Tumor Vascular Maturation and Improved Drug Delivery Induced by Methylselenocysteine Leads to Therapeutic Synergy with Anticancer Drugs
Open Access
- 15 June 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 14 (12), 3926-3932
- https://doi.org/10.1158/1078-0432.ccr-08-0212
Abstract
Purpose: Our previously reported therapeutic synergy between naturally occurring seleno-amino acid methylselenocysteine (MSC) and anticancer drugs could not be shown in vitro. Studies were carried out to investigate the potential role of MSC-induced tumor vascular maturation and increased drug delivery in the observed therapeutic synergy in vivo. Experimental Design: Mice bearing s.c. FaDu human head and neck squamous cell carcinoma xenografts were treated with MSC (0.2 mg/d × 14 days orally). Changes in microvessel density (CD31), vascular maturation (CD31/α-smooth muscle actin), perfusion (Hoechst 33342/DiOC7), and permeability (dynamic contrast-enhanced magnetic resonance imaging) were determined at the end of the 14-day treatment period. Additionally, the effect of MSC on drug delivery was investigated by determining intratumoral concentration of doxorubicin using high-performance liquid chromatography and fluorescence microscopy. Results: Double immunostaining of tumor sections revealed a marked reduction (∼40%) in microvessel density accompanying tumor growth inhibition following MSC treatment along with a concomitant increase in the vascular maturation index (∼30% > control) indicative of increased pericyte coverage of microvessels. Hoechst 33342/DiOC7 staining showed improved vessel functionality, and dynamic contrast-enhanced magnetic resonance imaging using the intravascular contrast agent, albumin-GdDTPA, revealed a significant reduction in vascular permeability following MSC treatment. Consistent with these observations, a 4-fold increase in intratumoral doxorubicin levels was observed with MSC pretreatment compared with administration of doxorubicin alone. Conclusion: These results show, for the first time, the antiangiogenic effects of MSC results in tumor growth inhibition, vascular maturation in vivo, and enhanced anticancer drug delivery that are associated with the observed therapeutic synergy in vivo.Keywords
This publication has 26 references indexed in Scilit:
- Bevacizumab-Induced Transient Remodeling of the Vasculature in Neuroblastoma Xenografts Results in Improved Delivery and Efficacy of Systemically Administered ChemotherapyClinical Cancer Research, 2007
- Tumor microvasculature and microenvironment: Targets for anti-angiogenesis and normalizationMicrovascular Research, 2007
- Activity of the Vascular-Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid against Human Head and Neck Carcinoma XenograftsNeoplasia, 2006
- Potentiation of irinotecan sensitivity by Se-methylselenocysteine in an in vivo tumor model is associated with downregulation of cyclooxygenase-2, inducible nitric oxide synthase, and hypoxia-inducible factor 1α expression, resulting in reduced angiogenesisOncogene, 2006
- A phase I and pharmacokinetic study of fixed-dose selenomethionine and irinotecan in solid tumors.Clinical Cancer Research, 2006
- The Distribution of the Anticancer Drug Doxorubicin in Relation to Blood Vessels in Solid TumorsClinical Cancer Research, 2005
- Lack of Microvessels in Well-Differentiated Regions of Human Head and Neck Squamous Cell Carcinoma A253 Associated with Functional Magnetic Resonance Imaging Detectable Hypoxia, Limited Drug Delivery, and Resistance to Irinotecan TherapyClinical Cancer Research, 2004
- Specialization of tumour vasculatureNature Reviews Cancer, 2002
- Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study GroupPublished by American Medical Association (AMA) ,1996
- Tumor Angiogenesis: Therapeutic ImplicationsNew England Journal of Medicine, 1971