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Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11.

Wildiers H, Guetens G, De Boeck G, Verbeken E, Landuyt B, Landuyt W, de Bruijn EA, van Oosterom AT - Br. J. Cancer (2003)

Bottom Line: However, these drugs decrease microvessel density, and it is not known whether this reduced vessel density (VD) results in decreased delivery of concomitantly administered classical anticancer drugs.Interestingly, a trend to increased intratumoral CPT-11 concentration was observed (P=0.09).In the growth delay study, CPT-11 was at least equally effective with or without pretreatment with A4.6.1.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Experimental Oncology (LEO), University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. hans.wildiers@uz.kuleuven.ac.be

ABSTRACT
Promising preclinical activity with agents blocking the function of vascular endothelial growth factor (VEGF) has been observed in various cancer types, especially with combination therapy. However, these drugs decrease microvessel density, and it is not known whether this reduced vessel density (VD) results in decreased delivery of concomitantly administered classical anticancer drugs. We designed an in vivo study to investigate the relation between VEGF-blocking therapy, tumoral blood vessels, and intratumoral uptake of anticancer drugs. Nude NMRI mice bearing colon adenocarcinoma (HT29) were treated with the anti-VEGFmAb A4.6.1 or placebo. After 1 week, CPT-11 was administered 1 h prior to killing the animals. In A4.6.1 treated tumours, there was a significant decrease in VD, more pronounced with potentially functional large vessels than endothelial cords. Interestingly, a trend to increased intratumoral CPT-11 concentration was observed (P=0.09). In parallel, we measured an increase in tumour perfusion, as estimated by high-performance liquid chromatography determination of intratumoural Hoechst 33342 concentration. In the growth delay study, CPT-11 was at least equally effective with or without pretreatment with A4.6.1. These data suggest that tumour vascular function and tumour uptake of anticancer drugs improve with VEGF-blocking therapy, and indicate the relevance for further investigations.

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CD34 (A, B) and CD105 (C, D) staining of colorectal tumours shows decreased VD in tumours treated with anti-VEGF mAb (A, C) vs placebo (B, D). Original magnification × 200.
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fig2: CD34 (A, B) and CD105 (C, D) staining of colorectal tumours shows decreased VD in tumours treated with anti-VEGF mAb (A, C) vs placebo (B, D). Original magnification × 200.

Mentions: Significant at level <0.05.


Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11.

Wildiers H, Guetens G, De Boeck G, Verbeken E, Landuyt B, Landuyt W, de Bruijn EA, van Oosterom AT - Br. J. Cancer (2003)

CD34 (A, B) and CD105 (C, D) staining of colorectal tumours shows decreased VD in tumours treated with anti-VEGF mAb (A, C) vs placebo (B, D). Original magnification × 200.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2741115&req=5

fig2: CD34 (A, B) and CD105 (C, D) staining of colorectal tumours shows decreased VD in tumours treated with anti-VEGF mAb (A, C) vs placebo (B, D). Original magnification × 200.
Mentions: Significant at level <0.05.

Bottom Line: However, these drugs decrease microvessel density, and it is not known whether this reduced vessel density (VD) results in decreased delivery of concomitantly administered classical anticancer drugs.Interestingly, a trend to increased intratumoral CPT-11 concentration was observed (P=0.09).In the growth delay study, CPT-11 was at least equally effective with or without pretreatment with A4.6.1.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Experimental Oncology (LEO), University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. hans.wildiers@uz.kuleuven.ac.be

ABSTRACT
Promising preclinical activity with agents blocking the function of vascular endothelial growth factor (VEGF) has been observed in various cancer types, especially with combination therapy. However, these drugs decrease microvessel density, and it is not known whether this reduced vessel density (VD) results in decreased delivery of concomitantly administered classical anticancer drugs. We designed an in vivo study to investigate the relation between VEGF-blocking therapy, tumoral blood vessels, and intratumoral uptake of anticancer drugs. Nude NMRI mice bearing colon adenocarcinoma (HT29) were treated with the anti-VEGFmAb A4.6.1 or placebo. After 1 week, CPT-11 was administered 1 h prior to killing the animals. In A4.6.1 treated tumours, there was a significant decrease in VD, more pronounced with potentially functional large vessels than endothelial cords. Interestingly, a trend to increased intratumoral CPT-11 concentration was observed (P=0.09). In parallel, we measured an increase in tumour perfusion, as estimated by high-performance liquid chromatography determination of intratumoural Hoechst 33342 concentration. In the growth delay study, CPT-11 was at least equally effective with or without pretreatment with A4.6.1. These data suggest that tumour vascular function and tumour uptake of anticancer drugs improve with VEGF-blocking therapy, and indicate the relevance for further investigations.

Show MeSH
Related in: MedlinePlus