Iw. Wainer et al., EFFICACY AND TOXICITY OF IFOSFAMIDE STEREOISOMERS IN AN IN-VIVO RAT MAMMARY-CARCINOMA MODEL, Cancer research, 54(16), 1994, pp. 4393-4397
Ifosfamide (IFF) is a nitrogen mustard with significant activity again
st a number of tumors. Since it is a chiral molecule, it has been sugg
ested that enaotioselective metabolism could result in different effic
acy and toxicity profiles for (R)- and (S)-ifosfamide. Both experiment
al animal and clinical data suggest that N-dechloroethyl metabolites o
f (S)-IFF are more significantly associated with neurological toxicity
, which may limit therapeutic use of IFF. We have used purified ifosfa
mide 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 demonstr
ated that the antitumor efficacy appears to be the same for (R)-IFF an
d (S)IFF, while the (R)-IFF has greater myelotoxicity. Pharmacokinetic
analysis of plasma concentration-time confirms that the (R)-IFF is me
tabolized to a greater extent than (S)-IFF via the activation pathway.
These data suggest that purified (R)-IFF may be an effective way to d
eliver active cytotoxic drug while limiting the generation of neurotox
ic metabolites.