Hypoxic tumors

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. 

Lin Q, Yun Z (2010) Impact of the hypoxic tumor microenvironment on the regulation of cancer stem ceU characteristics. Cancer Biol Ther 9 949-956... 

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). 

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... 

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). 

For its spectrum of activity against Gram-positive and Gram-negative bacteria, protozoa, the occasional helminth, and even hypoxic tumors. 

Considering the reductive condition in the anaerobic environment in the center of tumor tissue, Damen et al. designed and prepared 2 -carbonate and 3 -A -carbamate prodrugs of paclitaxel that release the parental drug targeting hypoxic tumor tissue. Two of 11 prodrugs are selected for additional investigation. " ... 

Nevertheless, even if the main therapeutic gain is brought by the precise localization of the energy deposition, the generation of molecular oxygen in hypoxic tumors is known to enhance the sensitization of the cells. But the production of molecular oxygen in the track is still questionable. Some studies have showed the possible direct detection by the pulse radiolysis method and have tried to explain how superoxide radical is formed in the tracks of heavy ions and many mechanisms have been suggested in the past. ... 

Mitomycin C (1, Scheme 2) is an anticancer agent that has been shown to be more cytotoxic to hypoxic tumor cells than to their aerobic counterparts. 

Kennedy, K. A., Teicher, B. A., Rockwell, S., Sartorelli, A. C. The hypoxic tumor cell a target for selective cancer chemotherapy. Biochem. Pharmacol. 1980, 29, 1-8. 

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