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

C Bokemeyer,A Harstrick,H-J Schmoll,E Ludwig,J Casper,T Dunn

doi:10.1038/bjc.1994.167

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.

Highlights

Active oxazaphosphorine metabolites by sulphydryl groups, which has been demonstrated in the case of the toxic metabolite acrolein
For ifosfamide 50% of the maximal tolerated dose (MTD) equivalent to the lethal dose 20 (LD 20) were used
The MTD of ifosfamide had been determined in previous experiments to be of the order of 100mgkg-'day-' (Schmoll, 1989; Harstrick et al, 1990)

Summary

Introduction

Active oxazaphosphorine metabolites by sulphydryl groups, which has been demonstrated in the case of the toxic metabolite acrolein. Acrolein is spontaneously formed in the urine from the primary metabolites eliminated via the kidneys (Brock et al, 1979). Different clinical studies have demonstrated the ability of mesna to reduce the incidence of haemorrhagic cystitis when given concomitantly with the oxazaphosphorine therapy (Bryant et al, 1980; Burkert, 1983; Pratt et al, 1989)

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Discussion

Conclusion