Synergistic activity of recombinant human endostatin in combination with adriamycin: analysis of in vitro activity on endothelial cells and in vivo tumor progression in an orthotopic murine mammary carcinoma model.
OBJECTIVE
Current combination treatment strategies in malignancy are designed to evaluate the use of cytotoxic drugs and antiangiogenic agents. Endostatin, a fragment of collagen XVIII, specifically inhibits proliferation, migration, and differentiation of endothelial cells in vitro as well as angiogenesis and tumor progression in in vivo models. In this study, we determine the antitumor effect of rhEndostatin administered alone or in combination with Adriamycin against established orthotopic murine mammary carcinoma.


METHODS
Mice bearing orthotopically established DA-3 mammary adenocarcinoma tumors received varying doses of rhEndostatin alone and in combination with Adriamycin to assess tumor growth inhibition. Additional studies of this in vivo combination included a determination of Adriamycin-induced cardiotoxicity and in vitro effects on human umbilical vein endothelial cell proliferation and cord formation.


RESULTS
For single-agent activity, optimal tumor growth inhibition was observed after s.c. administration of 50 mg/kg/day rhEndostatin or 5 mg/kg Adriamycin injected i.v. every 4 days. Combination of Adriamycin with optimal or suboptimal doses of rhEndostatin resulted in synergistic inhibition of DA-3 tumor growth. Importantly, unlike other antiangiogenic agents, rhEndostatin did not exacerbate the cardiotoxicity of Adriamycin. The synergistic interaction between rhEndostatin and Adriamycin was also observed in vitro for inhibition of human umbilical vein endothelial cell proliferation and inhibition of cord formation.


CONCLUSIONS
These data suggest that the synergy observed with rhEndostatin in combination with Adriamycin is exerted at the level of the endothelial cell and can result in enhanced tumor growth inhibition. The potential benefit of Adriamycin used in combination with rhEndostatin is being considered for clinical evaluation.
Plum
Stacy M
SM
EntreMed, Inc., Rockville, Maryland 20850, USA. Stacyp@entremed.com
Hanson
Arthur D
AD
Volker
Kirk M
KM
Vu
Hong A
HA
Sim
B Kim Lee
BK
Fogler
William E
WE
Fortier
Anne H
AH
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D043169:Endostatins / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000187:drug effects*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000627:therapeutic use
D043169:Endostatins; D011994:Recombinant Proteins; D004317:Doxorubicin