Improved tumor vascular function following high-dose epidermal growth factor receptor tyrosine kinase inhibitor therapy.
OBJECTIVE
To determine if inhibitors of the human growth factor receptor (HER) family can be used to enhance tumor vascular permeability and perfusion and optimize the efficacy of cytotoxic chemotherapeutics. Poor tumor vascular function limits the delivery and efficacy of cancer chemotherapeutics and HER family tyrosine kinases mediate tumor-endothelial signaling in both of these compartments.


METHODS
BT474 human breast cancer tumors were established in mice and the biologic effects of the HER tyrosine kinase inhibitor (TKI) gefitinib on tumor vascular function was determined by dynamic contrast-enhanced MRI (DCE-MRI), and on tumor vascular architecture and perfusion by immunofluorescence microscopy.


RESULTS
A brief dose of gefitinib enhances the antitumor activity of paclitaxel in vivo but not in cell culture, suggesting that its chemoenhancing activity involves the in vivo microenvironment. A brief high dose of gefitinib induces a decrease in endothelial transfer constant (Kps) and a concomitant increase in tumor fractional plasma volume (fPV). These changes are accompanied by a rapid reduction in tumor volume, likely due to decreased tumor edema, and modestly improved tumor vascular architecture and perfusion on microscopy.


CONCLUSIONS
These data suggest that HER family TKIs have the potential to optimize the tumor microenvironment for delivery of cytotoxic chemotherapeutics.
Moasser
Mark M
MM
Department of Medicine, University of California, San Francisco, San Francisco, California 94143, USA. mmoasser@medicine.ucsf.edu
Wilmes
Lisa J
LJ
Wong
Ching Hang
CH
Aliu
Sheye
S
Li
Ka-Loh
KL
Wang
Donghui
D
Hom
Yun Kit
YK
Hann
Byron
B
Hylton
Nola M
NM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D002199:Capillary Permeability / Q000187:drug effects*; D003287:Contrast Media; D019786:Gadolinium DTPA; D000077156:Gefitinib; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000473:pathology*; D011799:Quinazolines / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D003287:Contrast Media; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; D019786:Gadolinium DTPA; D000077156:Gefitinib