1: Cancer Lett. 2006 Nov 28;244(1):129-135. Epub 2006 Jan 19.

Potentiation of cyclophosphamide chemotherapy using the anti-angiogenic drug
thalidomide: Importance of optimal scheduling to exploit the 'normalization'
window of the tumor vasculature.

Segers J, Fazio VD, Ansiaux R, Martinive P, Feron O, Wallemacq P, Gallez B.

Laboratory of Biomedical Magnetic Resonance, Universite Catholique de Louvain,
B-1200 Brussels, Belgium.

The aim of this work was to study how administration schedule affects
potentiation of cyclophosphamide, an alkylating agent, by thalidomide, an
anti-angiogenic agent. Tumor oxygenation after thalidomide administration was
determined over time by EPR oximetry. Such measurements provide a surrogate
marker for determining the timing of 'normalization' of tumor vasculature.
Re-growth delays were measured using different combinations and schedules of
treatments. Additionally, the uptake of the metabolite of cyclophosphamide
(hydroxycyclophosphamide or OH-CP) into tumors was determined by high
performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS). A
significant increase in pO(2) was observed after 2 and 3 days of treatment
before eventually declining on day 4. Thalidomide potentiated the effect of
cyclophosphamide only when cyclophosphamide was administered after 2 days of
treatment with thalidomide (no significant benefit using other schedules). In
this time frame, the HPLC/MS/MS measurements showed that the quantity of OH-CP
penetrating into the tumor was about twice in mice treated by thalidomide
compared to controls. In conclusion, the present study demonstrates that the
benefit of combined therapy using an anti-angiogenic agent with a cytotoxic
agent requires knowledge of the time window during which the vessels initially
become normalized.

PMID: 16426744 [PubMed - as supplied by publisher]

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