Abstract
Ifosfamide (IFF) is a nitrogen mustard with significant activity against a number of tumors. Since it is a chiral molecule, it has been suggested that enantioselective metabolism could result in different efficacy and toxicity profiles for (R)- and (S)-ifosfamide. Both experimental animal and clinical data suggest that N-dechloroethyl metabolites of (S)-IFF are more significantly associated with neurological toxicity, which may limit therapeutic use of IFF. We have used purified ifosfamide enantiomers to examine the pharmacokinetics; spectrum of toxicity including lethality, weight loss, and myelosuppression; and antitumor effects of the mixture compared to each of the purified enantiomers. In the MatB mammary carcinoma grown in female Fischer rats we demonstrated that the anti-tumor efficacy appears to be the same for (R)-IFF and (S)-IFF, while the (R)-IFF has greater myelotoxicity. Pharmacokinetic analysis of plasma concentration-time confirms that the (R)-IFF is metabolized to a greater extent than (S)-IFF via the activation pathway. These data suggest that purified (R)-IFF may be an effective way to deliver active cytotoxic drug while limiting the generation of neurotoxic metabolites.
This work was supported by grants from the Cancer Research Society and Martinex Research, Inc.
