Abstract :
[en] 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 pO2 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.
[fr] e but de ce travail était d'étudier comment le schéma d'administration affecte potentialisation de cyclophosphamide, un agent d'alkylation, par la thalidomide, un agent anti-angiogénique. Tumor oxygenation after thalidomide administration was determined over time by EPR oximetry. oxygénation tumorale thalidomide après l'administration a été déterminée au fil du temps par oxymétrie EPR. 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. Ces mesures constituent un marqueur de substitution pour déterminer le moment de «normalisation» de la vascularisation tumorale. retards de croissance ont été mesurés Re utilisant différentes combinaisons et les horaires de traitements. 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). En outre, l'adoption du métabolite du cyclophosphamide (hydroxycyclophosphamide ou OH-CP) dans les tumeurs a été déterminée par chromatographie liquide haute / spectrométrie de masse en tandem (HPLC / MS / MS). A significant increase in pO(2) was observed after 2 and 3 days of treatment before eventually declining on day 4. Une augmentation significative dans les PO (2) a été observée après 2 et 3 jours de traitement avant de finalement en baisse sur 4 jours. Thalidomide potentiated the effect of cyclophosphamide only when cyclophosphamide was administered after 2 days of treatment with thalidomide (no significant benefit using other schedules). La thalidomide a potentialisé l'effet de cyclophosphamide que lorsque le cyclophosphamide a été administré après 2 jours de traitement avec la thalidomide (aucun avantage significatif en utilisant les autres annexes). 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. Dans ce délai, la HPLC / MS / MS mesures ont montré que la quantité de OH-CP pénétrer dans la tumeur était environ deux fois chez les souris traitées par la thalidomide par rapport aux témoins. En conclusion, la présente étude montre que les avantages de la thérapie combinée à l'aide AN-angiogéniques agent anti avec un agent cytotoxique nécessite une connaissance de la fenêtre de temps pendant lequel les bateaux initialement se normaliser.
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