Decreased tumor perfusion

Anti-tumor activity of bevacizumab has been reported in various preclinical animal models (primary and metastatic) with a broad array of tumor types [106, 107]. Clinical studies have further validated the focal role of VEGF in cancer. A single infusion of bevacizumab at 5 mg/kg in patients with primary and locally advanced adenocarcinoma of the rectum demonstrated direct and rapid antivascular effect in human tumors, with decreases in tumor perfusion, vascular volume, microvascular density, and interstitial pressure [108]. Clinical efficacy of bevacizumab in combination with 5-FU- and irinotecan-based regimens has been demonstrated in patients with metastatic colorectal cancer a significant improvement in overall survival time was observed compared with chemotherapy alone (20.3 versus 15.6 months for chemotherapy plus bevacizumab versus chemotherapy alone) [109]. 

Corticosteroids are used in clinical practice to relieve pressure symptoms caused by many tumor types, notably intracerebral tumors but also those causing airway or central venous obstruction. Their mode of action has been studied in animals (57) and humans (58), and is thought to involve first constriction of tumor vascular volume and then a reduction in water content. Reduced interstitial pressure should increase perfusion and extravascular diffusion rates, and high doses of steroids have been shown to increase blood flow in human colonic tumors transplanted into mice. Uptake of antibody into tumors has been assessed before and after administration of high-dose dexamethasone to decrease tumor interstitial pressure and thus increase antigen accessibility. Three patients with recurrent colorectal carcinoma had two antibody scans each, 72 h apart, and the injected dose was the same for all scans (20 mg). Dexamethasone was started 24 h before the second dose of antibody, with an initial iv dose of 10 mg followed by 4 mg four times daily orally for 48 h. 

To examine the pathophysiological impact of treatment with combretastatin A-4-phosphate on the regions of tumors that ultimately either necrose or survive treatment with this agent, proliferation, perfusion, and expression of vascular endothelial growth factor (VEGF) were analyzed in the KHT tumor model after treatment with GA-4-P [2]. Analyses were conducted on the whole tumor and the tumor periphery. It was shown that perfusion in the tumor periphery decreased 4 h after treatment but returned to baseline 20 h later. Whole-tumor perfusion also... 

Adenoma cells are arranged in cords and separated by sinusoids (Ishak 1994). The tumor lacks portal tracts or bile ducts, a key histological feature that helps distinguish hepatocellular adenoma from focal nodular hyperplasia (Boulahdour et al. 1993). Kupffer s cells are found in adenomas but probably they are often decreased in number or less functional than normal liver tissue, as reflected by absent or diminished uptake of technetium (Tc)-99m sulfur colloid (Fig. 10.1) (Rubin and Lichtenstein 1993). Because this neoplasm has no portal tracts, the tumor perfusion occurs solely by peripheral arterial feeders therefore the hypervascular nature of adenoma, related to sinusoids and feeding arteries, associated with poor connective tissue support, can lead frequently to hemorrhage. Because a tumor capsule is usually absent or incomplete, hemorrhage may spread into the liver or abdominal cavity (Molina and ScHiFF 1999). 

Stubbs M (1998) Tumour pH. In Molls M, Vaupel P (eds) Blood perfusion and microenvironment of human tumors. Implications for clinical radiooncology. Springer, Berlin Heidelberg, New York, pp 113-120 Stubbs M, McSheehy PMJ, Griffiths JR, Bashford CL (2000) Causes and consequences of tumour acidity and implications for treatment. Mol Med Today 6 15-19 Sullivan R. Pare GC, Frederiksen LJ, SemenzaGL, Graham CH (2008) Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity. Mol Cancer Ther 7 1961-1973... 

In 1958, Creech et al. used extracorporeal circulation to perfuse anticancer drugs locally in organs which could be separated from the systemic circulation. They attempted active intervention to eradicate all tumor cells and to decrease systemic adverse reactions more completely than can be achieved by arterial infusion therapy. This technique has been established primarily for primary or recurrent tumors located in the pelvic area. Up to now the technique of isolated perfusion has been established for different areas of the body such as the limbs, the liver, the thoracic region, the abdomen or the pelvis. 

Sometimes, hyperbilirubinemia without mechanical obstruction of the biliary tree is encoimtered postoperatively patients with this complication often suffer from bacterial infections and endotoxemia, which results in stimulation of Kupffer cells to secrete tumor necrosis factor-a (TNF-a) and interleukin (IL)-6. In a study by Ikeda and coworkers (Ikeda, Mitaka et al. 2003), bile was collected from rats treated with or without these cytokines. The livers, perfused with lanthanum after the injection of the cytokines, were examined ultrastructurally. In rats treated with cytokines, the total serum bile acid concentration increased and lanthanum temporarily accumulated in the bile canaliculi, which suggests that the cytokines may reduce bile canaliculi contractions and thereby decrease bile flow. 

Inner tumor areas are not only hypoxic due to an undersupply by blood vessels. Neo-angiogenesis in tumors frequently is also associated with malformed, tortuous, and leaky vessel formation (Harris 2002 Jain 2005). Malfunctioning blood flow affects the success of chemotherapy, as sufficient drug concentrations cannot reach the tumor tissue (Minchinton and Tannock 2006). Low oxygenation in tumors is accompanied by decreased NO production (Fukumura and Jain 1998). Indeed, administration of No-mimeticsubstances such as spermine NO (SNO), ISDN, GTN, or SNP dilates blood vessels and increases perfusion and oxygenation (Fukumura... 

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