24PubMedGoogle Scholar
  27. 27.
    Tahsildar HI, Biaglow JE, Kligerman MM, et al. Factors influencing the oxidation of the radioprotector WR-1065. Radiat Res 1988; 113: 243–51PubMedCrossRefGoogle Scholar
  28. 28.
    Shaw L, Glover D, Turrisi A, et al. Pharmocokinetics of WR-2721. Pharmacol Ther 1988; 39: 195–201PubMedCrossRefGoogle Scholar
  29. 29.
    Glover D, Glick J, Weiler C, et al. Phase I trials of WR-2721 and cisplatinum. Int J Radiat Oncol Biol Phys 1984; 10: 1781–4PubMedCrossRefGoogle Scholar
  30. 30.
    Kligerman M, Glover D, Turrisi A, et al. Toxicity of WR-2721 administered in single and multiple doses. Int J Radiat Oncol Biol Phys 1984; 10: 1773–6PubMedCrossRefGoogle Scholar
  31. 31.
    Turrisi AT, Glover DJ, Hurwitz S, et al. Final report of the phase I trial of single dose WR-2721 S-2-(3-aminoprophylamino)-ethylphosphorothioic acid. Cancer Treat Rep 1986; 70: 1389–93PubMedGoogle Scholar
  32. 32.
    Glover D, Riley L, Carmichael K, et al. Hypocalcemia and inhibition of parathyroid hormone secretion after administration of WR-2721 (a radioprotective and chemoprotective agent). N Engl J Med 1983; 309: 1117–41CrossRefGoogle Scholar
  33. 33.
    Walder S, Haynes H, Butler JJ, et al. Management of hypocalcemic effects of WR-2721 administered on a daily times five schedule with cisplatin and radiation therapy. J Clin Oncol 1993; 11: 1517–22Google Scholar
  34. 34.
    Glover D, Grabelsky S, Fox K, et al. Clinical trial of WR-2721 and cisplatinum. Int J Radiat Oncol Biol Phys 1989; 16: 1201–4PubMedCrossRefGoogle Scholar
  35. 35.
    Mollman JE, Glover DJ, Hogan WM, et al. Cisplatin neuropathy: risk factors, prognosis and protection by WR-2721. Cancer 1988; 61: 2192–5PubMedCrossRefGoogle Scholar
  36. 36.
    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
  37. 37.
    Glover D, Glick JH, Weiler C, et al. WR-2721 protects against the haematologic toxicity of cyclophosphamide: a controlled phase II trial. J Clin Oncol 1986; 4: 584–8PubMedGoogle Scholar
  38. 38.
    Woolley PV, Ayoob MJ, Smith FP, et al. Clinical trial of S-2-(3-aminoprophylamino)-ethylphosphorothioic acid (WR-2721) (NSC 296961) on the toxicity of cyclophosphamide. J Clin Oncol 1983; 1: 198–203PubMedGoogle Scholar
  39. 39.
    Glick J, Kemp G, Rose P, et al. A randomised trial of cyclophosphamide and cisplatin ± WR-2721 in the treatment of advanced epithelial ovarian cancer. Proc Am Soc Clin Oncol 1992; 11: 258Google Scholar
  40. 40.
    Luginbuhl W, Tester W, Shaw L, et al. One or two doses of WR-2721: does it protect patients receiving carboplatin? Proc Am Soc Clin Oncol 1992; 11: 312Google Scholar
  41. 41.
    Browne MJ, Clark JW, Weitberg A, et al. A phase I-II study of WR-2721 and carboplatin in patients with advanced lung and breast cancer. Proc Am Soc Clin Oncol 1993; 12: 452Google Scholar
  42. 42.
    Cox PJ. Cyclophosphamide cystitis: identification of acrolein as the causative agent. Biochem Pharmocol 1979; 28: 2045–9CrossRefGoogle Scholar
  43. 43.
    Brock N, Pohl J, Stekar J, et al. 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 1982; 18: 1377–87PubMedCrossRefGoogle Scholar
  44. 44.
    Scheef W, Klein HO, Brock N, et al. Controlled clinical studies with an antidote against the urotoxicity of oxaza-phosphorines: preliminary results. Cancer Treat Rep 1979; 63: 501–5PubMedGoogle Scholar
  45. 45.
    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
  46. 46.
    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
  47. 47.
    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
  48. 48.
    Blomgren H, Hallstrom M, Hillgren H. Antitumour activity of 2-mercaptoethane sulfonate (mesna) in vitro: its potential use in the treatment of superficial bladder cancer. Anticancer Res 1991; 11: 773–6PubMedGoogle Scholar
  49. 49.
    Burkert H. Clinical overview of mesna. Cancer Treat Rev 1983; 10: 175–81PubMedCrossRefGoogle Scholar
  50. 50.
    Pohl VJ, Brock N, Schneider B, et al. Zur Pharmakokinetik von uromitexan. Methods Find Exp Clin Pharmacol 1981; 3 Suppl. 1: 95–101Google Scholar
  51. 51.
    Burkert H, Lucker W, Wetzelsberger N, et al. Bioavailability of orally administered mesna. Arzneimittelformschung 1984; 34: 1597–600Google Scholar
  52. 52.
    Goodman TL, McKenna LM, Li JT, et al. Clinical pharmacology and efficacy of mesna given po to outpatients treated with ifosfamide for solid tumours. Proc Am Soc Clin Oncol 1992; 11: 272Google Scholar
  53. 53.
    Katz S, Epelman S, Annelli A, et al. Mesna (M) — based uroprotection: sustained and simplified schedule — results of a randomised trial. Proc Am Soc Clin Oncol 1992; 11: 1351Google Scholar
  54. 54.
    Dorr RT. Chemoprotectants for cancer chemotherapy. Semin Oncol 1991; 18 Suppl. 2: 48–58PubMedGoogle Scholar
  55. 55.
    Radford JA, Margison JM, Swindell R, et al. The stability of ifosfamide in aqueous solution and its suitability for continuous 7-day infusion by ambulatory pump. J Cancer Res Clin Oncol 1991; 117 Suppl. 4: 154–6CrossRefGoogle Scholar
  56. 56.
    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
  57. 57.
    Reinhold-Keller E, Mohr J, Christophers E, et al. Mesna side-effects which imitate vasculitis. Clin Investig 1992; 70: 698–704PubMedCrossRefGoogle Scholar
  58. 58.
    Hamers FPT, Gispen WH, Neijt JP. Neurotoxic side-effects of cisplatin. Eur J Cancer 1991; 27: 372–6CrossRefGoogle Scholar
  59. 59.
    Strand FL, Kung TT. ACTH accelerates recovery of neuromuscular function following crushing of peripheral nerve. Peptides 1980; 1: 135–8PubMedCrossRefGoogle Scholar
  60. 60.
    Gerritsen Van der Hoop R, de Koning P, Boven E, et al. Efficacy of the neuropeptide ORG-2766 in the prevention and treatment of cisplatin-induced neurotoxicity in rats. Eur J Cancer Clin Oncol 1988; 24: 637–42PubMedCrossRefGoogle Scholar
  61. 61.
    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
  62. 62.
    Hovestadt A, van der 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
  63. 63.
    van der Burg ME, Verbiest HB, van Putten WL, et al. Phase II study to assess the effect of ORG-2766 on the recovery of late cisplatin-induced neuropathy. Proc Am Soc Clin Oncol 1992; 33: 1542Google Scholar
  64. 64.
    Hamers FP, 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

Copyright information

© Adis International Limited 1994

Authors and Affiliations

  • Craig Lewis
    • 1
  1. 1.Department of Medical OncologyPrince of Wales HospitalSydneyAustralia

Personalised recommendations