The metabolism and antitumour activity of the enantiomers of cis- and trans-4-methylcyclophosphamide

Peter B. Farmer, Michael Jarman, Terenzio Facchinetti, Krzysztof Pankiewicz, Wojciech J. Stec

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Abstract

4-Methylcyclophosphamide, an analogue of the antitumour agent cyclophosphamide, exists in cis and trans forms, each of which comprises a pair of optical isomers. The extents of metabolism by rat liver microsomes during 20 min were compared for the four stereoisomers incubated separately, and for the racemic cis and trans-derivatives in admixture, using mass spectrometry and gas chromatography respectively. In comparative antitumour tests against the ADJ/PC6 plasma cell tumour in mice, the racemic cis and trans forms of 4- and 6-methylcyclophosphamide had similar therapeutic indices. The four stereoisomers of 4-methylcyclophosphamine exhibited an approx. two-fold range in therapeutic index so that there was no marked effect on either metabolism or antitumour activity occasioned by change of configuration either at C-4 or at phosphorus.

Original languageEnglish (US)
Pages (from-to)47-57
Number of pages11
JournalChemico-Biological Interactions
Volume18
Issue number1
DOIs
StatePublished - Jul 1977

Bibliographical note

Funding Information:
This investigatiown as supportedb y a grant (G973/786/Kt)o the Chester Beatty Research Institute {Institute of Cancer Research, Royal Cancer Hospital) from the Medical ResearchC ouncil and by a grant (PR6/1703)t o the Polish Academy of Sciences,C entreof Molecular and Macromolecular Studies from the National Cancer ProgrammeT. he financial supporto f the British Council is also gratefullya cknowledgedT.h e A.E.I. MS-12 spectrometer was purchasedo n a special grant (G969/189/C)f rom the Medical ResearchC ouncil.We thank ProfessorA .B. Foster for his advicea nd encouragement,M r. M. Jones for determinatioonf in vivo antitumoura ctivity, Mr. M.H. Baker and Mr. M.R. Oddy for assistancein the areas of mass spectrometrayn d chemicasl yntheticw ork respectively.

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