Tissue examination to monitor antiangiogenic therapy: a phase I clinical trial with endostatin.
OBJECTIVE
The purpose of this study was to determine the effect of the angiogenesis inhibitor endostatin on blood vessels in tumors and wound sites.


METHODS
In a Phase I dose escalation study, cancer patients were treated with daily infusions of human recombinant endostatin. Tumor biopsies were obtained prior to and 8 weeks after initiation of treatment. Blood vessel formation in nonneoplastic tissue was evaluated by creating a skin wound site on the arm with a punch biopsy device. The wound site was sampled with a second biopsy after a 7-day interval. This sequential biopsy procedure was performed prior to and 3 weeks after initiation of endostatin treatment. Vascular density, endothelial cell kinetics, and blood vessel maturity were determined in tumor and skin wound samples. The ultrastructure of tumor blood vessels was examined by electron microscopy.


RESULTS
As expected, the tumors were of variable vascular density. Skin wounding induced a vascular granulation tissue containing a high percentage of proliferating endothelial cells. The proportion of immature blood vessels was high in tumors and in wound sites and low in normal skin. No statistically significant difference was detected between pretreatment and treatment samples of tumors and of skin wounds for any of the parameters tested.


CONCLUSIONS
Endostatin treatment was not associated with any recognizable vascular changes in tumor samples and did not perturb wound healing at the doses and the treatment schedule used.
Mundhenke
C
C
Comprehensive Cancer Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI 53792, USA.
Thomas
J P
JP
Wilding
G
G
Lee
F T
FT
Kelzc
F
F
Chappell
R
R
Neider
R
R
Sebree
L A
LA
Friedl
A
A
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001706:Biopsy / Q000379:methods; D001808:Blood Vessels / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D003094:Collagen / Q000627:therapeutic use*; D043169:Endostatins; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008854:Microscopy, Electron; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D010446:Peptide Fragments / Q000627:therapeutic use*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D012867:Skin / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D014945:Wound Healing
D020533:Angiogenesis Inhibitors; D043169:Endostatins; D019394:Ki-67 Antigen; D010446:Peptide Fragments; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D003094:Collagen