Disparate effects of endostatin on tumor vascular perfusion and hypoxia in two murine mammary carcinomas.
OBJECTIVE
Recent results in the literature have demonstrated that the antiangiogenic agent endostatin can enhance antitumor effects when administered before or during radiotherapy. To better understand the underlying pathophysiologic basis for this radiosensitization, the current study investigated whether short-term endostatin administration is linked to alterations in tumor vascular perfusion and oxygen delivery.


METHODS
Three daily doses of recombinant endostatin (20 mg/kg) were administered to two murine mammary carcinomas, the highly vascularized MCa-35 and the less vascularized MCa-4. Image analysis techniques were used to quantify (1) total and perfused vascular spacing, and (2) changes in tumor hypoxia as a function of distance from the nearest blood vessel.


RESULTS
In MCa-35 tumors, endostatin had no effect on vessel spacing, tumor hypoxia, or tumor growth. In MCa-4 tumors, total and perfused vessel spacings were also unchanged, but tumor growth was inhibited, and tumor hypoxia significantly decreased. These tumors demonstrated an increased vascular functionality suggestive of an increase in the number of intermittently perfused vessels, without corresponding alterations in tumor oxygen consumption rate.


CONCLUSIONS
Poorly vascularized, hypoxic mammary carcinomas were much more responsive to short-term endostatin treatment than well-vascularized, more homogeneously oxygenated tumors. Oxygen levels in the responsive tumors were transiently improved after treatment, which could have substantial implications with respect to the therapeutic effectiveness of combining antiangiogenic agents with conventional therapies.
Fenton
Bruce M
BM
Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY 14642, USA. bruce.fenton@rochester.edu
Paoni
Scott F
SF
Grimwood
Brian G
BG
Ding
Ivan
I
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D002232:Carbocyanines; D002455:Cell Division; D015687:Cell Hypoxia / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D043169:Endostatins / Q000494:pharmacology*; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D009389:Neovascularization, Pathologic / Q000188:drug therapy*
D020533:Angiogenesis Inhibitors; D002232:Carbocyanines; D043169:Endostatins; C029652:3,3'-diheptyloxycarbocyanine