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. 1994 May;69(5):863–867. doi: 10.1038/bjc.1994.167

The anti-tumour activity of ifosfamide on heterotransplanted testicular cancer cell lines remains unaltered by the uroprotector mesna.

C Bokemeyer 1, H J Schmoll 1, E Ludwig 1, A Harstrick 1, T Dunn 1, J Casper 1
PMCID: PMC1968886  PMID: 8180015

Abstract

Ifosfamide is clinically used in combination chemotherapy regimens for the treatment of patients with high-grade lymphomas, sarcomas and metastatic germ cell tumours. In order to reduce the oxazophosphorine-related urothelial toxicity, sodium mercaptoethane sulphonate (mesna) is used in different schedules following the administration of ifosfamide. The proposed mechanism of mesna activity is the binding of toxic oxazaphosphorine metabolites such as acrolein in the urine of the patients. Since an influence of mesna on ifosfamide anti-tumour activity is controversial, the current study has used xenografts from two human testicular cancer cell lines heterotransplanted into nude mice to study the anti-tumour activity of ifosfamide in combination with different dosages and schedules of mesna. In both human testicular cancer cell lines, H 12.1 and 2102 EP, ifosfamide demonstrated anti-tumour activity as a single agent. No reduction in ifosfamide activity was observed with the application of mesna at a dose range from 50% to 200% of the ifosfamide dose. Furthermore, the application of mesna before and 3 h after ifosfamide, a schedule used in many clinical protocols because of the short half life of mesna, not only maintained high ifosfamide anti-tumour activity but also seemed to be associated with the lower systemic and urothelial toxicity of ifosfamide therapy compared with ifosfamide given alone. In conclusion, the experimental in vivo system using human heterotransplanted testicular cancer cell lines confirms the significant anti-tumour activity of ifosfamide in malignant germ cell tumours and demonstrates that mesna does not impair ifosfamide anti-tumour activity in this model. These results are most likely transferable to the use of mesna in patients with metastatic testicular cancer.

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Selected References

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  1. Blomgren H., Hallström M., Hillgren H. Antitumor activity of 2-mercaptoethanesulfonate (mesna) in vitro. Its potential use in the treatment of superficial bladder cancer. Anticancer Res. 1991 Mar-Apr;11(2):773–776. [PubMed] [Google Scholar]
  2. Bokemeyer C., Schmoll H. J. Treatment of advanced germ cell tumours by dose intensified chemotherapy with haematopoietic growth factors or peripheral blood stem cells (PBSC). Eur Urol. 1993;23(1):223–230. doi: 10.1159/000474598. [DOI] [PubMed] [Google Scholar]
  3. Brock N., Hilgard P., Pohl J., Ormstad K., Orrenius S. Pharmacokinetics and mechanism of action of detoxifying low-molecular-weight thiols. J Cancer Res Clin Oncol. 1984;108(1):87–97. doi: 10.1007/BF00390979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brock N., Stekar J., Pohl J., Niemeyer U., Scheffler G. Acrolein, the causative factor of urotoxic side-effects of cyclophosphamide, ifosfamide, trofosfamide and sufosfamide. Arzneimittelforschung. 1979;29(4):659–661. [PubMed] [Google Scholar]
  5. Bryant B. M., Jarman M., Ford H. T., Smith I. E. Prevention of isophosphamide-induced urothelial toxicity with 2-mercaptoethane sulphonate sodium (mesnum) in patients with advanced carcinoma. Lancet. 1980 Sep 27;2(8196):657–659. doi: 10.1016/s0140-6736(80)92703-8. [DOI] [PubMed] [Google Scholar]
  6. Brühl P., Günther U., Hoefer-Janker H., Hüls W., Scheef W., Vahlensieck W. Results obtained with fractionated ifosfamide massive-dose treatment in generalized malignant tumours. Int J Clin Pharmacol Biopharm. 1976 Jul;14(1):29–39. [PubMed] [Google Scholar]
  7. Burkert H. Clinical overview of mesna. Cancer Treat Rev. 1983 Sep;10 (Suppl A):175–181. doi: 10.1016/s0305-7372(83)80026-7. [DOI] [PubMed] [Google Scholar]
  8. Cabanillas F., Hagemeister F. B., McLaughlin P., Velasquez W. S., Riggs S., Fuller L., Smith T. Results of MIME salvage regimen for recurrent or refractory lymphoma. J Clin Oncol. 1987 Mar;5(3):407–412. doi: 10.1200/JCO.1987.5.3.407. [DOI] [PubMed] [Google Scholar]
  9. Casper J., Schmoll H. J., Schnaidt U., Fonatsch C. Cell lines of human germinal cancer. Int J Androl. 1987 Feb;10(1):105–113. doi: 10.1111/j.1365-2605.1987.tb00171.x. [DOI] [PubMed] [Google Scholar]
  10. Cerny T., Küpfer A. The enigma of ifosfamide encephalopathy. Ann Oncol. 1992 Nov;3(9):679–681. doi: 10.1093/oxfordjournals.annonc.a058317. [DOI] [PubMed] [Google Scholar]
  11. Crook T. R., Souhami R. L., Whyman G. D., McLean A. E. Glutathione depletion as a determinant of sensitivity of human leukemia cells to cyclophosphamide. Cancer Res. 1986 Oct;46(10):5035–5038. [PubMed] [Google Scholar]
  12. Elias A. D., Eder J. P., Shea T., Begg C. B., Frei E., 3rd, Antman K. H. High-dose ifosfamide with mesna uroprotection: a phase I study. J Clin Oncol. 1990 Jan;8(1):170–178. doi: 10.1200/JCO.1990.8.1.170. [DOI] [PubMed] [Google Scholar]
  13. Harstrick A., Schmoll H. J., Casper J., Wilke H., Poliwoda H. Activity of cytostatic drugs in two heterotransplanted human testicular cancer cell lines with different sensitivity to standard agents. Eur J Cancer. 1990;26(8):898–901. doi: 10.1016/0277-5379(90)90195-y. [DOI] [PubMed] [Google Scholar]
  14. Harstrick A., Schmoll H. J., Wilke H., Köhne-Wömpner C. H., Stahl M., Schöber C., Casper J., Bruderek L., Schmoll E., Bokemeyer C. Cisplatin, etoposide, and ifosfamide salvage therapy for refractory or relapsing germ cell carcinoma. J Clin Oncol. 1991 Sep;9(9):1549–1555. doi: 10.1200/JCO.1991.9.9.1549. [DOI] [PubMed] [Google Scholar]
  15. Kovach J. S., Schutt A. J., Hahn R. G., Reitemeier R. J., Moertel C. G. A phase 2 study of intermittent high dose isophosphamide therapy of advanced colorectal cancer. Oncology. 1974;29(1):34–39. doi: 10.1159/000224886. [DOI] [PubMed] [Google Scholar]
  16. Loehrer P. J., Sr, Einhorn L. H., Williams S. D. VP-16 plus ifosfamide plus cisplatin as salvage therapy in refractory germ cell cancer. J Clin Oncol. 1986 Apr;4(4):528–536. doi: 10.1200/JCO.1986.4.4.528. [DOI] [PubMed] [Google Scholar]
  17. Morgan L. R., Posey L. E., Rainey J., Bickers J., Ryan D., Vial R., Hull E. W. Ifosfamide: a weekly dose fractionated schedule in bronchogenic carcinoma. Cancer Treat Rep. 1981 Jul-Aug;65(7-8):693–695. [PubMed] [Google Scholar]
  18. Munshi N. C., Loehrer P. J., Sr, Williams S. D., Langefeld C., Sledge G., Nichols C. R., Roth B. J., Neuman A., Walsh W. B., Einhorn L. H. Comparison of N-acetylcysteine and mesna as uroprotectors with ifosfamide combination chemotherapy in refractory germ cell tumors. Invest New Drugs. 1992 Aug;10(3):159–163. doi: 10.1007/BF00877240. [DOI] [PubMed] [Google Scholar]
  19. PHILIPS F. S., STERNBERG S. S., CRONIN A. P., VIDAL P. M. Cyclophosphamide and urinary bladder toxicity. Cancer Res. 1961 Dec;21:1577–1589. [PubMed] [Google Scholar]
  20. Pratt C. B., Douglass E. C., Etcubanas E., Goren M. P., Green A. A., Hayes F. A., Horowitz M. E., Meyer W. H., Thompson E. I., Wilimas J. A. Clinical studies of ifosfamide/mesna at St Jude Children's Research Hospital, 1983-1988. Semin Oncol. 1989 Feb;16(1 Suppl 3):51–55. [PubMed] [Google Scholar]
  21. Rieche K. Carcinogenicity of antineoplastic agents in man. Cancer Treat Rev. 1984 Mar;11(1):39–67. doi: 10.1016/0305-7372(84)90016-1. [DOI] [PubMed] [Google Scholar]
  22. Schmoll H. J. The role of ifosfamide in testicular cancer. Semin Oncol. 1989 Feb;16(1 Suppl 3):82–95. [PubMed] [Google Scholar]
  23. Shaw I. C., Graham M. I. Mesna--a short review. Cancer Treat Rev. 1987 Jun;14(2):67–86. doi: 10.1016/0305-7372(87)90041-7. [DOI] [PubMed] [Google Scholar]
  24. Wagner T., Zink M., Schwieder G. Influence of mesna and cysteine on the systemic toxicity and therapeutic efficacy of activated cyclophosphamide. J Cancer Res Clin Oncol. 1987;113(2):160–165. doi: 10.1007/BF00391439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Willemse P. H., de Vries E. G. Mesna: continuous or bolus infusion? J Clin Oncol. 1989 Jun;7(6):817–819. doi: 10.1200/JCO.1989.7.6.817. [DOI] [PubMed] [Google Scholar]

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