Cell, hypoxic

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). 

A few interesting organic molecules may possess the ability to release hydroxyl radical under physiological conditions. The most extensively studied of these is 3-amino-l,2,4-benzotriazine 1,4-dioxide (tirapazamine, 95, Scheme 8.32). Tirapazamine is a bioreductively activated DNA-damaging agent that selectively kills the oxygen-poor (hypoxic) cells found in solid tumors. The biological activity of... 

Fig. 7. Hypoxic cell imaging agents A) TcO (PnAO 1,2-nitroimidazole) B) Butyleneamineoxime...

Fig. 18. (a) Representation of the tumor hypoxic state (diagram adapted from Ref. (83a). Arrow direction indicates decrease in pC>2 (< 1 mmHg), achieved for tumor depths larger than 100 pm (b) proposed mechanism for redox-mediated retention of [Cu(ATSM)] in hypoxic cells (101-105). Note Contrary to common belief cell membrane crossing solely by direct diffusion is unlikely for compounds of this family is unlikely, as indicated by fluorescence imaging work on aromatic Zn(II) analogs (vide infra). Endocytosis is the more likely uptake mechanism (112-113). 

Misonidazole [27 l-methoxy-3-(2-nitroimidazol-l-yl)-2-propanol] and the model compound l-methyl-2-nitroimidazole have been used as radiosensitizers in the treatment of certain types of human tumors. One important property of these compounds is that they are more toxic to hypoxic cells than to aerobic cells, indicating that reductive metabolism of the drug is involved in the toxicity. Results of a number of studies suggest that intracellular thiols play a significant role in the hypoxic cell toxicity, and it was found that reduction products formed stable thio ethers with GSH (for literature see References 181-183). The reaction mechanism of thio ether formation has not been fully established. It has been suggested that the 4-electron reduction product was involved in thio ether formation181,184,185, and that the hydroxylamine rather than the nitroso derivative was the reactant. On the other hand, an intermediate nitroso derivative is expected to give a sulfenamide cation (see Scheme 1) which easily allows thio ether formation. 

Bush RS, Jenkin RD, Allt WE, Beale FA, Bean H, Dembo AJ, Pringle JF (1978) Definitive evidence for hypoxic cells influencing cure in cancer therapy. Br J Cancer 37 (Suppl III), 302-306... 

The evidence presented earlier, on the effects of combined modality therapy in carcinoma of the anal canal, may exploit to some extent the properties of mitomycin C as a hypoxic cell cytotoxin. This strategy remains valid, as many human tumors are less well oxygenated than the tissues from which they arose. The literature suggests that not only are these hypoxic tumors more difficult to control locally with therapy but that they may possess a more malignant phenotype with a higher propensity for distant spread. Tirapazamine is a drug developed and introduced into the clinic for its ability to target... 

In an excellent review of the literature on the interaction between radiation and the taxanes, especially looking at the effects of paclitaxel, Milas et al.(38) outline how they came to realize that reoxygenation played such a substantial role in the potentiation of tumor radioresponse. It has been well established for years that tumors contain areas of hypoxic cells that are normally 2.5 to 3 times less sensitive to radiation than normal cells (37). Both radiation and chemotherapies can cause reoxygenation through their preferential killing of those oxygenated cells that are located close to blood vessels. Milas et al. summarized observations that showed ... 

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. 

Metronidazole (135) is a y-radiation sensitizer of hypoxic cells in cancer radiotherapy. Irradiation with UV light in oxygen-free neutral aqueous solution results in quantitative rearrangement to the oxadiazole (136) (Scheme 60) <87HCA171,87JCS(P1)1817>. 

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. 

Hypoxic cells are present in the malignant tumors they result from the fast proliferation of the cancer cells. 

Hypoxic cells are three times more radio-resistant than well-oxygenated cells (OER = 3) for low-LET radiation. The presence of a small percentage of hypoxic cells (1% or even 0.1%) can thus make the tumor radio-resistant. 

However, the mathematics describes an idealized situation, and the real situation in vivo may not be so straightforward. For example, with carbon monoxide, as already indicated, the toxicity involves a reversible interaction with a receptor, the protein molecule hemoglobin (see chap. 7 for further details of this example). This interaction will certainly be proportional to the concentration of carbon monoxide in the red blood cell. However, in vivo about 50% occupancy or 50% carboxyhemoglobin may be sufficient for the final toxic effect, which is cellular hypoxia and lethality. Duration of exposure is also a factor here because hypoxic cell death is not an instantaneous response. This time-exposure index is also very important in considerations of chemical carcinogenesis. 

Kehrer JP, Jones DP, Lemasters JJ, et al. Mechanisms of hypoxic cell injury. Toxicol AppI Pharmacol 1990 106 165-178. 

The actual use of nitro compounds such as misonidazole in cancer treatment is largely based on their toxicity against hypoxic cells. Here, they act as biore-... 

Adams GE (1977) Hypoxic cell sensitizers for radiotherapy. In Becker FF (ed) Radiotherapy, surgery, and immunotherapy. Plenum Press, New York, pp 181-223... 

Adams GE, Asquith JC, Watts ME (1974) Electron-affinic sensitizers for hypoxic cells irradiated in vitro and in vivo Current status. In Advances in chemical radiosensitization. International Atomic Energy Agency, Vienna, pp 1-12... 

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