| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Research Articles
Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice
1 Division of Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; 2 Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Pisa, Italy; and 3 Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, North Carolina
Requests for reprints: Robert S. Kerbel, Division of Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, S-217, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5. Phone: 416-480-5711; Fax: 416-480-5884. E-mail: robert.kerbel{at}sri.utoronto.ca
Abstract
Prolonged, frequently administered low-dose metronomic chemotherapy (LDM) is being explored (pre)clinically as a promising antiangiogenic antitumor strategy. Although appealing because of a favorable side effect profile and mostly oral dosing, LDM involves new challenges different from conventional maximum tolerated dose chemotherapy. These include possible altered pharmacokinetic characteristics due to long-term drug exposure potentially resulting in acquired resistance and increased risk of unfavorable drug interactions. We therefore compared the antitumor and antivascular effects of LDM cyclophosphamide (CPA) given to mice that had been pretreated with either LDM CPA or normal saline, obtained blood 4-hydroxy-CPA (activated CPA) concentrations using either gas chromatography/mass spectrometry or liquid chromatography/tandem mass spectrometry in mice treated with LDM CPA, and measured hepatic and intratumoral activity of enzymes involved in the biotransformation of CPA and many other drugs [i.e., cytochrome P450 3A4 (CYP3A4) and aldehyde dehydrogenase]. Exposure of mice to LDM CPA for 
8 weeks did not compromise subsequent activity of LDM CPA therapy, and biologically active 4-hydroxy-CPA levels were maintained during long-term LDM CPA administration. Whereas the effects on CYP3A4 were complex, aldehyde dehydrogenase activity was not affected. In summary, our findings suggest that acquired resistance to LDM CPA is unlikely accounted for by altered CPA biotransformation. In the absence of reliable pharmacodynamic surrogate markers, pharmacokinetic parameters might become helpful to individualize/optimize LDM CPA therapy. LDM CPA-associated changes of CYP3A4 activity point to a potential risk of unfavorable drug interactions when compounds that are metabolized by CYP3A4 are coadministered with LDM CPA. [Mol Cancer Ther 2007;6(8):2280–9]
Grant support: NIH grant CA-41233 and National Cancer Institute of Canada (R.S. Kerbel); Swiss Cancer League/Oncosuisse grant BIL SKL 1237-02-2002 and an unrestricted educational grant from Novartis Pharmaceuticals Canada, Inc. (U. Emmenegger); Associazione Italiana per la Ricerca sul Cancro (G. Bocci); and National Cancer Institute (Department of Health and Human Services), USPHS grant CA16783 (S.M. Ludeman and O.M. Colvin). R.S. Kerbel holds a Tier I Canada Research Chair in Tumor Biology, Angiogenesis and Antiangiogenic Therapy. U. Emmenegger was recipient of a Faculty of Medicine Award, University of Toronto. Y. Shaked was recipient of a Postdoctoral Fellowship Award from the Canadian Institutes of Health Research.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: U. Emmenegger and Y. Shaked contributed equally to this work.
4 S. Man et al., unpublished observation.
Received 3/14/07; revised 5/11/07; accepted 6/15/07.
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
