Tumor vascular maturation and improved drug delivery induced by methylselenocysteine leads to therapeutic synergy with anticancer drugs.
OBJECTIVE
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.


METHODS
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/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 ( approximately 40%) in microvessel density accompanying tumor growth inhibition following MSC treatment along with a concomitant increase in the vascular maturation index ( approximately 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.


CONCLUSIONS
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.
Bhattacharya
Arup
A
Department of Cancer Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. arup.bhattacharya@roswellpark.org
Seshadri
Mukund
M
Oven
Steven D
SD
Tóth
Károly
K
Vaughan
Mary M
MM
Rustum
Youcef M
YM
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002199:Capillary Permeability / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D003545:Cysteine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016503:Drug Delivery Systems; D004357:Drug Synergism; D005260:Female; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D016566:Organoselenium Compounds / Q000008:administration & dosage*; D017279:Selenocysteine / Q000031:analogs & derivatives; D023041:Xenograft Model Antitumor Assays
D016566:Organoselenium Compounds; D017279:Selenocysteine; D003545:Cysteine; C002979:selenomethylselenocysteine