The history of ifosfamide

Ifosfamide was developed by investigators at Asta-Werke in Germany. Its chemical structure differs from that of cyclophosphamide by the transposition of one of the side chain chloroethyl groups to the ring nitrogen. In several preclinical models, ifosfamide had greater activity than cyclophosphamide. It produced less myelosuppression, but more commonly produced hemorrhagic cystitis as its dose-limiting toxicity. This toxicity has been minimized with the urothelial protective agents mesna and N-acetylcysteine. Thus, increasing doses have been administered and a new spectrum of toxicities observed, including neurotoxicity, hematologic toxicity, nephrotoxicity, and acidosis. Ifosfamide has been shown to have a broad spectrum of clinical activity in various cancers. Questions remain as to the optimal doses and schedules.