5.3.1 History. The imperfect neovascularization that develops in growing solid tumors results in limited and inefficient blood vessel networks and restricted and often chaotic blood flow (340).This generates chronic or diffusion hypoxia, where cells sufficiently distant from the nearest blood capillary are hypoxic for long periods, caused by the steep diffusion gradient of oxygen in tissue. The high and variable interstitial pressures caused by the growing tumor (341) can also result in transient or perfusion hypoxia, resulting from the temporary shut down of blood vessels placing sections of tissue under hypoxia for shorter periods (342). Because severe hypoxia is a common and unique property of cells in solid tumors, it is thus an important potential mechanism for the tumor-specific activation of prodrugs. This concept grew initially out of the development of radiosensitizers, drugs designed to take the place of oxygen in hypoxic tissue by oxidatively "fixing" the initial DNA radicals formed by ionizing radiation to gener
ate cytotoxic strand breaks (343). Such compounds tended to be easily reduced electron-deficient species such as misonidazole (81). In addition to their radiosensitizing properties as "oxygen-mimetics,"many of these compounds were also found to have modestly higher levels (ca. 10-fold) of cytotoxicity in hypoxic compare with oxygenated cells in culture (344). THe mechanism of such hypoxia-selective cytotoxicity is the ability of the prodrug to the metabolized by reductive enzymes such as cytochrome P450 reductase and xanthine oxidase (345) to a transient one-electron intermediate. In normal oxygenated tissue, this is efficiently back-oxidized by molecular oxygen to the parent compound, but in hypoxic cells, it is further metabolized or spontaneously breaks down to more cytotoxicspecies (346) (Fig. 2.9).
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