EFFICACY AND TOXICITY OF IFOSFAMIDE STEREOISOMERS IN AN IN-VIVO RAT MAMMARY-CARCINOMA MODEL

Citation
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
Citations number
20
Categorie Soggetti
Oncology
Journal title
ISSN journal
00085472
Volume
54
Issue
16
Year of publication
1994
Pages
4393 - 4397
Database
ISI
SICI code
0008-5472(1994)54:16<4393:EATOIS>2.0.ZU;2-P
Abstract
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.