期刊
CANCER LETTERS
卷 244, 期 1, 页码 129-135出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2005.12.017
关键词
tumor microenvironment; tumor oxygenation/perfusion; chemotherapy; EPR; HPLC/MS/MS
类别
The aim of this work was to study how administration schedule affects potentiation of cyclophosphamide, an alkylating agent, by thalidonnide. 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/tandent mass spectrometry (HPLCIMS/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. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
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