The transformation from normal to a malignant phenotype results from a number of genetic changes. Subsequent progression and manifestation of the disease will depend on several factors including the cell type transformed and its location within the body. In over 90% of all cancers, progression is characterized by formation of a solid tumor mass. This cell mass can grow to a volume of 1 mm3; however, at this size, further growth is controlled by nutrient suppply via initiation of a blood vessel network. Induction of an angiogenic stimulus to facilitate the formation of tumor blood vessels is critical to tumor progression. The strong and continuous angiogenic stimulus evoked by tumor cells results in blood vessels that differ in many respects from their normal tissue counterparts. These differences include a lack of smooth muscle around many vessels, tortuosity, lack of collateral supply, arteriovenous anastomoses, abnormal vessel branching patterns, lack of nervous innervation, and vessels with no endothelial lining. In addition to structural abnormalities, the apparent absence in many solid tumors of a lymphatic system to assist intestitial fluid drainage results in abnormally high interstitial fluid pressures within solid tumor masses. Since such pressures exceed intravascular pressures, blood vessel patency can be compromised. All of these factors, both structural and physiological, contribute to making tumor blood flow more chaotic, heterogenous (both temporally and spatially), inadequate and, in addition, under less feedback control than that in normal tissues. The inadequacies of the tumour blood vessel network and the resulting sub-optimal distribution of blood flow to the tumor mass have been considered for many years to be a major contributing factor to the poor results obtained with many radiation and chemotherapy regimens. Indeed, areas of low oxygen tension, a sign of inadequate tissue perfusion, have been observed in many experimental and human solid tumors. Hypoxic cells are known to be three times more resistant to radiation than oxic cells. The reasons for the refractory response of hypoxic tumor cells to conventional chemotherapy agents include the slow proliferation rate (as a result of oxygen and nutrient deprivation) of such cells and the distance they are situated away from a functional blood and thus drug supply. Several approaches are available for reducing the detrimental consequences that hypoxic cells can have on conventional therapy. These include improving tumor oxygenation status, which is covered in a preceding session, and the use of bioreductive drugs, which can selectively destroy pockets of cells which exist in regions of reduced oxygenation. Many agents are known which can be metabolically reduced by reductase enzymes to yield chemical species that are toxic to mammalian cells. These include nitroheterocycles such as nitroimidazoles and nitrofurans, mitomycin and benzoquinone derivatives, and benzotriazines. Such agents show increased toxicity under anaerobic conditions in vitro. One of the first observations that such agents could kill hypoxic non-cycling cells situated at a distance from the nutrient and oxygen supply was that by Sutherland, who demonstrated that treatment of spheroids with the nitroimidazole metronidazole increased the amount of central necrosis. There have subsequently been many studies showing the differential toxicity of bioreductive drugs for hypoxic cells in vitro. There was also early indirect evidence that some agents could selectively kill hypoxic cells in vivo because of the ability to enhance radiation response when administered post-irradiation. The findings in the 1970’s led to increased efforts to design or elucidate agents with both more potency and more selectively against hypoxic mammalian cells. One of the agents discovered in the early 1980’s by synthesis of several derivatives of lsubstituted 2-nitroimidazoles was RSU1069. This agent incorporated an aziridine moiety at the terminal end of the alkyl side-chain facilitating formation of a monofunctional adduct to DNA. Subsequent reduction of the nitro moiety forms a more cytotoxic bifunctional adduct. This agent was shown to be a potent hypoxic cell cytotoxin both in vitro and in vivo. Cytotoxicity against hypoxic cells in vivo is identified by its ability to potentiate the
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Jun 1, 1996
J Rak + 1
