Hypoxia, solid tumors

Rockwell S. Use of hypoxia-directed drugs in the therapy of solid tumors. Semin Oncol 1992 19 29 -0. 

D. Procissi, F. Claus, J. Koziorowski, P. Burgman, C. Mate , S. Thakur, C. Ling, J.A. Koutcher, In vivo F MRS and F 2D-CSI investigation of a fluorine labeled 2-Nitroimidazole (TF-MISO). A potential functional reporter of hypoxia in solid tumors. Proc. Inti. Soc. Mag. Reson. Med. 2006, p. 1260. 

FI.W. Salmon, D.W. Siemann, Utility of F MRS detection of the hypoxic cell marker EF5 to assess cellular hypoxia in solid tumors, Radiother. Oncol. 73 (2004) 359-366. 

Most solid tumors develop regions of low oxygen tension because of an imbalance in oxygen supply and consumption. Clinical and experimental evidence suggests that tumor hypoxia is associated with a more aggressive phenotype (Hockel and Vaupel 2001 Vaupel 2008). Hypoxic tumor cells are resistant to conventional chemotherapy and radiotherapy. It is therefore rational to target the hypoxic regions of tumors or disrupt events initiated by hypoxia (Melillo 2004). 

One of the major features of solid tumors and even small deposits of tumor tissue is deficiency in the level of oxygen, because of an inadequate vascular supply. The adenosine elevation in response to hypoxia is not exclusive to tumor tissues, but, in this context, the adenosine elevation is localized to the tumor microenvironment, since the surrounding tissue is normally oxygenated. Adenosine is generated mainly by two enzymatic systems intra- or extracellularly localized 5 -nucleoti-dases and cytoplasmic S-adenosylhomocysteine hydrolase. The processes of adenosine elimination in the cell involve reactions catalyzed by adenosine deaminase and adenosine kinase (Shryock and Belardinelli 1997) yielding inosine or 5 -AMP,... 

Maxwell PH, Dachs GU, Gleadle JM, Nicholls LG, Harris AL, Stratford IJ, Hankinson O, Pugh CW, Ratcliffe PJ (1997) Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci USA 94(15) 8104—8109... 

Ryan HE, Lo J, Johnson RS (1998) HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J 17(11) 3005-3015 Semenza GL (1999) Perspectives on oxygen sensing. Cell 98(3) 281-284 Semenza GL (2000) HIF-1 mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 88(4) 1474-1480... 

Brown JM (1993) SR 4233 (Tirapazamin) a new anticancer drug exploiting hypoxia in solid tumors. BrJ Cancer 67 1163-1170... 

Along with these genetic features, a low growth rate and a low blood supply (conditions often present in solid tumors) can affect sensitivity to ionizing radiation with the following mechanisms (Brown, 1999) reduction of the rate of cells in the most sensitive phases of the cell cycle low efficiency of ROS formation within the irradiated tumor due to hypoxia clonal selection of cancer cells highly resistant to oxidative stress/apoptosis and with efficient anaerobic metabolism. 

Hypoxia appears to be a common and unique property of cells in solid tumors and is a target for tumor-specific activation of anticancer prodrugs.4 It is now well known that solid tumors often contain an inefficient microvascular system, and part of solid tumors exists under a hypoxic condition.12 Hypoxia can be classified into two broad types chronic and acute. Chronic hypoxia occurs in cells that are distant from their blood supply and suffer low oxygen tension permanently. Acute hypoxia results in cells experiencing temporary cessation of blood flow. 

Hypoxia of solid tumors has been exploited in designing hypoxia-selective anticancer dmgs or prodrugs. In particular, the elevated activities of various reductive enzymes under a hypoxic condition have been extensively targeted for tumor-selective prodrugs. Another feature associated with hypoxia is low extracellular pH.15 This is likely to be a result of an insufficient blood supply that leads to the accumulation of acidic metabolites. Anticancer prodrugs activated in a low-pH environment have also been reported.16... 

However, in solid tumors there are a few unique and important microenvironmental properties such as localized hypoxia, nutrient deprivation and low On the other hand, as... 

Solid tumors display a reductive environment because of hypoxia and the overproduction of bioreductive enzymes. To take advantage of the characteristics of the environment provided by the solid tumor, a bioreductive, tumor-targeted drug delivery system was designed. The system would undergo... 

Cancer cells grow more rapidly than the blood vessels to nourish them thus, as solid tumors grow, they are unable to obtain oxygen efficiently. In other words, they begin to experience hypoxia, a deficiency of oxygen. Under this condition, glycolysis leading to lactic acid fermentation becomes... 

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