Journal article
Tumor vascular maturation and improved drug delivery induced by methylselenocysteine leads to therapeutic synergy with anticancer drugs
Clinical cancer research, Vol.14(12), pp.3926-3932
06/15/2008
DOI: 10.1158/1078-0432.CCR-08-0212
PMCID: PMC2504718
PMID: 18559614
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 x 14 days orally). Changes in microvessel density (CD31), vascular maturation (CD31/alpha-smooth muscle actin), perfusion (Hoechst 33342/DiOC(7)), 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 (similar to 40%) in microvessel density accompanying tumor growth inhibition following MSC treatment along with a concomitant increase in the vascular maturation index ( similar to 30% > control) indicative of increased pericyte coverage of microvessels. Hoechst 33342/DiOC(7) 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.
Details
- Title: Subtitle
- Tumor vascular maturation and improved drug delivery induced by methylselenocysteine leads to therapeutic synergy with anticancer drugs
- Creators
- Arup Bhattacharya - Roswell Park Cancer InstituteMukund Seshadri - Roswell Pk Canc Inst, Dept Canc Biol, Buffalo, NY 14263 USASteven D. Oven - Roswell Pk Canc Inst, Dept Canc Biol, Buffalo, NY 14263 USAKaroly Toth - Roswell Pk Canc Inst, Dept Canc Biol, Buffalo, NY 14263 USAMary M. Vaughan - Roswell Park Cancer InstituteYoucef M. Rustum - Roswell Park Cancer Institute
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.14(12), pp.3926-3932
- DOI
- 10.1158/1078-0432.CCR-08-0212
- PMID
- 18559614
- PMCID
- PMC2504718
- NLM abbreviation
- Clin Cancer Res
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 7
- Grant note
- P30 CA016056-31; P30 CA016056; CA016056 / NCI NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) P30CA016056 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 06/15/2008
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359951202771
Metrics
6 Record Views