Varied Response of Spontaneous Tumors to Antiangiogenic Agents

Abstract

Since conventional therapies are directly dependent on the supply of either drugs or oxygen, a key question is whether antiangiogenic agents produce detrimental effects on tumor vascular function, thus compromising combination therapies. A second question is whether experimental results based on fast-growing, transplanted tumors mimic those in slowly developing spontaneous tumors, which may be more representative of response in human primary tumors. To investigate changes in tumor pathophysiology, three antiangiogenic agents were compared: a) endostatin, b) anti-VEGFR-2 (DC101), and c) celecoxib. Total blood vessels were identified using anti-CD31, perfused vessels using DiOC7, and hypoxia by EF5 uptake. Although individual tumor growth rates varied substantially, DC101 produced the most striking inhibition. DC101 increased total and perfused vessel spacing as well as overall hypoxia, while endostatin increased total vessel spacing, and hypoxia and celecoxib had no marked effects. These results reinforce the idea that pathophysiological changes in spontaneous tumors are in general reflective of response in transplanted tumors. Furthermore, although DC101 inhibited growth in roughly half of the spontaneous tumors, the remaining tumors were unaffected. A key focus of future studies will be to investigate the underlying rationale for the widely varying antiangiogenic response among tumors that outwardly appear so similar.