Establishment of a quantitative mouse dorsal air sac model and its application to evaluate a new angiogenesis inhibitor

We have developed an improved mouse dorsal air jar model for quantifying in vivo tumor-induced angiogenesis. In our improved model, tumor angiogenesis is determined by measuring the blood volume in an area of skin held in con tact with a tumor cell-containing chamber, using Cr-51-labeled red blood ce ll, (RBC). The blood volume induced by murine B16-BL6 melanoma cells increa sed linearly with the cell number in the range from 2 x 10(5) to 5 x 10(6). Ten of 11 human tumor cell lines examined induced a significant increment in blood volume. For three representative human tumor cell lines (A549, WiD r, and HT1080 cells) that showed different angiogenic potencies, the levels of vascular endothelial growth factor (VEGF) produced by the tumor cells c ultured under conditions of hypoxia and high cell density were correlated w ith the degree of in vivo angiogenesis. Using the improved model. it was co nfirmed that TNP-470, a well-known inhibitor, and borrelidin, an antibiotic from Streptomyces rochei, significantly inhibited the WiDr cell-induced an giogenesis. Borrelidin also inhibited spontaneous lung metastasis of B16-BL 6 melanoma at the same dose that inhibited angiogenesis. Our results sugges t that the improved mouse dorsal air sac model can be used for simple and q uantitative measurement of tumor-induced angiogenesis and its inhibition.