Hypoxic tumor cells

Phosphorothioates generally protect normal tissues more than tumors. Tumor protection reported in some animal studies can pardy be explained by physiological effects of the particular dmgs, which are specific to rodents (4). WR-2721 does not appear to protect human and most animal tumors, apparentiy because of the low availabiUty of the dmg to tumor cells (4). Many tumors appear to have a reduced capillary density (44), which may mean that these tumors have altered levels of alkaline phosphatase, the enzyme that converts WR-2721 to WR-1065. A reduced abiUty of thiols to protect the hypoxic cells characteristic of many tumors may also contribute to their selectivity for normal tissues. The observation that WR-1065 protects cultured normal human fibroblasts, but not fibrosarcoma tumor cells, suggests that additional factors may contribute to the selectivity of radioprotection by WR-2721 m vivo (18). 

In vitro clonal tumor cell studies have demonstrated the severe cytotoxicity of a-particles delivered by At single exponential cell survival-dose curves were obtained, with (37% survival) values of 29-48 cGy and 57-73 cGy for Chinese hamster V-79 (5J ) and HEp2 cells, respectively (55). In both studies the oxygen enhancement ratio (OER) was found to be slightly greater than unity, probably resulting from the low-LET components of At decay (see Fig. 5). In biological systems, such a-particle emissions enable comparable cytotoxicities to be effected in both hypoxic and euoxic tumor cell populations. 

Similarly, reaction of 2-nitroimidazole with l,2-epoxy-3-methoxypropane in the presence of potassium carbonate gives misonidazole (27).This agent also has the interesting and potentially useful additional property of sensitizing hypoxic tumor cells to ionizing radiation. 

Of course other methods of radiation enhancement may take place with reoxygenation of hypoxic tumor cells that may be increased with the use of chemotherapies like paclitaxel or gemcitabine (41,42), improved drug access to the tumor cells after radiotherapy, or a lowering of the threshold for radiation-induced apoptosis as has been described with the use of gemcitabine (43). 

These same authors also report a dose-dependent increase in the apoptotic rate after the administration of gemcitabine (33), which they believe correlates with the elimination of the more radioresistant S phase population of cells and redistribution of the remaining cells into more radiosensitive compartments of the cell cycle. They also report in another study that reoxygenation of the resistant hypoxic fraction of tumor cells is also a mechanism for the action of gemcitabine (34). Therefore, elimination of these S phase tumor cells may aid the radiation response by not only causing cell cycle synchronization but also by leading to reoxygenation of hypoxic cells. 

Preclinical models have established various methods to increase the cytotoxic activity of radiation therapy. This methodology includes promoting activity against cells in the most radiation-sensitive phase of the cell cycle, the G2/M phase, and eradicating hypoxic tumor cells to decrease radioresistance. The method of radiation therapy (con-... 

Novel mechanisms of interest include sensitizing hypoxic tumor cell lines to enhance radiotoxicity. Tirapazamine is a hypoxia-selective compound 1-2-fold greater in magnitude in comparison to mitomycin C or porfiromycin (84). Its mechanism of action results in a one-electron reduction inducing DNA double-strand breaks and cell death under hypoxic conditions. The free radical is oxidized back to the parent compound under aerobic conditions. When combined with the platinum compounds, the cytotoxic effects may be equivalent to that seen with five times the dose of cisplatin without the toxicities that would be encountered if actually administered (85). 

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). 

The resistance of many human cancers to immunotherapies has been attributed to the presence of immunosuppressive molecules located in tumor areas. Adenosine is present at elevated levels in hypoxic tissues due to an increased intracellular production and extracellular accumulation, as described above. This nucleoside activates cell surface receptors on T and NK cells that mediate cellular immune responses to tumor cells. It is well established that T cells recognize and destroy... 

Their best agent was the cobalt(lll) complex of 5,10-bis(4-methylpyridinium)-15,20-bis-(4-nitrophenyl)porphyrin, which had an SER of 1.22 at 50 pM towards CHO hypoxic cells. This complex was actually the most promising of over 50 studied. Using this CHO tumor cell line and identical XRT conditions (i.e. oxic and hypoxic lOOpM porphyrin concentration 16 Gy), O Hara et al. found that the cobalt(III) complexes, CoTPPS and COTMPyP, exhibited a weak sensitization effect (SER = 1.05-1.22, with or without serum-containing medium). These workers also concluded that the introduction of nitro and/or positively charged substituents on the porphyrin periphery serves to augment the net radiosensitization effect for these kinds of Co(lll) porphyrins [153,154]. Unfortunately, even when enhanced in this way, the net sensitization effect is small. 

Solid tumors, because of poor vascularization, generally contain hypoxic cancer cells that are resistant to treatment. PFC emulsions can deliver O2 deep into tumor regions that would otherwise be hypoxic, thereby improving the response of tumor cells to radio and chemotherapy without compromising the tolerance of normal tissues. 

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