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• _2 value "Angiogenic output can differ from one tumor type to another or among tumors of the same type. For example, one study showed that 60% of breast cancers express only one pro-angiogenic protein, VEGF, while 4 or 5 additional pro-angiogenic proteins can be expressed by other breast cancers [23]. A human pancreatic cancer, ASPC-1, generated no detectable negative regulators of angiogenesis and grew twice as fast in SCID mice as another human pancreatic cancer BxPC3 which generated three angiogenesis inhibitors including high levels of angiostatin [24]. Tumor cells proliferated at the same rate in both tumors, 60% proliferating cell nuclear antigen (PCNA). While prolonged antiangiogenic therapy gradually decreases blood flow to tumors, an apparent paradoxical early effect is a temporary increase in blood flow. Teicher et al. demonstrated that antiangiogenic therapy in tumor-bearing animals increased tumor blood flow and oxygen delivery-- at least during the first weeks of therapy [25]. This may explain why some tumors increase their size slightly before decreasing it during uninterrupted antiangiogenic therapy. While these experiments were short-term, the presumed mechanism was that antiangiogenic agents reduced leakage of plasma proteins from tumor vessels, resulting in decreased intratumoral pressure [26]. Studies by Jain indicate that antiangiogenic therapy may normalize tumor vasculature to make it less leaky [27]. Soker working with my laboratory showed that when Evans blue dye was injected intravenously into mice, subcutaneous injection of VEGF or platelet activating factor (PAF) caused a large blue stain to appear at the injection site (Miles test), which was prevented by prior treatment with the angiogenesis inhibitors endostatin or TNP-470 (Shay Soker, unpublished data). Several clinical studies indicate that despite an initial increase in tumor blood flow during the early phase of antiangiogenic therapy, chronic antiangiogenic therapy causes total tumor blood flow to reach a steady state or to gradually decrease. When endostatin was continued for weeks or months in cancer patients, PET scans revealed a gradual, dose-dependent reduction in total tumor blood flow [28]. This could be caused by a dropout of individual microvessels, followed by apoptosis of the surrounding tumor cells. Other studies of tumor blood flow during antiangiogenic therapy have been reported by clinical investigators at the National Cancer Institute [29-31]. In addition, there are several ongoing trials currently utilizing non-invasive imaging to assess changes in tumor blood flow following treatment with angiogenesis inhibitors. These include two clinical trials at the National Cancer Institute evaluating anti-VEGF antibody, one in renal cancer and the other in breast cancer (Steven Libutti, personal communication). There are also clinical trials of \"anti-vascular\" therapy which shuts off tumor blood flow early after initiation of therapy, and which may be antiangiogenic later. An example would be combretastatin [32]. Despite an initial temporary increased blood flow by some angiogenesis inhibitors, the resulting decreased leakage of plasma proteins from microvessels in the tumor bed [27], may contribute to the initiation of tumor cell apoptosis, which would continue as capillary drop-out continued. This speculation however, remains to be demonstrated. Nevertheless, these findings suggest that at least one rational design of a clinical trial for an angiogenesis inhibitor may be to provide for long-term therapy with assessment of tumor blood flow at constant time intervals. If a patient's tumor progresses during therapy, a provision in the trial design to increase the dose of inhibitor may halt tumor progression or bring about the original stable state. Because antiangiogenic therapy does not inhibit DNA synthesis in tumor cells--at least at the beginning of therapy--these cells should remain suscept..." provenance.